The anti-inflammatory effect of IL-37-IL-1R8-IL-18Rα complex


The canonical interleukin 1 (IL-1) signaling pathway includes the binding of ligand of the IL-1 family to an IL-1 receptor (IL-1R) chain, leads to the recruitment of a second IL-1R chain, which triggers signaling cascade. IL-37 and IL-1R8, two anti-inflammatory orphans, belong to IL-1 ligand family and IL-1 receptor family, respectively. Nold-Petry et al. identified the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The article was published in Nature Immunology.


Mice with transgenic expression of IL-37 (IL-37tg mice) with IL-1R8 were protected from endotoxemia, while those without IL-1R8 were not. In addition, the absence of IL-1R8 or IL-18Rα interfered the anti-inflammatory activity of IL-37. Mechanically, IL-1R8 is critical in IL-37-regulated anti-inflammatory activities, including signaling molecules such as Mer, PTEN, STAT3 and p62 (dok). IL-37 and IL1R8 also inhibit the kinases Fyn and TAK1, transcription factor NF-κB, as well as mitogen-activated protein kinases. Notably, IL-37 binds to the α-chain of IL-18R but does not trigger the recruitment of downstream signaling molecules or induce proinflammatory activities. However, lover concentrations of IL-37 are more effective for anti-inflammation effects, indicating IL-37 is not an antagonist of IL-18R. Indeed, IL-1R8 acts as a co-receptor once IL-37 binds to IL-18Rα, both in vitro and in vivo. This interaction is essential for the anti-inflammatory functions of IL-37.


Nat Immunol. 2015 Mar 2. doi: 10.1038/ni.3103.

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