187: Interleukin 37 employs the IL-1 family inhibitory receptor SIGIRR and the alpha chain of the IL-18 receptor to suppress innate immunity

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• 作者：Marcel F. Nold ; Claudia A. Nold-Petry ; Camden Lo ; Suzhao Li ; Ina Rudloff ; Jarod A. Zepp ; Tania Azam ; Philip Bufler ; Cecilia Garl ; a ; Alberto Mantovani ; Charles A. Dinarello
• 刊名：Cytokine
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：63
• 期：3
• 页码：287
• 全文大小：42 K

文摘

IL-1 family member IL-37 inhibits a broad spectrum of inflammatory assaults in cell lines and primary PBMC; in vivo, mice transgenic for IL-37 (IL-37tg) exhibit markedly reduced manifestations of LPS-induced shock, DSS colitis, antigen-specific immune responses and ischemia-reperfusion injury. Although previous studies reported that recombinant IL-37 associates with the IL-18 receptor alpha chain (IL-18R¦Á), no biological activity was observed. Here, we reveal a functional role of IL-18R¦Á for the anti-inflammatory properties of IL-37. We also identify that the inhibitory IL-1R family member, SIGIRR, associates with IL-37 and is required by IL-37tg mice for protection from LPS-induced shock. In IL-37-transfected THP-1 macrophages, we observed an 83 % reduction in IL-1¦Â, but only a 34 % reduction when endogenous SIGIRR was silenced. A similar attenuation of the anti-inflammatory effects was demonstrated in LPS-stimulated human PBMC and by silencing of IL-18R¦Á. By immunofluorescence, we observed that IL-37 associates with SIGIRR and IL-18R¦Á in LPS-stimulated RAW macrophages and in IL-1¦Â-treated A549 cells, both transfected with IL-37. Using proximity ligation assays and FRET in PBMC, thus exploring interactions of the naturally occurring pairs IL-37-SIGIRR, IL-37-IL-18R¦Á and SIGIRR-IL-18R¦Á, we demonstrated sub-40 nm co-localization of each complex. The interactions were hardly detectable at steady-state, reached maximal association 15 min after LPS stimulation, and decreased to background by 6 h. We next generated a strain of SIGIRR-KO mice that are also transgenic for IL-37 (IL-37tg-SIGIRR-KO). As expected, the systemic response to LPS was markedly reduced in IL-37tg mice; however, there was no reduction in IL-37tg-SIGIRR-KO mice. For example, LPS induced severe hypothermia (trough at 25 ¡ãC) and acidosis (pH 7.16) in wild-type mice; however, disease severity was markedly ameliorated in IL-37tg mice (29 ¡ãC, pH 7.32). In IL-37tg-SIGIRR-KO mice, this protection was considerably weaker. We conclude that IL-37 limits the severity of inflammation by exploiting the inhibitory properties of SIGIRR and by associating with IL-18R¦Á.