IL-37 restrains autoimmune diseases

Interleukin-37 (IL-37), a newly discovered member of the IL-1 family, has been identified as a natural inhibitor of immune responses [1]. The human IL-37 gene has been confirmed undergo alternative splicing and exists in five splice variants including IL-37a-e, but a mouse homologue has not been reported [2]. The most glaring is IL-37b that encodes the longest transcript variant includes exons 1 and 2 and expressing an N-terminal prodomain that contains a potential caspase-1 cleavage site, which result in IL-37b precursor cleaved into mature IL-37b [2]. What is noteworthy is that expression of IL-37 is apparently dependent on inflammation milieu and inflammatory cells. We and other studies showed that the expression of IL-37 level is markedly up-regulated in peripheral blood monocular cells (PBMCs), macrophages, epithelial cells, dendritic cells (DCs) and T cells following the stimulation of pro-inflammatory cytokines, e.g. IL-18, IFN-γ, IL-1β and TNF and Toll like receptor (TLR) ligands lipopolysaccharide (LPS), whereas it is lower or not continuously expressed in steady-state target cells and human normal tissues [1-4]. Increasing evidence indicated that modulation of immune system by IL-37 is involved in suppression of innate and adaptive immunity [1-2, 5]. In macrophages and DCs, IL-37 dramatically reduces proinflammatory cytokines secretion, as well as limits them activation and macrophages differentiation. Moreover, IL-37 induced tolerogenic DCs may contribute to induction of regulatory T cells [5]. However, it is still unclear how does IL-37 suppress adaptive immunity by regulating the function of innate immune cells? In recent years, the powerful inhibitory activity of IL-37 has been investigated in inflammation diseases including LPS induced shock, dextran sulfate sodium (DSS)-induced colitis and obesity-induced insulin resistance [1, 5]. The presence of IL-37 in these inflammation diseases appears to effectively alleviate the excessive inflammatory responses, whereas whether its immunosuppressive features contribute to autoimmune diseases is still poorly investigated. In human studies, our recent results may have clinical implications. Because increased serum IL-37 levels were observed in patients with systemic lupus erythematosus (SLE) [3] and rheumatoid arthritis (RA) [4]. Concomitantly, upregulated IL-37 significantly suppresses the production of proinflammatory cytokines in PBMCs from SLE and RA subjects in vitro [3-5]. Tracing the source of IL-37 expression, we clearly observed that CD3 + T cells and CD4 + T cells especially Th1-and Th17 polarization are mainly responsible for the expression of IL-37 in RA [4]. Based on the relationship between IL-37 and adaptive immunity, we therefore asked whether increased IL-37 …