Introduction
Obstructive sleep apnea (OSA) is characterized by repetitive complete or partial collapse of the upper airways that causes hypoxia, hypercapnia, autonomic nervous system activity, and intrathoracic pressure swings. A 2019 literature-based estimation of the global prevalence of OSA suggested that there are around 1,37 billion people with OSA [1]. Numerous articles have suggested that OSA is associated with increased markers of oxidative stress and inflammation [2–4]. Unlike prolonged sustained hypoxemia, the cycles of hypoxia and reoxygenation that occur due to apneic and hypopneic episodes are similar to ischemia-reperfusion injury and contribute to an increase in the production of reactive oxygen species (ROS) [5]. Studies also confirm that OSA contributes to a persistent, low-intensity inflammatory state, resulting in end-organ morbidity [6]. Obstructive sleep apnea is generally associated with cardiovascular, metabolic, and neurodegenerative diseases, but has recently also been linked to the incidence and outcomes of cancer. Both pathophysiological sequelae of OSA, namely episodes of intermittent hypoxia (IH) and chronic inflammation, are known causes of carcinogenesis both in human and animal studies [7–12].
Numerous papers show a crucial role of IH in the pathogenesis of OSA comorbidity. Intermittent hypoxia is associated with increased levels of oxidative stress or antioxidant deficiencies. Oxidative stress is involved in the activation of redox-sensitive transcription factors which regulate downstream products such as inflammatory proteins, interleukins, chemokines, and adhesion molecules [3, 5, 13].
The association between OSA and human cancer was first described by Nieto et al., who detected higher cancer mortality in a 22-year follow-up of data from the Wisconsin sleep cohort [14]. A year later, Campos-Rodriguez et al. were the first to report the increased incidence of cancer in patients with OSA in a multicenter cohort of nearly 5,000 patients [15].
Among other tumors, renal cell carcinoma (RCC) has been associated with the patient’s severity of OSA. The pathogenesis of RCC is linked to various genetic and immune-related mechanisms. Interleukins seem to play a crucial role in the development of RCC.
Interleukins (ILs) are cytokines historically thought to be secreted only by leukocytes, but later found to be produced by multiple other cells. The first IL was discovered in 1977 [16] . In 1979, during the Second International Lymphokine Workshop, the name “interleukin” was chosen to replace the various names of proteins acting on immune cells [17]. Interleukins play a role in immune cell activation, modulation, and differentiation. Cytokines bind to high-affinity receptors on the cell membrane, exerting pro- or anti-inflammatory actions [18].
This study aimed to review the current literature on interleukins in patients with OSA and RCC compared to controls. The key question was whether there might be a similar cytokine profile in both groups (OSA and RCC patients), suggesting a possible role for OSA in RCC tumorigenesis. Also, a potential role of continuous positive airway pressure (CPAP) treatment in OSA-positive patients with RCC is discussed. This analysis of IL data may enable a better understanding of the role of sleep apnea in RCC pathology and indicate areas for developing RCC therapeutic strategies in the future [19, 20].
Material and methods
This review aimed to examine interleukin profiles as the potential link between OSA and RCC carcinogenesis. The primary research question was: Which interleukins were studied among OSA and RCC patients? The second question was: What was the level of each interleukin in OSA and RCC patients and what was its role in RCC carcinogenesis? We have reviewed the literature from the PubMed database pulled from the year 1985 up to 2022. Search terms included ‘OSA and RCC’, ‘OSA and cancer’, ‘interleukins and RCC’, ‘interleukins and cancer’, ‘OSA or sleep apnea and IL-1 or IL-2 or IL-3 or IL-4... IL-37’. This analysis was conducted following PRISMA guidelines [21]. Our initial search identified 901 articles from the PubMed database. After duplicate records were removed, excluded, or not retrieved, 531 articles were retained. After further analysis, including reports sought for retrieval and assessed for eligibility, 444 articles were selected for full-text screening. During the review, publications meeting the eligibility criteria were analyzed: quantitative, peer-reviewed, English-language, scientific journal articles, papers presenting the levels of interleukins in OSA patients and controls, children, adults, and adolescents, interpretability and comparability of study. After analysis of all the articles, papers without control groups for OSA, without OSA diagnostics or not related to IL levels were excluded, and 66 articles remained.
The role of interleukins in obstructive sleep apnea and renal cell carcinoma
IL-1
Interleukin-1 (IL-1) is known as an ‘alarm’ cytokine, a pro-inflammatory interleukin produced by monocytes, macrophages, lymphocytes, neutrophils, keratinocytes, microglia, megakaryocytes, fibroblasts, and synovial lining cells [22]. The two main IL-1 subforms are IL-1α, present under homeostatic conditions in many cells, and IL-1β, not present under homeostatic conditions. IL-1 molecules (particularly IL-1β) are important in modifying the tumor microenvironment. These cytokines affect endothelial cells, T-cells, fibroblasts, and epithelial cells. IL-1 induces the expression of numerous metastatic mediators, such as matrix metalloproteinases (MMP), interleukins (IL-6, IL-8), TNF-α, transforming growth factor β (TGFβ), and vascular endothelial growth factor (VEGF) [23].
Obstructive sleep apnea
The level of IL-1β has been analyzed in OSA patients in some studies. Cizza et al. [24] analyzed IL-1β serum levels of IL-1β in obese adults with OSA. IL-1β concentration was higher in OSA-positive patients with a mean level of 32.4 pg/ml compared to 30.1 pg/ml in the OSA-negative group (p = 0.418). Tam et al. [25] presented results showing a non- significant elevation in plasma level of IL-1β (1.4–9 µg/l; mean 5.3) in the OSA group, compared to a normal control (1.1–8.7 µg/l mean 5.1) (p = 0.432). The same relation was observed by Kong et al. [26]. In their study, the serum level of IL-1β was elevated in the OSA group (27.15) compared to the control group (21.17) (p = 0.000). In another study, Tomiyama et al. [27] analyzed the plasma level of inflammatory cytokines. Patients with OSA had a higher le-vel of IL-1β (0.43 ±0.33 pg/ml) compared to controls (0.33 ±0.16 pg/ml). They also found a decreased level of IL-1β after CPAP therapy in comparison to results before treatment. Similarly, in the study by Celikhisar et al., the serum level of IL-1β was significantly higher in the OSA group compared to controls (23.74 vs. 1.7; p < 0.001) [28]. Chen et al. described increased IL-1β in the OSA group (10.53 ±4.92 pg/ml) in comparison to the control group (2.67 ±0.35 pg/ml) (p < 0.001) [29]. The serum level of IL-1β was also analyzed by Hirsch et al. in the pediatric population. The OSA group had non-significantly higher IL-1β (0.23–0.63 pg/ml; mean 0.34) compared to the children without OSA (0.14– 0.46 pg/ml; mean 0.33) [30]. Furthermore, Huang et al. investigated plasma levels of inflammatory markers in a group of children with OSA before and after adenotonsillectomy compared to healthy controls. The IL-1β serum level was higher in the OSA group (1.51 ±2.25 pg/ml) than in the control group (0.42 ±1.38 pg/ml). Surgical intervention decreased the IL-1β serum level (1.51 ±2.25 pg/ml before surgery vs. 0.43 ±0.34 pg/ml post-operatively) in a group with apnea hypopnea index (AHI) > 1 after surgery and (1.51 ±2.25 pg/ml before surgery vs. 0.22 ±0.12 pg/ml post-operatively) in a group with AHI < 1 after surgery (p = 0.022). They observed no significant differences between controls and the post-operative results of the IL-1β serum level [31]. Several studies present conflicting data. Huang et al. measured pro-inflammatory cytokines in children with OSA. They found that levels of IL-1β were 0.36 ±0.16 pg/ml and 0.42 ±0.27 pg/ml in OSA-positive and OSA-negative groups, respectively (p = 0.857) [32]. A lower IL-1β level was also observed by Sahlman et al. [33]. They measured cytokine profiles in obese and overweight patients with OSA patients (body mass index – BMI > 26 kg/m2). The serum level of IL-1β was significantly lower (p = 0.002) in patients with OSA (0.19 pg/ml) in comparison to control patients (0.23 pg/ml). On the other hand, the IL-1 receptor antagonist (IL-1RA), with anti-inflammatory potential, was significantly higher in patients with OSA than in the control group (478 pg/ml vs. 330 pg/ml; p = 0.002). Salhman et al. investigated a reduction in IL-1RA in OSA patients after weight loss in another study. Serum IL-RA level was associated with insulin metabolism [33].
Renal cell carcinoma
IL-1β is considered a prometastatic cytokine in RCC. It stimulates MCP-1, substantial production of monocyte chemoattractant proteins in RCC cells (786-O) by activating the nuclear transcription factor kappa B (NF-kB) and the activator protein 1 (AP-1) [34]. An intratumoral injection of MCP-1 into an RCC xenograft negatively regulated Ki-67 expression and reduced tumor size [34]. The knockdown of NF-kB1 inhibited IL-1β mRNA expression and protein production by Renca cells (the RCC cell line) [23].
Tumor-associated macrophages (TAMs) secrete IL-1β, modifying the tumor microenvironment and promoting tumor growth and metastasis [35, 36]. This effect of IL-1β was confirmed in vitro. IL-1β was shown to mediate RCC cell invasion (786-O cells) by activating the CCAAT enhancer binding protein β and acting through the activation of MMP-dependent pathways, namely MMP-1, MMP-3, MMP-10, and MT1-MMP [37].
IL-2
Interleukin-2 (IL-2) is a pro-inflammatory cytokine, a member of the type I cytokine family and part of the common k chain cytokine family. It is produced mainly by CD4+ and CD8+ T-lymphocytes and acts as a growth factor for these cells. However, it also affects other types of cells in the immune system, for example B-cells and NK-cells [38, 39]. For this reason, IL-2 is an essential therapeutic target in NK-cell-based immunotherapy in RCC [40]. The Food and Drug Administration approved high-dose IL-2 treatment in metastatic RCC in 1992 [41].
Obstructive sleep apnea
In all the studies analyzed, the serum level of IL-2 was higher in the OSA group than in non-OSA patients. The results of Tam et al. [25], Cizza et al. [24] and Hirsch et al. [30] are presented in Table 1. Galati et al. measured IL-2 in the serum of OSA patients. They observed a higher serum level of IL-2 in the OSA group (2.79 (0.00– 4.52 pg/ml) in comparison to the healthy group (1.64 (0.6–2.3) pg/ml) (p = 0.173) [42]. Furthermore, IL-2 was analyzed in lymphocytes. Dyugovskaya et al. analyzed the expression of IL-2 in CD4+ and CD8+ lymphocytes. In both types of cells, the expression of IL-2 was not significantly higher in the OSA group than in the controls [43]. Obstructive sleep apnea treatment was also examined in terms of IL-2 outcomes. Perrini et al. investigated the impact of CPAP combined with a weight loss intervention on the systemic inflammation of OSA subjects. They evaluated the serum level of IL-2 and found that it was significantly reduced in the CPAP group, compared to baseline (p < 0.05) [44]. Mahboub et al. analyzed CPAP therapy in the OSA and asthma patient group. They noted that the serum level of IL-2 was higher after CPAP therapy (pre-CPAP 0.006 ng/ml vs. post-CPAP 0.011 ng/ml; p = 0.002) [45].
Table 1
Nasal lavage fluid
| Marker | Marker increase in RCC patients correlates with | OSA | OSA | Controls |
|---|---|---|---|---|
| IL-1β | • Induces expression of numerous metastatic mediators, such as MMPs, interleukins (IL-6, IL-8), TNF-α, TGFβ, and VEGF [23] • High levels correlate with the advanced stage of RCC [37] • Pro-metastatic cytokine [34] | ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↓ ↓ | 32.4 pg/ml [24] 5.3 (1.4–9) µg/l [25] 23.74 [28] 10.53 ±4.92 pg/ml [29] 27.15 [26] 0.43 ±0.33 pg/ml [27] 0.34 (0.23–0.63) pg/ml [30] 1.55 ±2.25 pg/ml [31] 0.36 ±0.16 pg/ml [32] 0.19 pg/ml [33] | 30.1 pg/ml [24] 5.1 (1.1–8.7) µg/l [25] 1.7 [28] 2.67 ±0.35 pg/ml [29] 21.17 [26] 0.33 ±0.16 pg/ml [27] 0.33 (0.14–0.46) pg/ml [30] 0.45 ±1.38 pg/ml [31] 0.42 ±0.27 pg/ml [32] 0.23 pg/ml [33] |
| IL-2 | • High level of IL-2 receptor is related to poorer response to interferon-α and sequential VEGF-targeting therapy [49] | ↑ ↑ ↑ ↑ ↑ ↓ | 4.7 (2.4–6.6) µg/l [25] 10.1 (7.5–15.7) pg/ml [24] 2.79 (0.00–4.52) pg/ml [42] IL-2 expression in CD4+ [43] 2.13 (1.46–4.84) pg/ml [30] 0.006 ng/ml [45] | 3.9 (1.5–6.2) µg/l [25] 7.4 (4.5–12.3) pg/ml [24] 1.64 (0.6–2.3) pg/ml [42] IL-2 expression in CD4+ [43] 1.43 (1.15–2.42) pg/ml [30] 0.011 ng/ml [45] |
| IL-3 | • IL-3 targeting impairs tumor vessel formation and tumor growth [153] | No data | No data | |
| IL-4 | • IL-4 contributes to the higher risk of renal cell carcinoma [55] | ↑ ↑ ↑ ↑ ↑ ↓ ↑ | 4.1 (3.1–6.4) pg/ml [24] 1.91 (0.45–3.29) pg/ml [42] 2.7 pg/ml [44] 4.5 (2–7.5) µg/l [25] 234.24 ±12.16 pg/ml [53] 4.87 (2.46–8.14) pg/ml [30] 0.13 ng/ml [45] | 3.2 (2.3–4.6) pg/ml [24] 1.50 (0.27–2.11) pg/ml [42] 2.3 pg/ml [44] 3.7 (1.5–6.9) µg/l [25] 186.42 ±11.43 pg/ml [53] 5.48 (2.79–8.39) pg/ml [30] 0.01 ng/ml [45] |
| IL-5 | • Not detected in any RCC cell line [62] | ↑ ↑ | 8.2 (5.3–10.7) pg/ml [24] 0.63 (0.44–1.08) pg/ml [30] | 6.9 (4.2–9.0) pg/ml [24] 0.45 (0.37–0.82) pg/ml [30] |
| IL-6 | • Tumor progression and metastasis [87] • Higher levels were associated with poor survival rates [88] • IL-6 induces drug resistance in RCC [90] | ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ | 3.33 ±1.35 pg/ml [65] 3.4 ±1.0 pg/ml [66] 3.6 (1.9–6.7) pg/ml 67] 4.2 ±3.4 pg/ml [68] 5.3 (3.9–7.1) µg/l [25] 3.22 (2.25–4.21) pg/ml [30] 5.8 (4.4–9.3) pg/ml [24] 4.56 ±2.92 pg/ml [75] 20.1 ±5.6 pg/ml [82] 5.12 ±0.15 pg/ml [71] 2.93 ±1.74 pg/ml [69] 20.1 ±5.6 pg/ml [77] 58.49 ±8.03 [84] 42.67 ±4.11 [84] (BAL) 61.59 ±9.76 [26] 1.66 ±0.23 pg/ml [32] 2.4 ±1.6 pg/ml [27] 0.062 ±0.077 pg/ml [78] 0.36 ±1.13 pg/ml [85] NLF pre-op tonsillectomy: 10.2 ±11.3 pg/ml [76] Pre-op tonsillectomy: 2.98 ±0.27 pg/ml [63] 2.25 ±0.28 pg/ml [72] 129.41 ±36.56 ng/ml [73] 6.96 (4.35–16.03 pg/ml [42] 1.59 ±1.58 pg/ml [31] Mild OSA 44.46 pg/ml [80] Moderate OSA 42.74 pg/ml [80] Severe OSA 57.98 pg/ml [80] | 1.5 ±0.67 pg/ml [65] 2.3 0.3 pg/ml [66] 2.5 (0.9–4.6) pg/ml [67] 2.7 ±2.9 pg/ml [68] 4.8 (3.6–7) µg/l [25] 2.31 (0.97–2.95) pg/ml [30] 4.5 (2.6–9.0) pg/ml [24] 2.83 ±1.54 pg/ml [75] 16.5 ±4.6 pg/ml [82] 3.08 ±0.13 pg/ml [71] 1.72 ±1.21 p g/ml [69] 15.4 ±3.5 pg/ml [77] 9.11 ±10.13 [84] 10.41 ±5.18 [84] (BAL) 54.46 ±9.43 [26] 1.1 ±0.18 pg/ml [32] 1.5 ±0.6 pg/ml [27] 0.06 ±0.013 pg/ml (after CPAP) [78] –0.14 ±0.97 pg/ml [85] NLF post-op tonsillectomy: 6.2 ±3.1 pg/ml [76] Post-op tonsillectomy: 1.96 ±0.07 pg/ml [63] 0.91 ±0.15 pg/ml [72] 88.85 ±41.48 ng/ml [73] 1.9 (1.14–2.40) pg/ml [42] 1.1 ±0.92 pg/ml [31] 40.57 pg/ml [80] 40.57 pg/ml [80] 40.57 pg/ml [80] |
| IL-7 | • Allogeneic tumor cell vaccine for RCC patients [94] | No data | No data | |
| IL-8 | • Promote the EMT of an RCC cell line [102] • Critical molecular targets for RCC [103] | ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ | 5 (3.27.2) µg/l [25] 4.07 (3.48–6.41) pg/ml [30] 8.29 ±5.2 pg/ml [77] Mild OSA 106.83 pg/ml [80] Moderate OSA 105.66 pg/ml [80] Severe OSA 126.31 pg/ml [80] 12.2 (7.7–21.8) pg/ml [24] 1.3 (0.8–2.0) pg/ml [67] 43.50 ±7.22 pg/ml [98] 88.1 ±30.1 pg/ml [99] (BAL) 19.7 (15.8–23.5) pg/ml) [97] 0.40 ±0.87 pg/ml [85] NLF IL-8 expression in human coronary artery endothelial cells [96] IL-8 plasma level [79] Before CPAP: 25.3–30.1 pg/ml [100] | 4.1 (1.6–5.5) µg/l [25] 3.46 (2.63–5.71) pg/ml [30] 4.98 ±3.67 pg/ml [77] 100.12 pg/ml [80] 100.12 pg/ml [80] 100.12 pg/ml [80] 10.8 (4.7–15.4) pg/ml [24] 1.1 (0.8–1.8) pg/ml [67] 24.63 ±3.66 [98] 57.9 ±22.8 pg/ml [99] (BAL) 17 (13.95–20.1) pg/ml [97] –0.34 ±0.89 pg/ml [85] NLF IL-8 expression in human coronary artery endothelial cells [96] IL-8 plasma level [79] After CPAP: 10.1–14.8 pg/ml [100] |
| IL-9 | No data | No data | ||
| IL-10 | • Higher serum level in RCC patients with unfavorable outcome [112] | ↑ ↑ ↑ ↓ ↑ ↓ ↑ ↓ ↑ ↑ ↓ | 3.3 (1.5–4.9) µg/l [25] 2.09 (1.26–2.91) pg/ml [30] 8.0 (5.8–11.3) pg/ml [24] 261.71±18.55 pg/ml[53] 2.62 ±0.39 pg/ml [32] 195.2 ±33.6 pg/ml [63] 2.48 (1.83–3.02) pg/ml [42] 26.11 ±20.98 ng/ml [73] IL-10 expression [43] 2.74 ±2.94 [31] 74.4 ±17.0 pg/ml [109] | 2.8 (0.7–4.4) µg/l [25] 1.71 (1.13–2.08) pg/ml [30] 7.8 (4.6–12.0) pg/ml [24] 338.24 ±25.20 pg/ml [53] 2.1 ±0.28 pg/ml [32] 458.5 ±10 pg/ml [63] 0.96 (0.72–1.60) pg/ml [42] 38.6 ±10.6 ng/ml [73] IL-10 expression [43] 2.1 ±1.41 [31] 113.2 ±12.1 pg/ml [109] |
| IL-11 | No data | No data | ||
| IL-12 | • Systemic administration of IL-12 reduced growth of 786-0 RCC and significantly prolonged mouse survival [118] | ↑ ↑ ↑ ↑ | 6.7 (1.2–22) µg/l [25] 11.5 (7.8–14.1) pg/ml [24] 1.77 ±1.15 pg/ml [31] 405.3 ±57.4 pg/ml [109] | 4.6 (0.9–15.8) µg/l [25] 10.6 (5.0–12.8) pg/ml [24] 0.97 ±0.75 pg/ml [31] 217.4 ±43 pg/ml [109] |
| IL-13 | • Sceptibility to renal cell cancer [166] • Sunitinib resistance in clear cell renal cell carcinoma [167] | ↑ | 14.3 (11.8–17.5) pg/ml [24] | 13.2 (10.2–15.0) pg/ml [24] |
| IL-14 | No data | No data | ||
| IL-15 | • Candidate for RCC therapy, major regulator of human kidney physiology and cancer [168] • Involved in cell-microenvironment interactions in RCC [169] | ↑ | 13.3 (11.3–15.5) pg/ml [24] | 12.4 (9.9–14.7) pg/ml [24] |
| IL-16 | No data | No data | ||
| IL-17 | • Expression is dependent on grade of RCC malignancy [134] | ↑ ↑ ↑ ↑ ↑ | 15.12 ±1.38 pg/ml [32] 14.3 (12.2-17.5) pg/ml [24] 63.76 ±8.52 pg/ml [111] 15.12 ±1.38 pg/ml [77] 13.78 ±7.18 [31] | 10.20 ±1.25 pg/ml [32] 13.9 (10.6–17.8) pg/ml [24] 42.15 ±11.98 pg/ml [111] 10.20 ±1.25 pg/ml [77] 10.2 ±6.36 [31] |
| IL-18 | • Biomarker for early RCC recognition [136] | ↑ ↑ ↑ | 273.5 ±16.8 pg/ml [72] 9797.64 ±109.83 pg/ml [138] Pre-op tonsillectomy: 197.2 ±100.2 pg/ml [76] | 181.9 ±20.3 pg/ml [72] 250.27 ±76.48 pg/ml [138] Post-op tonsillectomy: 160.8 ±67.2 pg/ml [76] |
| IL-19–22 | No data | No data | ||
| IL-23 | • Direct role of IL-23 was not proofed in RCC [170] | ↑ ↑ ↑ | 14.58 ±0.75 pg/ml [32] 145.7 (123.9–187.2) pg/ml [24] 20.14 ±7.08 pg/ml [31] | 12.29 ±0.73 pg/ml [32] 134.7 (95.2–204.2) pg/ml [24] 12.29 ±3.66 pg/ml [31] |
| IL-24–32 | No data | No data | ||
| IL-33 | • Stimulates RCC cell proliferation and chemotherapy resistance [144] • Poor prognosis [144] | ↑ ↑ | 5.8 (5.6–6.2) pg/ml [145] 14.5 (2.3–25.2) pg/ml [146] | 5.48 (5.4–5.5) pg/ml [145] 8.4 (2.2–14.3) pg/ml [146] |
| IL-34–37 | No data | No data |
Renal cell carcinoma
As mentioned above, high-dose IL-2 treatment is an accepted therapy in RCC [46]. Furthermore, low-dose first-line IL-2 treatment has been shown to be effective in patients with RCC [47]. The idea behind this therapeutic approach is to stimulate an immunological response. IL-2 therapy stimulates the production of anti-IL-2 antibodies, thus increasing the number of CD8+, NK and macrophages, as shown in naïve experimental animals injected with anti-IL-2 antibodies [48].
Interestingly, a high serum level of the soluble interleukin-2 receptor was shown to be related to a poorer response of metastatic clear cell RCC to interferon-α and sequential VEGF-targeting therapy [49].
IL-4
IL-4 is an anti-inflammatory cytokine that type 2 T-helper (Th2) cells, eosinophils, basophils, and mast cells produce. IL-4 is the key stimulator of Th2-cells and suppresses the development of Th1-cells. This cytokine increases the expression of class II MHC molecules in B-cells [50]. IL-4 is structurally and functionally linked to interleukin-13 [51]. IL-4 and IL-13 mediate the interaction between T-cells and fibroblasts, contributing to inflammation and transition to the fibrotic phase [52].
Obstructive sleep apnea
Serum levels of IL-4 were analyzed by Cizza et al. in obese adults with OSA. IL-4 concentration was significantly higher in the OSA-positive group (4.1 (3.1–6.4) pg/ml) in comparison to controls (3.2 (2.3–4.6) pg/ml) (p = 0.038) [24]. Galati et al. also measured IL-4 in the serum of OSA patients. They observed a higher serum level of IL-4 in the OSA group (1.91 (0.45–3.29) pg/ml) in comparison to the healthy group (1.50 (0.27–2.11) pg/ml) (p = 0.453) [42]. Interestingly, Perrini et al. investigated the effect of CPAP therapy and a weight loss intervention on systemic inflammation in OSA patients. They found significantly higher IL-4 values in OSA patients (2.7 pg/ml) than in the non-OSA group (2.3 pg/ml) (p < 0.05). Continuous positive airway pressure therapy reduced the level of IL-4 in the OSA group (p < 0.05) [44]. Furthermore, Su et al. measured plasma levels of various cytokines in children with a high or a low risk of OSA. IL-4 was higher in the high-risk OSA group than in children with a low risk of OSA (median 234.24 pg/ml vs. 186.42 pg/ml; p < 0.05) [53]. Similarly, Tam et al. investigated the status of pro-inflammatory cytokines in OSA children who showed a non-significant elevation of IL-4 in the OSA-positive group (4.5 (2–7.5) µg/l) compared to healthy controls (3.7 (1.5–6.9) µg/l; p = 0.198) [25]. On the other hand, Hirsch et al. observed a lower IL-4 level in a group of OSA-positive children (4.87 (2.46–8.14) pg/ml) in comparison to controls (5.48 (2.79–8.39) pg/ml), though again without statistical significance (p = 0.52) [30]. Mahboub et al. analyzed CPAP therapy in the OSA and asthma patient group. They noted that the serum level of IL-4 was higher before CPAP therapy than after treatment (pre-CPAP 0.13 ng/ml vs. post-CPAP 0.01 ng/ml; p = 0.0003) [45]. Dyugovskaya et al. took a different approach, investigating the expression of IL-4 in CD4+ and CD8+ lymphocytes. In both types of cells, the expression of IL-4 was higher in the OSA group (24.4% and 11.2% respectively) compared to controls (3.5% and 2.0%, respectively), and was found to be statistically significant (p = 0.004; p = 0.0001) [43].
Renal cell carcinoma
In patients with localized clear cell renal cell carcinoma (ccRCC), higher IL-4 expression was shown to be correlated with shorter recurrence-free survival, and overall survival (OS) [54]. The study by Lin et al. [51] in 786-O (renal carcinoma cell line) and A-498 (kidney carcinoma cell line) demonstrated that IL-4R was associated with a risk of RCC and that the polymorphism of rs4787951 in IL-4R contributes to a higher risk of RCC in the Chinese population. Kim et al. [55] demonstrated that IL-4 activates senescence in human renal carcinoma cell lines through STAT6 (signal transducer and activator of transcription factor 6) and p38 MAPK signaling. This study was carried out on four human RCC cell lines: Caki-1, A-498, SNU482, and SNU228. Contrary to other studies, it showed that IL-4 at a concentration of 10 ng/ml inhibits the progression of the cell cycle in the G1 phase in the Caki-1 cell line. IL-4 induces the expression of CDKN1A and interferon regulatory factor IRF1, which serves to decrease the activity of cyclin-dependent kinase CDK2 and cell cycle progression [56]. IL-4 inhibits RCC cell proliferation 20–68% dose-dependently. The IL-4R receptor on RCC cells is of high affinity and was shown to have a dissociation constant of 112 +/– 11 pM to 283 +/– 71 pM in primary RCC cultures [57].
IL-5
Interleukin-5 (IL-5) is produced by Th2-cells and mast cells; it supports the development of eosinophils from bone marrow cultures [58]. Its main role is related to the differentiation, recruitment, and survival of eosinophils [59]. Its gene is close to the genes encoding IL-3, IL-4, and the colony stimulating factor of granulocyte macrophages (GM-CSF) [60]. IL-5 contributes to the induction of airway hyperreactivity in patients with asthma. IL-5, Th2-cells, and eosinophils have been shown to correlate with asthma severity [61].
Obstructive sleep apnea
IL-5 is the next cytokine measured in the plasma of OSA patients. Cizza et al. analyzed serum levels of IL-5 in obese adults with OSA. The concentration of IL-5 was 8.2 (5.3–10.7) pg/ml and 6.9 (4.2–9.0) pg/ml in the OSA-positive and OSA-negative group, respectively (p = 0.033) [24]. In addition, Hirsch et al. analyzed serum levels of pro-inflammatory cytokines in OSA children. Interestingly, they found that the serum level of IL-5 was lower in OSA patients (0.63 (0.44–1.08) pg/ml) in comparison to controls (0.45 (0.37–0.82) pg/ml), but without statistical significance (p = 0.27) [30].
Renal cell carcinoma
IL-5 and IL-3 play a role in the proliferation, differentiation, and stimulation of hematopoietic cells. The study by Gerharz et al. [62] demonstrated that IL-5 secretion was not detected in any RCC cell line out of the 40 tested.
IL-6
Interleukin 6 (IL-6) is a member of the IL-6 family of cytokines [38, 63] that also includes other interleukins such as IL-11, 27, 30, and 31, as well as factors such as ciliary neurotrophic factor, leukemia inhibitory factor, cardiotrophin-like cytokine, oncostatin M and many others. These cytokines bind to glycoprotein 130 as a β-receptor, thus activating intracellular pathways. In addition, regulatory T-cells, interleukin IL-6 together with IL-8, VEGF, CXCL10, CXCL11, epidermal growth factor (EGF), and hepatocyte growth factor are all surrogate markers of host immunity in patients with RCC [64].
Obstructive sleep apnea
Many authors have presented studies on IL-6 in OSA. All the analyzed papers described a higher level of IL-6 in OSA-positive patients than controls. Ciccone et al. analyzed inflammatory markers in OSA. They measured plasma levels of IL-6 and observed significantly higher IL-6 concentrations in the OSA group (3.33 ±1.35 pg/ml) than in controls (1.5 ±0.67 pg/ml, p < 0.01) [65]. Kotsiou et al. analyzed the serum level of IL-6 in OSA patients and found a significantly higher level of IL-6 in the OSA group (3.4 ±1.0 pg/ml) in comparison to the controls without OSA (2.3 ±0.3 pg/ml; p < 0.001) [66]. Similarly, Thunström et al. found that serum levels of IL-6 in OSA patients (3.6 (1.9–6.7) pg/ml) were significantly higher than in those without OSA (2.5 (0.9– 4.6) pg/ml; p < 0.005) [67]. Prasad et al. analyzed sleepiness and other factors in OSA patients. They found that among patients with high sleepiness, the level of IL-6 is higher compared to patients with OSA (4.2 pg/ml vs. 2.7 pg/ml) [68]. In a different study, Motamedi et al. investigated the correlation of pro-inflammatory markers with the severity of OSA. Serum IL-6 levels were significantly higher in patients with severe OSA (2.93 pg/ml) compared to mild OSA (1.74 pg/ml) and in controls (1.72 pg/ml) (p < 0.05) [69]. The serum level of IL-6 was also elevated in the OSA-positive group (61.59 ±9.76) compared to the control group (54.46 ±9.43) in a study by Kong et al. (p = 0.001) [26]. Tomiyama et al. analyzed the plasma level of inflammatory cytokines and found an increased level of IL-6 in patients with OSA (2.4 ±1.6 pg/m) in comparison to controls (1.5 ±0.6 pg/ml) (p < 0.05) [27]. Similarly, Heizati et al. reported a non-significant elevation in the OSA-positive group compared to controls [70]. Given that OSA coexists with other comorbid diseases, Abdel-Fadeil et al. analyzed possible mechanisms linking hypertension (HT) and cardiovascular disease with OSA. They measured the serum level of inflammation markers, finding a higher serum level of IL-6 in patients with OSA compared to controls (5.12 pg/ml vs. 3.08 pg/ml; p < 0.001). Furthermore, in the OSA-positive group with HT, the serum level of IL-6 was higher (6.04 pg/ml) in comparison to the group without HT (5.12 pg/ml) p < 0.001 [71]. Cizza et al. analyzed a group of obese patients with OSA. They noted that IL-6 concentration was 5.8 (4.4–9.3) pg/ml and 4.5 (2.6–9.0) pg/ml in OSA-positive and OSA-negative patients, respectively (p = 0.041) [24]. In another study, Minoguchi et al. analyzed plasma levels of IL-6 in OSA patients and obese controls. Patients with severe OSA (mean AHI 48.4) had a higher plasma level of IL-6 (2.25 ±0.28 pg/ml) in comparison to obese patients without OSA (mean AHI 3.3) (0.91 ±0.15 pg/ml) p < 0.01 [72]. Sahlman et al. [49] also observed a lower IL-6 level in non-OSA patients [33]. They measured cytokine profiles in overweight and obese OSA patients (BMI > 26 kg/m2) and controls. The serum level of IL-6 was 2.36 pg/ml in patients with OSA, compared to the control patients at 2.14 pg/ml(p = 0.767). Qian et al. examined patients with OSA and HT. Serum levels of IL-6 were significantly higher in OSA groups with HT (129.41 ±36.56 ng/ml) (89.56 ±36.19 ng/ml) in comparison to controls (88.85 ±41.48 ng/ml; p < 0.01). The differences between controls and patients without HT were non-significant (89.56 ±36.19 ng/ml) [73]. Arnardottir et al. analyzed the interaction of serum IL-6 levels with OSA severity and obesity. They found that oxygen desaturation index, hypoxia time and minimum oxygen saturation (SaO2) were significantly correlated with IL-6 levels, but that OSA severity was associated with IL-6 levels in obese participants only (BMI > 30 kg/m2) [74]. The serum level of IL-6 was also analyzed in the pediatric population with OSA. Tam et al. investigated the status of pro-inflammatory cytokines in children with OSA. They found a nonsignificant elevation of IL-6 in the OSA group (5.3 (3.9–7.1) pg/ml) compared with healthy controls (4.8 (3.6–7) pg/ml; p = 0.302) [25]. Hirsch et al. measured plasma cytokine levels in a different study using a multiplex beads-based assay. Obstructive sleep apnea positive children showed a significantly higher IL-6 level than OSA-negative (3.22 (2.25–4.21) pg/ml vs. 2.31 (0.97–2.95) pg/ml) (p = 0.046) [30]. Huang et al. examined serum levels of IL-6 in children with OSA. This cytokine was higher in the OSA-positive group (1.66 ±0.23 pg/ml) in comparison to controls (1.1 ±0.18 pg/ml), but without statistical significance (p = 0.104) [32]. In another study, Huang et al. investigated plasma levels of IL-6 in a group of sleep apneic children before and after adenotonsillectomy compared to healthy controls. The serum level of IL-6 was higher in the OSA group (1.59 ±1.58 pg/ml) than in the control group (1.1 ±0.92 pg/ml). In the group with AHI > 1, the IL-6 level decreased slightly but non-significantly after surgery (pre-operative 1.59 ±1.58 pg/ml vs. postoperative 1.39 ±1.44 pg/ml; p > 0.05). In the group with AHI < 1, there was a more pronounced but still non-significant decrease in level of IL-6 after surgery (pre-operative 1.59 ±1.58 pg/ml vs. after surgery 0.94 ±0.60 pg/ml; p > 0.05). They observed non-significant differences between controls and postoperative results of serum IL-6 level [31]. Shalitin et al. measured serum IL-6 levels in an obese population of children and adults with and without diabetes mellitus, investigating its association with OSA. Plasma IL-6 concentrations were elevated in patients with OSA compared to those without OSA (4.56 ±2.92 pg/ml vs. 2.83 ±1.54 pg/ml, respectively; p = 0.025) [75]. Kheirandish-Gozal et al. investigated plasma levels of inflammatory markers in a group of OSA-positive children before and after adenotonsillectomy. Surgical intervention decreased serum IL-6 level (pre-operative 10.2 ±11.3 pg/ml vs. postoperative 6.2 ±3.1 pg/ml; p < 0.0001) in the group with AHI < 5 after surgery. On the other hand, among children with OSA and AHI > 5, the IL-6 level changes non-significantly after surgery (pre-operative 9.5 ±7.9 pg/ml vs. post-operative 9.2 ±6.7 pg/ml; p = 0.7) [76]. Another study by Gozal et al. measured the serum level of IL-6 in children with OSA before and then 4–6 months after adenotonsillectomy. The level of IL-6 was found to be higher in the OSA group (2.98 ±0.27 pg/ml) in comparison to the same group after surgery (1.96 ±0.07 pg/ml; p < 0.01) and healthy controls (1.67 pg/ml; p < 0.01) [63]. Another study in the pediatric population was conducted by Bhat et al. They analyzed the relationship between OSA in overweight/obese children and various inflammatory markers. IL-6 was higher in the OSA group (20.1 ±5.6 pg/ml) in comparison to controls (15.4 ±3.5 pg/ml; p = 0.05) [77]. Continuous positive airway pressure therapy has been shown to improve not only the symptoms, but also some cytokine parameters. With this in mind, Dogan et al. analyzed blood samples from OSA-positive patients, before and after CPAP treatment. The daily duration of CPAP therapy was about 5 hours for 3 months. The serum level of IL-6 was lower after CPAP treatment (before CPAP 0.062 ±0.077 pg/ml vs. after CPAP 0.06 ±0.013 pg/ml; p = 0.137) [78]. Thunström et al. analyzed plasma levels of IL-6 in patients with coronary artery disease and OSA before and after CPAP therapy. They noted a significantly reduced serum level of IL-6 after CPAP therapy (3.1 vs. 2.2 pg/ml; p < 0.006) [79]. In a different study, Perrini et al. investigated the effect of CPAP therapy combined with a weight loss intervention on systemic inflammation in patients with OSA. They assessed the serum level of IL-6 and found that it was significantly reduced compared to baseline in the therapeutic CPAP group (p < 0.05). They also evaluated the expression of IL-6 mRNA in subcutaneous abdominal adipose tissue collected from tissue biopsies. Obstructive sleep apnea positive patients without therapy presented higher expression of IL-6 than patients treated with CPAP. The lowest expression of IL-6 was observed in the OSA-negative group [44]. Bilal et al. evaluated changes in cytokine levels from the preoperative state to the third month after expansion sphincter pharyngoplasty. They noted a higher serum level of IL-6 in the OSA group with mild (44.46 pg/ml), moderate (42.74 pg/ml), and severe disease (57.98 pg/ml) in comparison to the control group (40.57 pg/ml; p < 0.001). Furthermore, they observed a significant postoperative reduction in the mild (41.61 pg/ml; p < 0.001), moderate (40.62 pg/ml; p < 0.001), and severe (55.17 pg/ml; p < 0.062) OSA group [80]. Other authors assessed IL-6 in molecular analysis. Kaditis et al. analyzed associations of variants in IL-6 genes and susceptibility to OSA. IL-6 DNA samples were extracted from venous blood. A significant association was found between OSA and genotype distribution for the single nucleotide polymorphisms IL-6-174G/C [81]. Galati et al. measured IL-6 in the serum of OSA patients. They observed a higher serum level of IL-6 in the OSA group (6.96 (4.35–16.03 pg/ml) in comparison to the healthy group (1.9 (1.14–2.40) pg/ml, p < 0.0001). In addition, they analyzed dendritic cells (DCs) and their circulation. The authors observed depleted DCs in the OSA group compared to healthy controls. Abnormalities in DCs were negatively correlated with the expression of IL-6, which is recognized as a pivotal inhibitor of DC maturation [42]. In another study, Bhat et al. analyzed OSA patients with nonalcoholic fatty liver disease, looking at their inflammation markers and genes. The prevalence of the variant genotypes C/T of CRP and G/C of the IL-6 gene was significantly higher in subjects with OSA compared to patients without OSA. Furthermore, the serum level of IL-6 was higher in patients with OSA (20.1 pg/ml ±5.6) in comparison to the non-OSA group (16.5 pg/ml ±4.6) (p < 0.05) [82]. Kyotani et al. analyzed the expression of IL-6 in smooth muscle cells of the human coronary artery after exposure to IH. Intermittent hypoxia increased IL-6 mRNA expression compared to normoxia [83]. The serum concentration of IL-6 was higher in OSA patients than controls (58.49 vs. 9.11 respectively; p = 0.0003) in a study by Lu et al. analyzing inflammation cytokines in bronchoalveolar lavage fluid (BALF). A lower BALF level of IL-6 was observed in the control group compared to the OSA-positive group (10.41 vs. 42.67; p < 0.0001) [84]. In another study, Wu et al. collected nasal lavage fluid from patients with and without OSA. They analyzed the level of IL-6 in nasal lavage and found that the group with severe OSA had a significantly higher level of IL-6 (0.36 ±1.13 pg/ml) compared to patients without OSA (–0.14 ±0.97 pg/ml, p < 0.01) [85].
Renal cell carcinoma
IL-6 is a factor associated with poor prognoses in RCC patients; in particular, it can induce drug resistance and lead to overexpression of VEGF and the promotion of tumor angiogenesis. IL-6 has been shown to contribute to doxorubicin resistance in ACHN and A498 cells [86].
Recent studies have also shown that the expression of this pro-inflammatory cytokine by cancer cells leads to tumor progression and metastasis [87]. A recent meta-analysis by Wang et al. [88] on the prognostic role of IL-6 in RCC suggested that a higher level of IL-6 in patients with RCC is associated with poor survival. Song et al. (2019) found that serum levels of IL-6 were higher in ccRCC patients than in controls. Furthermore, a link between low vitamin D status and hyperactivation of IL-6/STAT3 (activator of transcription 3) was observed in patients with RCC. Another investigation demonstrated that under hypoxic conditions (1% O2), RCC cell lines (ACHN, Caki-1, Caki-2, 769-P) secreted significantly more soluble receptor IL-6 (sR-IL-6) than under normoxic conditions [89]. IL-6sR is emitted from the membrane-bound receptor IL-6 (IL-6R) by enzymes belonging to the family of A disintegrin and metalloproteinase (ADAM) gene of metalloproteases ADAM-10 and ADAM-17. Based on their in vitro results, the authors proposed that the IL-6/IL-6sR complex may be responsible for enhancing the proliferation rate of RCC cells in the development of RCC lung metastases. A study by Ishibashi et al. showed that IL-6 induces drug resistance in RCC, suggesting a novel approach to the therapy of RCC of a combination of IL-6R inhibitors and other factors such as IFN/TKI [90].
IL-7
Interleukin-7 (IL-7) is a homeostatic cytokine in most T-cells, progenitors of B-cells, and bone marrow macrophages. IL-7, IL-2, IL-4, IL-9, IL-15, and IL-21 are members of the family of common γ chain cytokines [38]. IL-7 was recognized to induce T and NK-cell responses in peripheral blood [91]. IL-7 and its receptor, IL-7R, contribute to the proliferation and survival of thymocytes and the development of naive and memory T- and B-cells, as well as mature T- and NK-cells [92].
Obstructive sleep apnea
We did not find studies on IL-7 and OSA. Only Benedict et al. [93] analyzed the association of sleep effectiveness and serum IL-7 level. They found that, compared to continuous wakefulness, sleep increased serum IL-7 concentrations.
Renal cell carcinoma
Sica et al. [91] observed that IL-7 improved the proliferation and effector role of tumor-infiltrating lymphocytes (TIL) from RCC. Frankenberger et al. [94] published a study involving RCC-26 cells (genetically engineered to express CD80 alone or in combination with IL-2 or IL-7). They reported that RCC-26 cells presented enhanced immunogenic characteristics, supporting their use as allogeneic tumor cell vaccines for RCC patients. Another study, by Trinder et al. [95], demonstrated that IL-7 and IL-15 (with similar biological functions) could be involved in determining the value of antitumor-directed immune responses. The expression of proteins and IL-15 and IL-7 mRNA levels in several human tumor cell lines was tested with IFN-γ (belonging to a different interleukin group). IL-7-specific transcripts were detected and the expression level of IL-15 mRNA was detected in renal cell cancer cell lines, although only IL-7 appeared to be expanded by tumor cells in situ.
IL-8
Interleukin-8 (IL-8) and IL-16 belong to the interleukin group with CXC chemokine activity [38]. IL-8 is a neutrophil-specific chemotactic factor produced by many cells, such as neutrophils, lymphocytes, monocytes, macrophages, endothelial and epithelial cells, specifically after stimulation with other interleukins, including IL-1α, IL-1β, IL-17, TNF-α, and TLRs. CXCR1 (IL-8RA) and CXCR2 (IL-8RB) are the receptors of IL-8.
Obstructive sleep apnea
Most studies on IL-8 in OSA described increased levels of this cytokine in patients with sleep disturbances. Cizza et al. analyzed serum IL-8 levels in obese adults with OSA positivity. IL-8 concentration was 12.2 (7.7–21.8) pg/ml and 10.8 (4.7–15.4) pg/ml in OSA-positive and OSA- negative cases, respectively (p = 0.050) [24]. Similarly, Thunström et al. found that serum levels of IL-8 in OSA patients (1.3 (0.8–2.0) pg/ml) were higher than in those without OSA (1.1 (0.8–1.8) pg/ml), but without statistical significance (p = 0.123) [67]. Additionally, Hirsch et al. analyzed plasma cytokine levels using a multiplex bead-based assay. Obstructive sleep apnea patients had a non-significantly higher level of IL-8 than OSA patients (4.07 (3.48– 6.41) pg/ml vs. 3.46 (2.63–5.71) pg/ml, respectively; p = 0.52) [30]. Bilal et al. evaluated changes in cytokine levels from the preoperative state to the third month after expansion sphincter pharyngoplasty. They noted a higher serum level of IL-8 in the OSA group with mild (106.83 pg/ml), moderate (105.66 pg/ml), and severe disease (126.31 pg/ml) in comparison to the control group (100.12 pg/ml; p < 0.001). Additionally, they observed postoperative reduction in IL-8 in the mild (99.73 pg/ml; p = 0.005), moderate (97.21 pg/ml; p < 0.001), and severe (112.87 pg/ml; p = 0.006) OSA group [80]. Tam et al. investigated the status of pro-inflammatory cytokines in OSA children. They detected a non-significant elevation of serum level IL-8 in the OSA group (5 (3.2–7.2) µg/l) compared to healthy controls (4.1 (1.6–5.5) µg/l; p = 0.051) [25]. Another study in the pediatric population was carried out by Bhat et al. They analyzed the relation between OSA in overweight/obese children and various inflammatory markers. IL-8 was higher in the OSA group (8.29 ±5.2 pg/ml) in comparison to the non-OSA controls (4.98 ±3.67 pg/ml; p = 0.034) [77]. Obstructive sleep apnea occurs with comorbid diseases, which led Thunström et al. to analyze plasma levels of IL-8 in patients with coronary artery disease and OSA before and after CPAP therapy. No significant changes from baseline values were observed regarding IL-8 (1.4 pg/ml vs. 1.3 pg/ml; p = 0.378) [79]. Interestingly, Zychowski et al. analyzed inflammatory markers in human coronary artery endothelial cells in OSA patients. The obstructive sleep apnea serum induced significantly higher endothelial cell expression of IL-8 compared to the serum of healthy control subjects (p < 0.05). Furthermore, CPAP therapy resulted in a statistically non-significant reduction in IL-8 expression compared to controls (p > 0.05) [96]. In another study, Santamaria-Martos et al. measured plasma level IL-8 in patients with cutaneous melanoma and OSA. In the group without OSA, the level of IL-8 was lower (17 (14–20.1) pg/ml) in comparison to the group with severe OSA (19.7 (15.8–23.5) pg/ml) p = 0.436 [97]. Cheng et al. analyzed patients with metabolic syndrome and OSA. They observed an increase in IL-8 levels in the OSA group (43.50 ±7.22 pg/ml) in comparison to healthy controls (24.63 ±3.66 pg/ml) (p < 0.05) [98]. In addition, Wu et al. collected nasal lavage fluid from patients with and without OSA. IL-8 levels were measured in nasal lavage, and the group without OSA was found to have a significantly lower IL-8 level (–0.34 ±0.89 pg/ml) in comparison to patients with severe OSA (0.40 ±0.87 pg/ml; p < 0.01) [85]. Wang et al. compared the levels of inflammatory markers in bronchoalveolar lavage fluid (BAL) in patients with OSA and patients with chronic obstructive pulmonary disease (COPD). The BAL fluid of OSA patients showed a significantly higher concentration of IL-8 (88.1 ±30.1 pg/ml) than that of COPD patients (57.9 ±22.8 pg/ml); p < 0.001. Furthermore, they presented data after CPAP treatment which revealed a significant decrease in IL-8 levels in BAL compared to untreated patients (63.1 ±23.4 vs. 80.1 ±26.9 pg/ml; p < 0.05) [99]. Given the theory that OSA therapy may affect inflammatory cytokine levels, Ohga et al. assessed the effects of CPAP on circulating IL-8 in OSA patients. The serum level of IL-8 changed 25.3–30.1 pg/ml before CPAP therapy to 10.1–14.8 pg/ml after 8 months of CPAP therapy (p < 0.05) [100]. Guo et al. induced IH in rats and measured inflammatory markers. They analyzed IL-8 in cocultural supernatants from rat aortic endothelial cells and lymphocytes. In the control group (under normal oxygen conditions) the level of IL-8 was 90 pg/ml, while in the IH group the level of IL-8 was 195 pg/ml (p < 0.01) [101].
Renal cell carcinoma
In the case of RCC, IL-8 provides the epithelial-mesenchymal transition (EMT) of RCC cells through the activation of AKT (serine-threonine kinase) signaling, based on an in vitro study using the human RCC 786-O cell line [102]. IL-8 was proposed to promote EMT of an RCC cell line by increasing N-cadherin expression and reducing the level of E-cadherin. Furthermore, IL-8 is a chemokine that controls the features of cancer stem cells (CSC) in RCC [103]. A study by Peng et al. (testing cell lines: adenocarcinoma lines 786-O, 789-P and A-704 and clear cell carcinoma Caki-1 and Caki-2) showed that USP21 – a member of the ubiquitin-specific protease family – binds to the promoter region of IL-8 and mediates transcriptional initiation [103]. The authors proposed that USP21 and IL-8 are critical molecular targets for improving therapeutic strategies for RCC. High levels of IL-8 were correlated with significantly shorter OS (hazard ratio – HR, = 3.55) in patients with RCC. Significantly shorter progression-free survival on sunitinib and everolimus was reported in patients with high (> median) levels of IL-8 (HR = 3.13) in non-ccRCC patients [104].
IL-10
Interleukin 10 (IL-10) belongs to the IL-10 subfamily of cytokines, also including IL-19, IL-20, IL-22, IL-24, IL-26, IL-28 and IL-29. It binds to the IL-10R2 receptor [38], and Th2 lymphocytes produce this immunosuppressive factor. IL-10 stimulates mast cell proliferation and thymocyte proliferation, along with proliferation and differentiation of B-cells [105]. It inhibits MHC class II expression and cytokine expression in lipopolysaccharide-activated macrophages [106]. Another effect of IL-10 is suppression of IFNg, TNFa, IL-1b and IL-6 [105]. IL-10 may play a key role in cancer development and metastasis, as it modulates and suppresses the immune response. It is the human cytokine synthesis inhibitory factor [107]. In contrast, IL-10 is known to stimulate CD8+ T-cell proliferation and cytotoxicity [108].
Obstructive sleep apnea
IL-10 is another important cytokine in OSA. Galati et al. measured IL-10 in the serum of OSA patients. They observed a higher serum level of IL-10 in the OSA group (2.48 (1.83–3.02) pg/ml) in comparison to the healthy group (0.96 (0.72–1.60) pg/ml) (p = 0.006) [42]. Cizza et al. analyzed obese patients with OSA. IL-10 concentration was 7.8 pg/ml in the group without sleep apnea and 8 pg/ml in the group with sleep apnea (p = 0.615) [24]. In another study, Leon-Cabrera et al. investigated obese patients with OSA. Serum levels of IL-10 were significantly lower in the study group (74.4 ±17.0 pg/ml) than in non-obese controls without OSA (113.2 ±12.1 pg/ml). Interestingly, a decrease in IL-10 serum level was significantly related to increased AHI, hyperinsulinemia, and insulin resistance [109]. Similarly, Qian et al. measured levels of inflammatory markers in patients with OSA and HT. The serum level of IL-10 was significantly lower in the OSA groups with (14.79 ±9.13 ng/ml) and without HT (26.11 ±0.98 ng/ml) in comparison to controls (38.6 ±10.6 ng/ml ng/ml) [73]. Sahlman et al. [49] also observed a lower level of IL-10 in OSA patients [33]. They measured cytokine profiles in overweight and obese OSA patients (BMI > 26 kg/m2) and controls. The serum level of IL-10 was significantly lower in OSA patients compared to control patients (1.28 pg/ml vs. 0.7 pg/ml, p < 0.001). Studies in children also describe increased and decreased levels of IL-10. Tam et al. presented a non-significant elevation of IL-10 in OSA children (3.3 (1.5–4.9) µg/l) compared to healthy controls (2.8 (0.7–4.4) µg/l; p = 0.163) [25]. Similarly, Huang et al. examined serum levels of IL-10 in children with OSA. They found that the cytokine was higher in the OSA group (2.62 ±0.39 pg/ml) in comparison to controls (2.1 ±0.28 pg/ml), but without statistical significance (p = 0.332) [32]. Rogers et al. analyzed cytokines in sera and tonsils in children with OSA. They noted higher levels of IL-10 in the group with a lower SaO2 [110]. On the other hand, Su et al. measured plasma levels of various cytokines in children at high and low risk of OSA. IL-10 was lower in the high-risk OSA group than in children at low risk (median 261.71 ±18.55 pg/ml vs. 338.24 ±25.20 pg/ml, p < 0.01) [53]. Hirsch et al. measured plasma cytokine levels in children with and without OSA. Obstructive sleep apnea positive patients showed a higher level of IL-10 than OSA-negative patients, 2.09 (1.26–2.91) pg/ml vs. 1.72 (1.13–2.08) pg/ml) (p = 0.85) [30]. In another study, Gozal et al. measured the serum level of IL-10 in children with OSA before and 4–6 months after adenotonsillectomy. The level of IL-10 was lower in the OSA group (195.2 ±33.6 pg/ml pg/ml) than in both the group after surgery (476.3 pg/ml; p < 0.001) and healthy controls (458.5 pg/ml; p < 0.001) [63]. Huang et al. investigated plasma levels of inflammatory markers in a group of children with OSA before and after adenotonsillectomy compared to healthy controls. The serum level of IL-10 was higher in the OSA group (2.74 ±2.94 pg/ml) than in the control group (2.1 ±1.41 pg/ml). Surgical intervention significantly decreased serum IL-10 level (pre-operative 2.74 ± 2.94 pg/ml vs. postoperative 1.6 ±1.01 pg/ml; p = 0.035) in a group with AHI > 1 after surgery. They did not observe significant differences between controls and postoperative results of the serum IL-10 level (p = 0.463) [31]. Furthermore, Dyugovskaya et al. analyzed the expression of IL-10 in CD4 and CD8 lymphocytes. In both cell types, IL-10 expression was higher in the OSA group (12.0 ±6.1% and 9.7 ±6.5% respectively) compared to controls (2.4 ±1.3% and 8.5 ±9.7% respectively). In their study, the difference in IL-10 expression in CD4 T-cells was found to be statistically significant (p = 0.001) [43]. A lower serum IL-10 level was observed in the OSA group in the study by Ni et al. They analyzed the level of IL-10 in children with OSA and adenoid hypertrophy. Patients with OSA (3.67 ±1.59 pg/ml) presented lower serum levels of IL-10 compared to controls (14.43 ±5.68 pg/ml) (p < 0.05) [111].
Renal cell carcinoma
IL-10 was detected in cultures of RCC cells. Wittke et al. [130] proposed it as a prognostic factor for metastatic RCC [112]. Serum levels for IL-10 were > 1 pg/ml and were detected in patients with an unfavorable outcome. Research by Ménétrier-Caux et al. [113] demonstrated that monocytes’ RCCs induce IL-10 and TNF-α production, which down-regulate the expression of cell-surface molecules involved in antigen presentation. Another study by Cai et al. [114] showed that in patients with renal cell carcinoma, both CD3(+) T-cells and CD19(+) B-cells contributed to elevated IL-10 expression. At the same time, treatment with pegilodecakin – a long-acting form of interleukin-10 linked to polyethylene glycol (PEGylated hIL-10, AM0010) – achieved a 25% partial response (PR) rate in patients with RCC heavily pretreated who received at least three lines of treatment. Furthermore, treatment with pegilodecakin combined with nivolumab or pembrolizumab resulted in 41% PR, 9% complete responses and an additional 44% stable disease; the 1-year OS of 1 year for pegilodecakin + anti-PD-1 is 89% [108].
IL-12
Interleukin-12 (IL-12) is a member of the IL-12 family, together with IL-23, IL-27, and IL-35 [38]. Activated monocytes, macrophages, neutrophils, microglia, and DCs produce it. IL-12 is a cytokine that increases cytolytic activity, proliferation, and interferon-γ (IFN-γ) synthesis by T lymphocytes and natural killer cells. This gives it significant antitumor activity in various murine tumor models [115]. IL-12 regulates inflammation as it orchestrates innate and adaptive immune responses via interferon-γ secretion [116].
Obstructive sleep apnea
We found four studies that evaluated IL-12 levels in OSA. All found a higher level of IL-12 in OSA compared to controls. Cizza et al. analyzed IL-12 serum levels in OSA-positive obese adults. IL-12 concentration was 10.6 (5.0–12.8) pg/ml in OSA-negative patients and 11.5 (7.8–14.1) pg/ml in OSA-positive patients (p = 0.391) [24]. In another study, Leon-Cabrera et al. described a significantly higher serum level of IL-12 in obese patients with OSA (405.3 ±57.4 pg/ml) than in non-obese controls without OSA (217.4 ±43 pg/ml), p < 0.00001. Furthermore, elevated IL-12 level was associated with increased AHI, hyperinsulinemia, and insulin resistance [109]. In the third study, children with OSA were analyzed by Tam et al. They measured the plasma level of IL-12 and found that it was non-significantly elevated in the OSA group (6.7 (1.2– 22) µg/l ) compared to the normal control (4.6 (0.9– 15.8) µg/l; p = 0.469) [25]. Further, Huang et al. investigated plasma levels in OSA children before and after adenotonsillectomy, compared to a control group. The serum level of IL-12 was higher in the OSA group (1.77 ±1.15 pg/ml) than in the control group (0.97 ±0.75 pg/ml). Surgical intervention decreased serum IL-12 level (pre- operative 1.77 ±1.15 pg/ml vs. postoperative 1.18 ±1.12 pg/ml, p = 0.229) in a group with AHI > 1 after surgery [31].
Renal cell carcinoma
The first in vitro effects of IL-12 were observed in RCC-derived TIL [117]. Gao et al. [136] proposed the first therapeutic potential of human mesenchymal stem cells producing IL-12 in a murine xenograft model of RCC [118]. In their study, intravenous injection of mesenchymal stem cells expressing murine IL-12 reduced the growth of RCC xenografts and prolonged the survival of tumor-bearing mice. IL-12 was also shown to enhance the cytotoxic response of CD8+ T-cells against Renca cells [119]. In particular, a combination of Renca cell-derived exosome-stimulated CD8+ T-cells and GM-CSF cytokine with IL-12 seemed to exert the strongest antitumor effect in this study.
A phase I human trial was designed to evaluate increasing doses of recombinant human interleukin-12 (rHuIL-12) administered subcutaneously to pretreated patients. Phase II trials of rHuIL-12 were conducted in RCC 1 line treatment [120]. For intravenous rhIL-12, the phase I trial demonstrated that it is a well-tolerated therapy that stimulates the production of IL-12 co-stimulatory cytokines and IFN-γ, resulting in delayed progression [121]. Unfortunately, the antitumor response exerted by IL-12 has not been successfully translated into clinical practice [116].
IL-13
According to the Akdis et al. [38] classification, interleukin-13 (IL-13) belongs to the group of cytokines of type 2 immune response (together with IL-4, IL-5, IL-9, IL-25, IL-31, and IL-33). It is produced during the initiation of Th2 and ILC2 responses with the participation of epithelial cells, DC, ILC, T-cells, eosinophils, mast cells, and basophils. It comprises IL-13Rα1 and IL-13Rα2 receptors, although signaling occurs through the IL-4R receptor.
Obstructive sleep apnea
The serum level of IL-13 was analyzed by Cizza et al. in obese adults with OSA. They observed a lower serum level of IL-13 (13.2 (10.2–15.0) pg/ml) in OSA-negative adults compared to 14.3 (11.8–17.5) pg/ml in OSA-positive patients (p = 0.039) [24].
Renal cell carcinoma
In a hospital study, Chu et al. found a correlation between six functional polymorphisms of the IL-4, IL-13, and IL-4R genes and susceptibility to renal cell cancer [122]. Shibasaki et al. [123] demonstrated that increased expression of the interleukin-13 receptor α-2 (IL13RA2) in primary ccRCC tumors is associated with the sunitinib-resistant metastatic site. These results indicate that IL13RA2 is a potential target of sunitinib resistance in patients with RCC. Renal cell carcinoma cells express a high affinity for IL-13 binding sites/receptors, and the in vitro model has shown that IL-13 strongly inhibits the proliferation of RCC cells through the specific receptor (IL13Rα1 chains) [124].
IL-15
Interleukin-15 (IL-15) is structurally homologous to IL-2. Together with IL-2, IL-4, IL-7, IL-9, and IL-21, IL-15 is a member of the common γ chain cytokine family [38]. It is a pleiotropic cytokine and seems to be physiologically active in a complex with its high-affinity IL-15Rα receptor. Monocytes, macrophages, DC, activated CD4+ T-cells, keratinocytes, skeletal muscle cells, fibroblasts, various epithelial cells, bone marrow stromal cells, and nerve cells produce IL-15. IL-15 affects both specific and nonspecific immunity mechanisms and controls the activation and proliferation of T-cells and natural killer (NK) cells. This leads to increased cytotoxic activity of NK-cells and intensive secretion of IFN-γ by these cells [125].
Obstructive sleep apnea
There was only one study in OSA patients that described serum levels of IL-15. Cizza et al. measured IL-15 in the plasma of obese patients with OSA. IL-15 concentration was 12.4 (9.9–14.7) pg/ml in the OSA-negative group and 13.5 (11.3–15.5) pg/ml in the OSA-positive group (p = 0.102) [24].
Renal cell carcinoma
IL-15 activates numerous immune antitumor mechanisms, making this cytokine a good candidate for the therapy of solid tumors, predominantly RCC. Giron-Michel et al. demonstrated that it plays a major role in human kidney physiology and cancer via the γc
signaling pathway [126]. It is also an important regulator of cell-microenvironment interactions in RCC, where loss of CD132 by epithelial cells establishes a tumor microenvironment in which IL-15 generates downregulation of E-cadherin and EMT [127]. IL-15 in physiological concentrations presents novel functions as a key regulator of renal epithelial homeostasis. Furthermore, the role of IL-15 and γc-receptor signaling was presented in renal homeostasis through the control of E-cadherin expression. IL-15 was recently shown to enhance γδ T-cell cytotoxicity in a patient-derived xenograft model of RCC. IL-15 suppressed tumor growth in RCC-positive mice and prolonged the survival of these mice [128].
IL-17
Interleukin-17 (IL-17) is a pro-inflammatory cytokine in the IL-17 family [38]. IL-17 is produced by Th17-cells, a subset of T-helper cells derived from activated CD4+ T-cells [129]. IL-17A binds as a homodimer/heterodimer with IL-17F to its receptor, IL-17RA. It is expressed by activated CD4+ Th17-cells, CD8+ T-cells, γδ T-cells, neutrophils and NK-cells [130]. IL-17A/F may stimulate cancer cell growth and progression through immune cell orchestration through macrophage crosstalk. IL-17A acts in several cells by upregulating the expression of pro-inflammatory cytokines, chemokines, and metalloproteases. IL-17A attracts neutrophils to mediate defenses against various pathogens by inducing cells to produce chemokines [131]. IL-17’s role in chronic inflammation is indicated as tumor-promoting, as it blocks the influx of cytotoxic CD8+ T-cells into the tumor and actually promotes infiltration of myeloid-derived suppressor cells. In addition, IL-17 can induce the release of the pro-inflammatory cytokine IL-6 from cancer cells and the activation of the STAT3 and NFκB pathways within tumor cells. IL-17 may also act precancerously through the overexpression of antiapoptotic genes such as BCL2, BCL2A1, and MCL1 and the increased survival of CSC by activation of MAPKs, ERK1/2, ERK5, as well as JNK kinases [129]. Th17-cells have been shown to increase in number in the tumor niche during cancer development and progression [132].
Obstructive sleep apnea
The serum level of IL-17 was analyzed in obese patients with OSA by Cizza et al. The concentration of IL-17 was 13.9 (10.6–17.8) pg/ml in the group without sleep apnea and 14.3 (12.2–17.5) pg/ml in the group with sleep apnea (p = 0.358) [24]. In the pediatric population, Ni et al. analyzed the level of IL-17 in children with OSA and adenoid hypertrophy. They noted higher serum levels of IL-17 in the OSA group (63.76 ±8.52 pg/ml) in comparison to controls (42.15 ±11.98 pg/ml) (p < 0.05) [111]. In another study, Huang et al. [32] examined serum IL-17 levels in children with OSA. They found higher levels of cytokines in the OSA group (15.12 ±1.38 pg/ml) in comparison to controls (10.20 ±1.25 pg/ml), and the difference was statistically significant (p = 0.024). Several years later, Huang et al. [31] investiga- ted plasma levels of IL-17 in a group of OSA children before and after adenotonsillectomy compared to healthy controls. The serum level of IL-17 was higher in the OSA group (13.78 ±7.18 pg/ml) than in the control group (10.2 ±6.36 pg/ml). Surgical intervention decreased serum levels (pre-operative 13.78 ±7.18 pg/ml vs. postoperative 11.02 ±4.72 pg/ml; p = 0.035) in the group with AHI > 1 after surgery. The authors did not observe significant differences between the control group and the postoperative results of the serum IL-17 level. Another study was carried out in the pediatric population by Bhat et al. They analyzed the relationship between OSA in overweight/obese children and various inflammatory mar-kers. IL-17 was significantly higher in the OSA group (15.12 ±1.38 pg/ml) than in controls (10.20 ±1.25 pg/ml; p = 0.024) [77]. Continuous positive airway pressure treatment reduced IL-17 serum level in OSA patients [45].
Renal cell carcinoma
IL-17 is produced by tumor-reactive T-cells and leads to the release of IL-8 by human RCC cells [133]. The expression of genes and protein (in the peripheral blood mononuclear cells, and in RCC tumor lysate) of IL-17 and IL-18 was significantly higher in the blood and tumors of RCC patients. Those elevated levels are observed in RCC tissue and expression depends on the grade of the malignancy [134]. Exogenous IL-17 plays a pathogenic role in RCC. In response to T-cell-derived IL-17, RCC cells secrete IL-8, which can further modulate the immune response of the host against cancer [135]. Renal cell carcinoma was identified as a tumor type with IL-17/Th17 infiltrating cells [132].
IL- 18
Interleukin-18 (IL-18) (interchangeably named interferon-γ inducing factor) is a pro-inflammatory cytokine mediator in the development and progression of many types of inflammatory diseases (e.g., Hashimoto’s thyroiditis) and infections. It belongs to the IL-1 family (with IL-33, IL-36, IL-37, and IL-38) based on the expression of various types of inflammatory cells [38, 136]. It is produced by hematopoietic and non-hematopoietic cells (intestinal epithelial cells, keratinocytes, and endothelial cells). IL-18 and IL-2 stimulate NK-cells, CD4+ NKT-cells, and established Th1-cells to generate other interleukins such as IL-3, IL-9, and IL-13. In addition, it induces basophils and mast cells to form IL-4, IL-13, and certain chemical mediators (e.g., histamine) [137].
Obstructive sleep apnea
Minoguchi et al. [72] analyzed the plasma level of IL-18 in obese OSA patients and in obese controls. Patients with severe OSA (mean AHI 48.4) had a higher plasma level of IL-18 (273.5 ±16.8 pg/ml) in comparison to obese patients without OSA (mean AHI 3.3) (181.9 ±20.3 pg/ml); p < 0.01. Furthermore, carotid intima-media thickness (IMT) significantly correlated with serum levels of this cytokine (p = 0.005). Similarly, Li et al. analyzed IL-18 level. They confirmed a significantly higher IL-18 level in the OSA group (9797.64 ±109.83 pg/ml) than in healthy controls (250.27 ±76.48 pg/ml). They found positive a correlation of carotid IMT with IL-18 serum level. Moreover, they investigated CPAP therapy in the OSA group. They found a significantly reduced IL-18 level after 90 days of CPAP treatment [138]. In another study, Kheirandish-Gozal et al. [76] investigated plasma levels of inflammatory markers in children with OSA before and after adenotonsillectomy. Surgical intervention did not change the level of IL-18 serum in the obese group with residual OSA after surgery (pre-operative 280.7 ±171.2 pg/ml vs. postoperative 297.9 ±188.6 pg/ml; p < 0.3), but it decreased significantly in the obese group, where OSA resolved after treatment (pre-operative 197.2 ±100.2 pg/ml vs. postoperative 160.8 ± 67.2 pg/ml, p < 0.0001).
Renal cell carcinoma
The expression of IL-18 was shown to be elevated both in RCC tumors and in plasma [134]. Serum IL-18 levels seem to correlate with tumor classification – patients with more advanced disease (grades 3 and 4) were found to have higher serum IL-18 levels than patients with less advanced tumors (grades 1 and 2) [139]. Chang et al. [136] demonstrated that IL-18 genotypes contribute to RCC. A survey was carried out on Taiwanese patients and suggested that genotypes may play a role in the etiology and development of RCC, thus becoming a biomarker for early recognition of RCC. Furthermore, parenchymal levels of myeloid-derived suppressor cells, a subtype of cells that are elevated in cancer patients, were shown to correlate with high levels of IL-18 [134].
IL-23
Interleukin-23 (IL-23) belongs to the IL-12 family, sharing receptors and ligand chains with IL-27 and IL-35 [38]. IL-23 is produced mainly by phagocytic cells and macrophages (M1 macrophages). IL-23 acts on Th17-cells and macrophages by stimulating the production of pro-inflammatory IL-17 and promoting the proliferation of memory T-cells [140].
Obstructive sleep apnea
The serum level of IL-23 was analyzed in a group of children with OSA by Huang et al. This cytokine was higher in the OSA group (14.58 ±0.75 pg/ml) than in controls (12.29 ±0.73 pg/ml), with statistical significance (p = 0.047) [32]. In another study, Cizza et al. analyzed serum levels of IL-23 in obese adults with OSA. The IL-23 concentration was 134.7 (95.2–204.2) pg/ml in the group without sleep apnea and 145.7 (123.9–187.2) pg/ml in the group with sleep apnea (p = 0.268) [24]. Treatment of OSA patients with CPAP reduced the IL-23 level significantly [141]. Huang et al. described plasma levels of inflammatory markers in children with OSA before and after adenotonsillectomy compared to healthy controls. The serum level of IL-23 was higher in the OSA group (20.14 ±7.08 pg/ml) than in the control group (12.29 ±3.66 pg/ml). Interestingly, surgical intervention increased the serum level of IL-23 serum (pre-operative 20.14 ±7.08 pg/ml vs. postoperative 24.32 ±6.51 pg/ml (p < 0.001)) in a group with AHI > 1 after surgery [31].
Renal cell carcinoma
As IL-23 is mainly generated by phagocytic cells and macrophages (M1 macrophages). Its role could be linked to inhibition of RCC, since progression and metastasis are mediated by M2 TAM macrophages infiltrating the microenvironment of RCC [142]. However, IL-23 also activates regulatory T-cell (Treg) proliferation. It promotes the expression of IL-10 and TGFβ expression in Tregs, which induces the suppression of cytotoxic lymphocyte activity [143].
For the TCGA and Shanghai cohorts of ccRCC, high expression of IL-23 was significantly associated with poor OS (HR = 2.04, 2.07, respectively) and CSS (HR = 2.95, HR = 3.92, respectively). In vitro IL-23 promotes T-cell-mediated cytotoxicity. In an animal model, IL-23 blockade prolongs the survival of RCC-bearing mice and increases the activity of anti-PD-1 therapy [143]. Therefore, IL-23 seems to be a promising target for immunotherapy in ccRCC [143].
IL-33
Fibroblasts, mast cells, dendritic cells, macrophages, osteoblasts, endothelial cells, and epithelial cells express interleukin-33 (IL-33). It belongs to the IL-1 family of cytokines [144]. Its biological function is based on activating the IL-33 receptor – ST2 (IL1RL1) associated with the Toll-like receptor superfamily. It stimulates Th cells, mast cells, eosinophils, and basophils to produce type-2 cytokines. Interestingly, it could act intracellularly as a nuclear factor and extracellularly as a cytokine.
Obstructive sleep apnea
Sozer et al. observed that IL-33 is one of the inflammatory mediators in patients with OSA and that its levels in blood serum were significantly elevated (5.8 (5.6–6.2) pg/ml) in comparison to healthy controls (5.48 (5.4–5.5) pg/ml) (p < 0.001) [145]. Furthermore, Nizam et al. analyzed inflammatory cytokines in saliva. They noted a significantly higher concentration of IL-33 in saliva from OSA patients (14.5 (2.3–25.2) ng/ml) in comparison to the control group (8.4 (2.2–14.3) ng/ml) (p < 0.05) [146]. Continuous positive airway pressure therapy for OSA patients reduced expression of IL-33 [147].
Renal cell carcinoma
IL-33 is involved in the pathogenesis of several cancers [148, 149]. However, its role seems complicated and could exert contradictory actions for tumor immune escape and survival [150]. The role of IL-33 in RCC is currently poorly understood. A single study by Wu et al. [144] addressed this issue. In that study, the authors found that high expression of the serum level of IL-33 in RCC was positively correlated with the stage of tumor lymph node metastasis (TNM). In a study of nephrectomy samples from 203 patients with ccRCC, high expression of IL-33 was significantly associated with the advanced stage of TNM stage (p = 0.017) and a higher Fuhrman grade (p < 0.001). IL-33 expression within the tumor was shown to be an independent negative OS prognostic factor in these patient [151].
Higher levels of IL-33 were also correlated with a poor prognosis. Researchers have observed that IL-33 enriches RCC cell growth in vivo and stimulates RCC cell proliferation, thus preventing chemotherapy-induced tumor apoptosis in vitro in 786-O RCC cells. IL-33 may stimulate the proliferation and resistance of RCC cells through its receptor, signaling ST2 and c-Jun N-terminal kinase (JNK) in tumor cells.
Other cytokines
Interleukin 3 (IL-3) and IL-5 and GM-CSF (granulocyte macrophage colony stimulating factor) were initially associated with hematopoiesis [58]. Furthermore, IL-5 and IL-3 are essential in the proliferation, differentiation, and stimulation of hematopoietic cells. The receptor for IL-3 – IL3-Rα – is expressed in granulocyte-monocyte progenitors, and at a minor level in common dendritic progenitors. The main sources of IL-3 are activated T-cells, monocytes/macrophages, and stromal cells during inflammation [152]. In the context of kidney cancer, it was demonstrated that IL-3 released by tumor-derived endothelial cells (TECs) (isolated from breast and kidney carcinomas) supports their autocrine growth and stimulates in vivo vessel formation and tumor angiogenesis [153]. In this case, both cell lines were derived from primary tumors: breast carcinoma cells were derived from a 48-year-old woman – T3bG2N0M0; renal carcinoma cells were derived from a 55-year-old man – T1bG2N0M0. The experiment consisted of primary renal carcinoma cells injected into mice with severe combined immunodeficiency in the presence/absence of a specific IL-3 neutralizing Ab, suggesting that targeting IL-3 affects tumor vessel formation and tumor growth. Furthermore, a study by Gerharz et al. [62] showed that, among 40 tes-ted RCC cell lines, 14 exhibited secretion of IL-3, although IL-5 and erythropoietin were not detected. However, we found no reports presenting data about the serum level of IL-3 in the OSA population. We also did not find data on OSA or RCC patients on IL-9, IL-11, IL-19, IL-20, IL-21 or IL-22 serum levels.
Discussion
An increasing number of studies have found an association between OSA and risk of developing certain types of cancer. The possible reasons for this link are still being investigated, but there are a few proposed mechanisms including generation of hypoxia. Obstructive sleep apnea involves repeated interruptions in breathing during sleep, leading to intermittent drops in blood oxygen levels, and chronic hypoxia may create a pro-inflammatory environment and oxidative stress, which could promote the development of cancerous cells. Renal cell carcinoma is one of the most studied cancers in terms of the role of OSA in carcinogenesis. It is the most common type of kidney cancer, accounting for around 90% of all kidney malignancies. The incidence of RCC in the United States is among the highest in the world, where it is the seventh leading cancer type in men. According to Siegel et al. (Cancer Statistics 2017), there are approximately 64 000 new cases yearly in the United States, with 14 000 deaths [154, 155]. A 2020 GLOBOCAN report stated that RCC accounts for up to 2.2% of all cancer cases, with more than 431 000 new patients diagnosed around the world every year [156]. Clear cell renal cell carcinoma is highly resistant to conventional chemotherapy with cytostatic agents. At the same time, metastatic disease is diagnosed in many patients. Between 18% and 30% of patients with RCC present with metastases at diagnosis (referred as to synchronous metastasis), and more than 50% patients will develop metastatic RCC after nephrectomy during a follow-up (metachronous metastasis) [157], with 85% of cases recurring within first three years after nephrectomy [158]. Renal cell carcinoma, particularly ccRCC, is closely associated with inflammation and cytokine activity, which play significant roles in tumor progression, metastasis, and immune evasion. Key mechanisms include cancer-cell-intrinsic inflammation, hypoxia and cytokine production, and the immune microenvironment. Inflammation contributes to RCC progression through multiple pathways, including oxidative stress, systemic inflammation, and immune escape. These processes not only enhance tumor growth and metastasis but also serve as important prognostic markers for patient outcomes [159].
A 2016 study by Gozal et al. showed a higher incidence of RCC among patients with OSA [160]. This was confirmed in another epidemiological study by Sillah et al. in 2018 [161]. In addition, among patients who undergo RCC surgery, a higher Fuhrman grade has been associated with OSA-positive individuals [162]. However, experimental data that would shed light on the molecular mechanisms of the possible link between OSA and RCC are very scarce. An experimental study suggested that OSA enhances angiogenesis in an animal model of RCC through VEGF overexpression [163].
Several studies have demonstrated that a significant number of interleukins (IL-1, IL-4, IL-6, IL-8, IL-17, IL-18, IL-23, IL-33) analyzed in renal cancer exhibit pro-tumorigenic properties, contributing to cancer progression. Multiple studies have confirmed their overexpression in OSA patients. Moreover, their high expression is associated with a worse prognosis in affected patients, correlating with increased tumor aggressiveness and decreased survival rates. Emerging evidence suggests that CPAP therapy in patients with OSA leads to a reduction in the levels of these interleukins, potentially mitigating the inflammatory and tumor-promoting environment. This observation highlights a possible indirect benefit of CPAP beyond respiratory function, warranting further investigation into its role in modulating systemic inflammation and its impact on cancer prognosis.
A cancer-protective effect of CPAP was analyzed in two studies. A study published in the European Respiratory Journal investigated cancer incidence in patients with OSA based on their adherence to CPAP therapy. Among 4,499 patients studied, 9.7% developed cancer over a median follow-up of 5.4 years. While there was a slightly higher incidence of cancer among non-adherent patients, the study did not find a statistically significant reduction in overall cancer incidence with CPAP therapy. However, trends suggest that adherence may have a protective effect, particularly against lung cancer and in patients with more severe nocturnal hypoxia [164]. A prospective multicenter study by Gomez-Olivas et al. was performed on 443 patients diagnosed with cutaneous melanoma. Having a median follow-up of 60 months, they confirmed that CPAP is associated with improved melanoma outcomes compared with untreated moderate to severe OSA [165].
Conclusions
This review highlights the significantly elevated levels of pro-cancerogenic interleukins in patients with obstructive sleep apnea, suggesting a potential link between OSA and renal cell carcinoma. The findings emphasize that these inflammatory markers, including IL-1, IL-6, IL-8, and IL-17, are more pronounced in OSA patients, which may contribute to cancer progression. Importantly, CPAP therapy has been shown to reduce these interleukin levels, indicating its potential role in mitigating inflammation and possibly improving RCC prognosis in OSA patients. Therefore, CPAP could serve as a valuable adjuvant treatment in patients with both OSA and RCC, helping to reduce systemic inflammation and its associated oncogenic effects. Further research is needed to clarify the long-term benefits of CPAP in reducing cancer-related inflammatory markers and improving outcomes in RCC patients with coexisting OSA.
