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. 2018 Nov 22;2(2):e1151. doi: 10.1002/cnr2.1151

IL‐37: An anti‐inflammatory cytokine with antitumor functions

Yu Mei 1, Haiyan Liu 1,✉
PMCID: PMC7941439  PMID: 32935478

Abstract

Background

IL‐37 is a newly identified IL‐1 family cytokine. Unlike other members in IL‐1 family, IL‐37 has been demonstrated to be an anti‐inflammatory cytokine in many inflammatory and autoimmune diseases. IL‐37 is regarded as a dual‐function cytokine as both the extracellular and intracellular IL‐37 are biologically functional. Extracellular IL‐37 can bind to IL‐18Rα and IL‐1R8 to form a triple complex, regulating the downstream STAT3 and PTEN signaling. Intracellular IL‐37 can interact with Smad3, translocate into nucleus, and regulate downstream target gene expressions. Recently, the role of IL‐37 in tumor development has been extensively studied.

Recent findings

IL‐37 has been found to play an antitumor role in various types of tumors, such as non‐small cell lung cancer, hepatocellular carcinoma, and renal cell carcinoma. Many mechanism studies have been carried out to elaborate the possible effects of IL‐37 on tumor growth, immune responses, and tumor angiogenesis. More importantly, the function of IL‐37 may be dependent on its concentration and receptor expression. It can form dimers at high concentrations to be inactivated, thus inhibiting its anti‐inflammatory function. We focused on the role of IL‐37 in various tumor types and provided the hypothesis regarding the underlying mechanisms.

Conclusion

IL‐37 may affect tumor development through multiple mechanisms: (1) IL‐37 directly influences tumor cell viability; (2) IL‐37 regulates the immune response to promote the antitumor immunity; and (3) IL‐37 suppresses tumor angiogenesis in the tumor microenvironment. Future studies are warranted to further investigate the mechanisms of these multifaceted functions of IL‐37 in animal models and cancer patients.

Keywords: angiogenesis, antitumor immune response, IL‐37, inflammation

1. IL‐37 BIOLOGY

IL‐37 was identified by three independent groups in the early 21st century.1, 2, 3 IL‐37 has five transcriptional variants due to alternative splicing (IL‐37a‐IL‐37e) as listed in Table 1. Similar to the other members of IL‐1 family, IL‐37 is located on chromosome 2 and is composed of 12 β strands,4 which is closely related to IL‐18 structurally5, 6 and IL‐36 phylogenetically.7 Recently, IL‐37b has been proved to form head‐to‐head symmetrical homodimer with nanomolar affinity.8 However, the function of each isoform is still not clear. Up to now, IL‐37b is the only isoform that has been extensively studied. Therefore, the current review will mainly focus on IL‐37b.

Table 1.

Different isoforms of IL‐37

Isoform Exons Protein Size
IL‐37a Exons 3, 4, 5, 6 192aa
IL‐37b Exons 1, 2, 4, 5, 6 218aa
IL‐37c Exons 1, 2, 5, 6 178aa
IL‐37d Exons 1, 4, 5, 6 197aa
IL‐37e Exons 1, 5, 6 157aa
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Like other members in IL‐1 family, IL‐37 can be cleaved and processed before maturation. The IL‐37 exon 1 encodes a caspase‐1 cleavage site and can be cleaved into the mature form of IL‐37. Both the precursor and mature forms can be released during cell death. However, the detailed mechanism of IL‐37 secretion is still unclear.

Precursor IL‐37b can be cleaved to form mature IL‐37. Similar to some members of IL‐1 family, both the precursor and mature IL‐37 are biologically active. Intracellular IL‐37 precursor can be cleaved by caspase‐1 at D20 site. While extracellular IL‐37 precursor can also be cleaved at the same site, the extracellular protease for IL‐37 cleavage is still unknown.9 Notably, IL‐37 has not been discovered in mouse despite exon 1 found to be located in murine chromosome; however, no ORF was presented.10 Interestingly, human IL‐37 is still biologically functional on murine cells and in murine disease models,4, 11, 12 indicating that there is a high possibility that IL‐37 was present in ancient mouse but lost the expression during evolution for unknown reasons.

2. IL‐37 RECEPTOR AND SIGNALING

IL‐37 shares similar structure with IL‐18 and can bind to IL‐18 receptor alpha chain (IL‐18Rα).3 IL‐18 is an inflammatory cytokine which plays a crucial role in the differentiation and proliferation of T cells.13 After IL‐18 binds to its IL‐18Rα, the coreceptor IL‐18R beta chain (IL‐18Rβ) will be recruited and form the IL‐18/IL‐18Rα/IL‐18Rβ complex. After the formation of IL‐18/IL‐18Rα/IL‐18Rβ complex, the Toll‐IL‐1 receptor (TIR) domains approximate, triggering the inflammation signal through the molecule myeloid differentiation factor 88 (MyD88) adaptor protein.14 IL‐18 binding protein (IL‐18bp), a secretion protein with a high affinity for IL‐18, can bind to IL‐18 to prevent the binding of IL‐18 to its receptor, thus inhibiting the inflammation induced by IL‐18 signaling.15, 16

IL‐37 is expressed by various cells such as macrophages, epithelial cells, and PBMCs. Immunofluorescence microscopy shows that IL‐37 is located both in the cytoplasm and in the nucleus.4 Thus, IL‐37 is regarded as a dual‐function cytokine.10 Both IL‐37 precursor and mature forms can be released into extracellular space and bind to its receptor IL‐18Rα; then, coreceptor IL‐1R8 (TIR8/SIGIRR) is recruited to form the IL‐37‐IL‐18Rα‐IL‐1R8 complex.17 It is not surprising that IL‐37 can bind to IL‐18Rα because IL‐37 shares similar protein structure with IL‐18. However, the affinity of IL‐37 to IL‐18Rα is 50 times lower compared with IL‐18.5 IL‐1R8 is expressed by various cell types, including epithelial cells, macrophages, DCs, and T cells, and can inhibit both innate and adaptive immune responses.18, 19 IL‐37 is the first ligand identified to interact with IL‐1R8. After the IL‐37‐IL‐18Rα‐IL‐1R8 triple complex formation, the downstream STAT3 and PTEN signaling will be activated (Figure 1).17 STAT3 activation can promote the polarization of macrophages and DCs from proinflammatory state to anti‐inflammatory or tolerate state,20, 21 while PTEN activation can inhibit inflammation through inhibiting NK‐κB transcription by blocking PI3K/Akt/mTOR signaling pathway.22, 23 Furthermore, IL‐37 can bind to IL‐18bp to form a complex with IL‐18Rβ; this complex will reduce the recruitment of IL‐18Rβ to IL‐18Rα upon IL‐18 binding, thus blocking the IL‐18–induced inflammation.5

Figure 1.

Figure 1

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IL‐37 signaling pathways. IL‐37 is a dual‐function cytokine. Extracellular IL‐37 binds to its receptor IL‐18Rα, recruiting the coreceptor IL‐1R8 to form the IL‐37/IL‐18Rα/IL‐1R8 complex. Intracellular IL‐37 can bind to p‐Smad3 and translocate into the nucleus to regulate the downstream signaling. Intracellular IL‐37 can also bind to the HVR domain of Rac1, inhibiting Rac1 migrating to the membrane. These processes result in the activation and/or inhibition of downstream signaling pathways, thus exerting the anti‐inflammation function of IL‐37

Acting as a dual‐function cytokine, intracellular IL‐37 can regulate cellular behavior. Overexpression of IL‐37 in human hepatocellular carcinoma (HCC) cell lines HepG2 and SMMC‐7721 significantly suppressed HCC cell growth and proliferation through converting Smad3 phospho‐isoform.24 Intracellular mature IL‐37 can directly bind to Rac1 and subsequently suppress the migration ability of A549 and BEL‐7402 cell.25 In addition, intracellular IL‐37 can bind to Smad3 and regulate immune responses.4 Smad3 is the transcription factor triggered by TGF‐β signaling.26 After phosphorylation, Smad2, Smad3, and Smad4 would form the Smad2/3/4 complex, translocate into the nucleus, and affect the downstream gene expression, such as FOXA2, S100A2, RRAS, MYO1D, SERPLNE1, and TAGLN.27, 28, 29, 30, 31 Intracellular IL‐37 can compete with Smad2 and Smad4 for binding to Smad3; IL‐37/smad3 complex can then translocate into nucleus and upregulate the PTPN gene expression.32 Silencing of Smad3 could diminish the anti‐inflammatory function of intracellular IL‐37, suggesting an important role of Smad3 in regulating intracellular IL‐37 function.4 Taken together, both extracellular and intracellular IL‐37 are functional in conveying the biological function of IL‐37.

3. ANTI‐INFLAMMATORY FUNCTION OF IL‐37

The concentration of IL‐37 in human peripheral blood is quite low due to the short half‐life of IL‐37 mRNA.33 During inflammatory conditions, such as systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease,34, 35, 36 the expression of IL‐37 was found to be increased. Many studies have proven that IL‐37 is an important anti‐inflammatory cytokine involved in various inflammatory diseases. IL‐37 treatment could inhibit the LPS‐induced IL‐1, IL‐6, and TNF‐α expression by macrophages.37 In murine Aspergillus fumigatus infection and asthma models, recombinant IL‐37 injection could reduce the proinflammatory cytokine expression and alleviate inflammation severity.12, 38 The role of IL‐37 in inflammatory diseases was further described in IL‐37 transgenic mice. In DSS‐induced colitis model, aging‐induced inflammation model, spinal cord injury model, ConA‐induced hepatitis model, influenza infection model, leukemogenesis in aged mice, pulmonary aspergillosis model, and acute myocardial infraction model, IL‐37 transgenic mice exhibited less inflammation and better outcomes of the diseases.11, 12, 39, 40, 41, 42, 43

4. IL‐37 IN TUMOR

It has been well established that inflammation is closely related to carcinogenesis.44, 45 As an anti‐inflammatory cytokine, many studies have suggested the antitumor role of IL‐37 in various tumor types, which have been reviewed previously.46, 47 Here, we will describe the most recent progress for the role of IL‐37 in fibrosarcoma, breast cancer, lung cancer, ovarian cancer, renal cell carcinoma (RCC), oral squamous cell carcinoma (OSCC), cervical cancer, colon cancer, multiple myeloma (MM), prostate cancer, and HCC. We will also discuss in details about the recent studies on the immune regulatory function of IL‐37 in antitumor immune response, as well as its role in angiogenesis.

4.1. Fibrosarcoma

Three years after the discovery of IL‐37, the first study of IL‐37 on tumor growth was published.48 Gao et al generated the recombinant adenovirus expressing IL‐37 (AdIL‐37) and injected the virus intratumorally in a mouse subcutaneous fibrosarcoma model. They observed a reduction in tumor growth after a single dose of injection. This result indicated an antitumor function of IL‐37. In addition, multiple injections of AdIL‐37 showed further antitumor activity and resistance to tumor rechallenge, demonstrating that the acquired antitumor immunity was established. Moreover, AdIL‐37 injection failed to inhibit fibrosarcoma growth in NOD‐SCID mice, indicating that the antitumor activity mediated by AdIL‐37 was T and/or B cell dependent. The antitumor activity was also abrogated in mice lacking IFN‐γ, IL‐12, or FasL. This early finding suggested that IL‐37 could activate adaptive antitumor immune response.

4.2. Breast cancer

IL‐37 has been found to be elevated in the breast carcinoma tissues compared with the normal breast tissue, indicating that IL‐37 may play a role during breast carcinoma development.49 Wang et al found that IL‐37 significantly suppressed 4T1 breast cancer growth in Balb/c mice. However, this antitumor activity was totally abolished in NOD/SCID mice, indicating that IL‐37 inhibited 4T1 tumor growth through modulating immune response. In vitro studies further proved that rhIL‐37 directly promote CD4+ T‐cell proliferation. These results suggested an antitumor role of IL‐37 in breast cancer, probably through activating T‐cell responses.50

4.3. Lung cancer

Non‐small cell lung cancer (NSCLC), which accounts for 80% to 85% of all lung cancer types, is the most common cause of tumor‐related mortality in the world.51 Ge et al found that both mRNA and protein expression levels of IL‐37 in the NSCLC tissues were decreased compared with the corresponding normal tissues.52 Further analysis showed that IL‐37 expression level in the tumor tissue was a prognostic factor for patient overall survival (OS); low IL‐37 expression was significantly associated with advanced tumor status and TNM stage. In the same study, they found no direct effect of IL‐37 on proliferation and apoptosis of H1299 and A549 lung cancer cells. However, another recent study showed decreased proliferation of A549 cells when IL‐37 was overexpressed.53 Furthermore, cotransfection of CCL22 and IL‐37 could further lower the proliferation rate and inhibit the epithelial‐mesenchymal transition (EMT) of A549 cells. Similarly, Jiang et al found that serum IL‐37 level was decreased in NSCLC patients compared with healthy control. This low IL‐37 expression level was significantly associated with advanced TNM stage.54

A significant decrease in tumor growth was observed with IL‐37 overexpression in a murine NSCLC model.52 Tumor angiogenesis plays a crucial role for carcinogenesis and metastasis in NSCLC.55, 56 In vitro study utilizing the supernatant of IL‐37–overexpressing H1299 cells showed that IL‐37 could dramatically inhibit HUVEC proliferation and tube formation.52, 55 Indeed, decreased IL‐37 expression in the tumor tissue was associated with high microvessel density (MVD) in NSCLC patients. These results demonstrated that the antitumor role of IL‐37 in NSCLC development could be through inhibiting tumor angiogenesis. However, some studies have suggested IL‐37 as a proangiogenic factor,57, 58 which needs further investigation.

Two recent studies demonstrated the role of IL‐37 in human and murine lung adenocarcinoma. In human lung adenocarcinoma patients, decreased IL‐37 expression was correlated with tumor metastasis and poor prognosis.25 They also proved that the intracellular mature form of IL‐37, not the precursor IL‐37, could inhibit Rac1 activation and subsequent downstream signaling by binding to the CAAX motif of Rac1. As a member of Rho GTPase family, Rac1 signaling activation was proved to promote tumorigenesis in various tumor types.59, 60, 61 In nude mice xenografted with A549 lung adenocarcinoma, IL‐37 significantly suppressed the tumor growth. In vitro assay proved that IL‐37 could directly inhibit A549 cell viability as well as reduce the chemotaxis of Treg cells.62 Thus, IL‐37 may be served as a novel antitumor agent for lung adenocarcinoma.

4.4. Ovarian cancer

Huo et al reported that serum IL‐37 level in epithelial ovarian cancer (EOC) patients was significantly higher than that in healthy donors.63 High serum IL‐37 level was associated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, bigger tumor size, more lymph node metastasis, and bigger residual tumor size. They concluded that serum IL‐37 level was an independent prognostic factor for EOC patients. However, the mechanism for IL‐37 influencing EOC development is not known.

4.5. Renal cell carcinoma

Serum IL‐37 level was decreased in RCC patients and negatively associated with RCC progression.64 Further studies showed that IL‐37 could sufficiently inhibit RCC cell proliferation and migration while promoting apoptosis. Overexpression of IL‐6 in RCC cell lines could restore the function of IL‐37, suggesting that IL‐37 may function through IL‐6/STAT3 axis. IL‐6/STAT3 axis activation was reported to be responsible for HIF‐1α expression, which was crucial for hypoxia‐induced tumor angiogenesis.65 As expected, HIF‐1α expression in RCC cell lines was decreased with IL‐37 treatment. IL‐37 administration significantly inhibited RCC tumor growth in SCID mice. However, the survival rate showed no significant difference in the same model.

4.6. Oral squamous cell carcinoma

OSCC was one of the most common malignancies worldwide with low survival rate and high mortality.66 Lin et al investigated the role of IL‐37 in OSCC patients and found that IL‐37 expression was increased in pathologically changed tissues during the oral mucosa cancerous process.67 Low IL‐37 expression level in OSCC patients was associated with high lymph node metastasis. In vitro experiments suggested that IL‐37 could modulate RAW264.7 macrophage polarization through downregulating inflammatory cytokine expressions, which could contribute to its antitumor effect.

4.7. Cervical cancer

Cervical cancer is the second common cancer and the fifth leading cause of cancer death in women.68 Wang et al reported that IL‐37 overexpression suppressed the proliferation and invasion of cervical cancer cell lines, Hela and C33A, through downregulating STAT3 expression and phosphorylation.69 Upregulation of STAT3 could restore the cell proliferation and inflammatory cytokine expressions. These results indicated a direct role of IL‐37 on cervical cancer cell lines. However, no clinical data or animal model results have been reported to support the antitumor effect of IL‐37 during cervical cancer development.

4.8. Colon cancer

The occurrence of colon cancer is closely associated with inflammation.51 As an anti‐inflammatory cytokine, IL‐37 was investigated in colon cancer.70 The clinical data showed that IL‐37 expression was lower in tumor tissues compared with its paired adjacent noncancerous tissues. Lack of IL‐37 expression in tumor tissues was related to the advanced American Joint Committee on Cancer (AJCC) stage, more invasion, and metastasis. They found that colon cancer patients with IL‐37 expression had higher rates of disease‐free survival (DFS) and OS compared with those lacking IL‐37 expression. Furthermore, the deficiency of IL‐37 expression was proved to be an independent prognostic marker for colon cancer recurrence. In vitro treatment of IL‐37 inhibited proliferation, invasion, and migration and induced apoptosis of colon cancer cell lines, DLD1 and HT‐29. Colon cancer development was closely related with beta‐catenin signal activation.71 IL‐37 treatment could reduce beta‐catenin expression in DLD1 and HT‐29 cells. This finding indicated that IL‐37 might inhibit colon cancer development through suppressing beta‐catenin pathway. Moreover, IL‐37 suppressed colon cancer growth in a murine model, and the expression of beta‐catenin from isolated tumor cells was downregulated in IL‐37–treated mice. These results demonstrated the antitumor role of IL‐37 in colon cancer through beta‐catenin inhibition.

4.9. Multiple myeloma

MM is characterized by abnormal expansion of malignant plasma cells in the bone marrow, and it is closely associated with inflammation and angiogenesis.72, 73 IL‐37 expression was found to be lower in MM patients compared with healthy donors.74 Moreover, IL‐37 expression level is negatively associated with Ang‐2 and VEGF levels. Ang‐2 and VEGF are important angiogenesis factors during lymphatic and blood vessel formation.75 Therefore, IL‐37 might decrease the proangiogenetic factors VEGF and Ang‐2 expression through unknown mechanism, which may result in impaired tumor angiogenesis and delayed tumor growth. In summary, IL‐37 could serve as a biomarker for the disease stage and angiogenesis processes in MM patients.

4.10. Prostate cancer

Prostate cancer is the most common noncutaneous cancer in men in the United States.76 Radiation therapy is the standard treatment for prostate cancer patients. However, prostate cancer cells can be radioresistant in most cases77; thus, there is a strong need in finding a radiosensitizing agent for prostate cancer radiotherapy. One study found that although IL‐37 had little direct effects on the viability of prostate cancer cells, it could increase their radiosensitivity by upregulating the expression of p27, Fas, and bax and downregulating the expression of cdk2.78 This study suggested IL‐37 as a promising radiosensitizing agent for prostate cancer therapy.

4.11. Hepatocellular carcinoma

HCC is the fifth most common liver malignancy and the third leading cause of cancer‐related death worldwide.79 Numerous studies have proved a critical role of inflammation in liver carcinogenesis.80, 81 HCC has been the most well‐studied cancer type regarding the role of IL‐37, so far all pointing to an antitumor effect of IL‐37 during HCC development.

One study described a decreased expression of IL‐37 in the HCC tumor tissues compared with the normal liver tissues and adjacent nontumor tissues.82 IL‐37 expression level was negatively associated with the tumor size. High intratumoral IL‐37 expression was linked to better DFS and OS in HCC patients. Multivariate analyses showed that IL‐37 was an independent risk factor, indicating that the IL‐37 expression level could potentially serve as a valuable prognostic marker for HCC. Moreover, intratumoral IL‐37 expression was positively related to NK‐cell infiltration in the tumor tissue, which was also significantly associated with better OS in HCC patients. Overexpression of IL‐37 significantly inhibited tumor growth with increased NK‐cell infiltration in a murine subcutaneous HCC model. Therefore, these results suggested that IL‐37 might be a valuable prognostic marker as well as a therapeutic candidate for HCC.

Another study mainly focused on the direct effect of IL‐37 on hepatocarcinogenesis.24 They observed a reduction of IL‐37 expression in the tumor area. They also found that intratumoral IL‐37 expression was negatively related with Barcelona Clinic Liver Cancer (BCLC) stage and microvascular invasion. Kaplan‐Meier analysis showed that HCC patients with low IL‐37 expression had worse prognosis than those with high IL‐37 expression. Cox multivariate analyses indicated that IL‐37 was an independent risk factor for HCC prognosis. The in vitro results indicated that IL‐37 suppressed HCC cell proliferation, colony formation, and arrested cell cycle by regulating the G2/M checkpoint proteins and c‐Myc expression. Further study showed that the antitumor effect of IL‐37 was due to the conversion of Smad3 phosphorylation isoforms from JNK/pSmad3L/c‐Myc oncogenic signaling to pSmad3C/p21 tumor‐suppressive signaling. These results demonstrated that IL‐37 could directly influence tumor cell viability to inhibit HCC development.

Autophagy was a self‐eating process that was responsible for cellular homeostasis.83 Recent studies also demonstrated that autophagy was involved in inflammatory diseases as well as cancers.84 Autophagy played a dual role in the development of HCC by suppressing tumor initiation and promoting subsequent tumor growth.85 Recently, Li et al reported that IL‐37 treatment could induce the production of autophagosomes and apoptosis in HCC cell lines.86 Further study showed that IL‐37 triggered HCC cell autophagy by inhibiting PI3K/AKT/mTOR signaling pathway. Therefore, IL‐37 could directly influence HCC cell viability by triggering autophagy and apoptosis through inhibiting PI3K/AKT/mTOR signaling pathway. Taken together, these studies suggested that IL‐37 could inhibit HCC development through both direct effects on HCC cell viability and promoting antitumor immune response.

5. MECHANISMS INVOLVED IN IL‐37 ANTITUMOR EFFECTS AND FUTURE PERSPECTIVES

All published studies so far have suggested an antitumor role of IL‐37 in various tumor types except for ovarian cancer. As an anti‐inflammatory cytokine, IL‐37 may affect tumor development through multiple mechanisms. By reviewing the published studies, we propose three aspects of IL‐37's function that may be involved in its role of tumor inhibition.

5.1. The direct effect of IL‐37 on tumor cells

IL‐37 can directly inhibit tumor cell growth and/or induce apoptosis. IL‐37 treatment could significantly reduce tumor cell viability in human NSCLC, renal carcinoma, cervical cancer, colon cancer, and HCC cells.24, 25, 53, 62, 64, 69, 70, 86 The mechanism may vary in different cancer types. IL‐37 could regulate STAT3 expression and activation to suppress NSCLC and cervical cancer cell growth,53 while inhibiting HCC cell expansion by changing the Smad3 phosphorylation isoforms from JNK/pSmad3L/c‐Myc oncogenic signaling to pSmad3C/p21 tumor‐suppressive signaling24 or inducing autophagy by inhibiting the PI3K/AKT/mTOR pathway86 as well as suppressing lung cancer cell proliferation by inhibiting Rac1 signaling.25 However, IL‐37 had no direct effect on fibrosarcoma tumor cell growth.48 Therefore, IL‐37 could directly inhibit tumor cell growth in most cancer types through various mechanisms, which could be related to the different carcinogenesis pathways involved in those tumors. It is still unclear, in the tumor microenvironment, which types of cells are the dominant source of IL‐37. As IL‐37 could be produced by many types of cells, including epithelial cells, macrophages, DCs, NK cells, and B cells. One possible source is tumor‐derived IL‐37. Extracellular IL‐37 expressed by tumor cells could not only inhibit tumor growth but also have regulatory effects on immune cells and endothelial cells in the tumor microenvironment. More importantly, intracellular IL‐37 produced and processed inside tumor cells could further inhibit tumor growth by inhibiting Rac1 activation.25 Therefore, tumor‐derived IL‐37 could have potent antitumor effects.

Although the expression of IL‐37 in tumor or serum was upregulated in many cancers, including breast cancer,49 ovarian cancer,63 and OSCC,67 it was shown to be downregulated in NSCLS,52 renal cell carcinoma,64 colon cancer,70 MM,74 and HCC.24 The IL‐37 serum levels in RCC and MM patients were significantly lower compared with those in healthy controls; the IL‐37 expression levels in tumor tissues were decreased compared with noncancerous tissues in NSCLS, colon cancer, and HCC patients. This downregulation of IL‐37 in cancer patients could be a possible mechanism for cancer cells to evade the antitumor activity of IL‐37. Different expression levels of IL‐37 may have different effect on tumor progression in the tumor microenvironment. As reported, IL‐37 was more active at low concentrations as IL‐37 could form dimers to be inactive at high concentrations.8 On the other hand, the expression levels of IL‐37 receptors IL‐18Rα and IL‐1R8 were also important when one try to interpret the role of IL‐37 in vivo. Recent evidences have suggested that IL‐1R8 is a crucial checkpoint molecular in NK cells in antitumor immunity.87 Both IL‐37 and IL‐18Rα expressions in the tumor were upregulated in OSCC patients, indicating that IL‐37 and its receptor had similar expression pattern in cancer.67 The expression of IL‐1R8 in colon cancer was downregulated due to exon 8 skipping,88 which was consistent with the finding that IL‐37 level was decreased in the tumor of colon cancer patients.70 The expression of IL‐1R8 was also downregulated in chronic lymphocytic leukemia.89 However, the IL‐1R8 expression level in other cancer types is still not clear. It would be interesting to investigate the IL‐1R8 expressions in various cancer types as downregulation of IL‐1R8 expression might serve as another possible mechanism for cancer cells to evade the IL‐37–mediated antitumor activity. Although IL‐37 could directly inhibit tumor cell growth, this direct inhibition was diminished in immune‐incompetent nude and SCID mice in murine fibrosarcoma and breast cancer models.48, 50 These findings may lead to an unexpected fact that the in vitro direct effect of IL‐37 on tumor cell growth may not be sufficient for its antitumor role in vivo.

5.2. The immune regulatory role of IL‐37 in the tumor microenvironment

IL‐37 can regulate immune system to promote the antitumor immunity. IL‐37 could inhibit fibrosarcoma development in an IFN‐γ, IL‐12, and FasL‐dependent way indicating an essential role of immune system in IL‐37–mediated antitumor effect.48 Moreover, IL‐37 protected hosts against fibrosarcoma rechallenge, suggesting a memory immune response. In murine subcutaneous HCC model, IL‐37 could facilitate the recruitment of NK cells to the tumor site.82 In murine breast cancer model, the antitumor activity of IL‐37 was abrogated in nude and SCID mice.50 Although the evidence is still quite limited, IL‐37 could exert its antitumor function through promoting antitumor immune response. IL‐37 has been shown to promote CD4+ T‐cell proliferation in vitro, indicating that IL‐37 might enhance antitumor T‐cell response.50 Although IL‐37 has been reported to drive the Treg‐mediated suppression of canonical NK cells,90 it could also recruit NK cells to the tumor microenvironment in murine HCC model, which was further confirmed by the positive correlation between intratumoral IL‐37 level and NK‐cell infiltration, as well as its antitumor function.82 As an anti‐inflammatory cytokine, IL‐37 has been shown to affect DC function to inhibit adaptive immune response.4, 91, 92, 93 One hypothesis is that IL‐37 inhibits protumor inflammation that releases the immune suppression in the tumor microenvironment, therefore activating antitumor adaptive immune response. The other possible mechanism is that IL‐37 may function differentially on DCs in different immune environment. It may inhibit DC function in inflammatory models, while promoting DC function in tumor settings. Another possibility might be determined by the concentration of IL‐37 in the tumor microenvironments. Monomeric IL‐37 has enhanced anti‐inflammatory activity as IL‐37 could form dimers at high concentrations. Surprisingly, the anti‐inflammatory activity was inverted when the concentration of IL‐37 reached 100 ng/mL.8 This switch from anti‐inflammatory cytokine to proinflammatory cytokine might explain the immune‐promoting role of IL‐37 in certain cancers. Nevertheless, further investigations are needed to understand the immune regulatory role of IL‐37.

5.3. The proangiogenesis and antiangiogenesis role of IL‐37

The role of IL‐37 in angiogenesis varies in different disease models. In 2015, Yang et al reported the proangiogenic function of IL‐37 in both pathological and physiological settings.57 They found that IL‐37 secretion by endothelial cells was increased under hypoxia conditions. Furthermore, IL‐37 could promote the endothelial cell proliferation, migration, tube formation, ex vivo sprouting of aortae, and in vivo angiogenesis process. Activation of ERK1/2 and AKT signaling pathways is crucial for the proliferation, survival, and migration of endothelial cells induced by IL‐37. Moreover, this proangiogenic effect was not influenced when IL‐1R8 or IL‐18Rα were neutralized, indicating that other unknown receptors are involved in this process. Two years later, the same research group identified this unknown receptor as ALK1 receptor complex.58 They found that TGF‐β may act as the bridging molecular that mediates IL‐37 binding to the TGF‐β receptor complex, thus promoting the angiogenesis process.

However, there are also reports of the antiangiogenesis function of IL‐37 in tumor models. Ge et al found decreased microvessel density and VEGF levels in IL‐37‐expressing tumors, indicating an antiangiogenetic role of IL‐37 during tumor development. Furthermore, HUVECs treated with supernatant from IL‐37–transfected H1299 cells showed impaired cell viability and capillary structure formation capacity.52 Li et al also reported that serum IL‐37 level had a negative correlation with VEGF and Ang‐2 levels. More interestingly, the tube formation of HUVECs was suppressed by rhIL‐37 pretreatment.74

The possible mechanism of these contradictory findings might be (1) the concentration of IL‐37. IL‐37 is more active at low concentrations as IL‐37 could form dimers at high concentrations. Yang et al reported that IL‐37 promoted HUVEC tube formation at relatively low concentration (1‐10 ng/mL), while the tube formation suppression reported by Li et al applied 100 ng/mL IL‐37 in the same experiment; (2) the direct and indirect function of IL‐37. Low‐level rhIL‐37 had a direct proangiogenetic function on HUVECs. However, when treated HUVECs with supernatant from IL‐37–overexpressing tumor cells, this proangiogenetic function switched to the antiangiogenetic function. This switch might be due to the indirect function of IL‐37 on endothelial cells. Various tumor cells express angiogenesis factor to favor their growth and metastasis. IL‐37 treatment inhibited tumor cells from producing such factors, such as VEGF, HIF‐1α, and IL‐6.64 This suppression may overcome the direct proangiogenetic function of IL‐37; thus, the overall effect of IL‐37 is antiangiogenesis in the tumor microenvironment.

Taken together, IL‐37 has been shown to be a potential prognosis factor in many types of cancers. Current clinical and animal studies all suggest an antitumor role for IL‐37. However, the detailed mechanisms for its antitumor activity could be tumor‐specific and are still not known. It may function directly on tumor cells to inhibit their growth, promote antitumor immune response, as well as inhibit angiogenesis (Figure 2). Therefore, IL‐37 is a promising candidate for cancer prognosis and therapy. More investigations are needed to elucidate the exact role of IL‐37 in various tumor types and the detailed underlying mechanisms.

Figure 2.

Figure 2

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Possible mechanisms of the antitumor activity by IL‐37. IL‐37 inhibits tumor development through multiple mechanisms. (1) IL‐37 directly inhibits tumor cell growth and/or induces apoptosis. IL‐37 can regulate the STAT3 expression, convert Smad3 phospho‐isoform, and inhibit Rac1 signaling to directly affect the tumor cell viability. (2) IL‐37 can promote the antitumor immune response and probably inhibit the tumor‐promoting inflammation. IL‐37 can regulate T‐ and NK‐cell function in tumor‐bearing mice to promote the antitumor immunity; meanwhile, IL‐37 could probably suppress the tumor‐promoting inflammation by regulating the macrophage and DC function. (3) IL‐37 can inhibit tumor growth by suppressing the tumor angiogenesis. IL‐37 can inhibit tumor angiogenesis by downregulating the proangiogenesis factor HIF‐1, VEGF, and Ang‐2 expression in the tumor microenvironment

CONFLICT OF INTEREST

Authors declare no conflict of interest.

AUTHORS' CONTRIBUTION

All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, Y.M., H.Y.L.; Methodology, Y.M., H.Y.L.; Investigation, Y.M., H.Y.L.; Formal Analysis, Y.M., H.Y.L.; Resources, Y.M., H.Y.L.; Writing ‐ Original Draft, Y.M.; Writing ‐ Review & Editing, H.Y.L.; Visualization, Y.M., H.Y.L.; Supervision, H.Y.L.; Funding Acquisition, H.Y.L.

ACKNOWLEDGMENTS

The work has been supported by a Singapore Ministry of Education Tier II grant (MOE2018‐T2‐1‐072) and a start‐up grant from the National University of Singapore.

Mei Y, Liu H. IL‐37: An anti‐inflammatory cytokine with antitumor functions. Cancer Reports. 2019;2:e1151. 10.1002/cnr2.1151

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