Interleukin-37 suppresses tumor growth through inhibition of angiogenesis in non-small cell lung cancer.

Guanqun Ge,Yize Li,Yan Chen,Aiqin Wang,Yan Xue,Jingyue Yang,Jin Yang

doi:10.1186/s13046-016-0293-3

Abstract

BackgroundInterleukin-37 (IL-37), a newly identified member of the IL-1 family, has been known to play an immunosuppressive role in a variety of inflammatory disorders, but whether it participates in the regulation of pathogenesis of non-small cell lung cancer (NSCLC) has not been investigated.MethodsReal-time polymerase chain reaction (PCR), western blotting, and immunohistochemical staining were employed to detect IL-37 expression in NSCLC tissues and corresponding adjacent tissues. The correlations between IL-37 expression and clinicopathological characteristics, prognosis were analyzed. Stable clone with overexpression of IL-37 was generated in H1299 cell lines. Cell growth, cell cycle and cell apoptosis assays were carried out for detecting proliferation and apoptosis of H1299 cells. The effects of IL-37 on NSCLC progression in vivo was performed in a xenografted lung tumor model in nude mice. The concentrations of IL-37 and VEGF in the s growth medium supernatants were quantified by ELISA. The antiangiogenic effect of IL-37 on HUVEC was measured by tube formation assay.ResultsIL-37 mRNA and protein expressions were significantly decreased in NSCLC tissues, and decreased intratumoral IL-37 expression was significantly associated with tumor state, TNM stage and poor prognosis in NSCLC patients. In addition, intratumoral IL-37 expression was an independent prognostic factors for Overall survival (hazard ratio = 2.047; P = 0.011). Overexpression of IL-37 exerted no direct effect on cell proliferation and apoptosis of H1299 lung cancer cells in vitro, but significantly inhibited tumor growth in a H1299 xenograft model in vivo. Furthermore, there was no significant change in immune cell infiltration in IL-37 over-expressing tumors; instead, we found decreased microvessel density (MVD) and VEGF levels in IL-37-expressing tumors. Additional studies showed IL-37 could directly inhibit HUVEC cells growth and capillary structure formation. Finally, we found that decreased IL-37 expression was associated with high MVD in NSCLC patients.ConclusionsOur findings demonstrate a protective role for IL-37 in lung cancer development, possibly through inhibiting tumor angiogenesis. IL-37 could serve as a promising therapeutic target for NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0293-3) contains supplementary material, which is available to authorized users.

Highlights

Interleukin-37 (IL-37), a newly identified member of the IL-1 family, has been known to play an immunosuppressive role in a variety of inflammatory disorders, but whether it participates in the regulation of pathogenesis of non-small cell lung cancer (NSCLC) has not been investigated
The cells were plated onto the layer of Matrigel (BD Bioscience, San Diego, CA, Fig. 1 Decreased IL-37 expression is associated with poor prognosis in NSCLC patients. a The expression of IL-37 in 182 paired of NSCLC samples and their corresponding normal lung tissues was detected using Quantitative reverse transcription polymerase chain reaction (PCR) (qRT-PCR). b Western blot analysis of IL-37 expression in NSCLC samples (n = 97)
Depicted are 4 individual pairs of NSCLC samples c. d IL-37 mRNA levels were positively correlated with its expression on protein levels

Summary

Introduction

Interleukin-37 (IL-37), a newly identified member of the IL-1 family, has been known to play an immunosuppressive role in a variety of inflammatory disorders, but whether it participates in the regulation of pathogenesis of non-small cell lung cancer (NSCLC) has not been investigated. IL-37b is the largest isoform and was detected in several human tissues, including lung and testis, and in colon tumors and human cell lines, such as THP-1, U937 and A431 [6, 7]. Three groups have demonstrated that IL-37 requires the receptors IL-18Rα and IL-1R8 to carry out its multifaceted anti-inflammatory program upon innate signal transduction [10,11,12]. It has been demonstrated that IL-37 can be induced by several toll-like receptor (TLR) ligands and pro-inflammatory cytokines such as IL-1β, TNF-α, IFN-γ in PBMCs [13, 14]. Higher levels of serum IL-37 have been detected in patients with autoimmune diseases, such as rheumatoid arthritis [21], inflammatory bowel disease [22], systemic lupus erythematosus [23], Graves’ Disease [24] and Guillain-Barré Syndrome [25]

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Conclusion