IL-37: a new anti-inflammatory cytokine of the IL-1 family

The IL-1 family of cytokines encompasses eleven proteins that each share a similar beta-barrel structure and bind to Ig- like receptors. Some of the IL-1-like cytokines have been well characterised, and play key roles in the development and regulation of inflammation. Indeed, IL-1 alpha (IL- 1F1), IL-1 beta(IL- 1F2), and IL- 18 (IL- 1F4) are well- known inflammatory cytokines active in the initiation of the inflammatory reaction and in driving Th1 and Th17 inflammatory responses. In contrast, IL- 1 receptor antagonist (IL- 1Ra, IL- 1F3) and the receptor antagonist binding to IL-1Rrp2 (IL- 36Ra, IL- 1F5) reduce inflammation by blocking the binding of the agonist receptor ligands. In the case of IL- 37 (IL- 1F7), of which five different splice variants have been described, less is known of its function, and identification of the components of a heterodimeric receptor complex remains unclear. Some studies suggest that IL-37 binds to the alpha chain of the IL-18 receptor in a non- competitive fashion, and this may explain some of the disparate biological effects that have been reported for mice deficient in the IL-18R. The biological properties of IL-37 are mainly those of down- regulating inflammation, as assessed in models where human IL-37 is expressed in mice. In this review, an overview of the role of IL-37 in the regulation of inflammation is presented. The finding that IL-37 also locates to the nucleus, as do IL- 1 alpha and IL- 33, for receptor- independent organ/tissue- specific regulation of inflammation is also reviewed.