IL-37 inhibits the production of pro-inflammatory cytokines in MSU crystal-induced inflammatory response

Abstract

Acute gouty arthritis (AGA) is an auto-inflammatory disease characterized by resolving spontaneously, which suggests that negative feedback loops control inflammatory and immunological responses to monosodium urate (MSU) crystals. By now, the molecular mechanism for spontaneous resolution of acute GA remains unclear; this study was undertaken to evaluate whether IL-37 is involved in spontaneous resolution of AGA. A total of 45 acute GA (AGA),29 non-acute GA (NAGA) male patients and 82 male health control (HC) were involved in this study, we measured IL-7 expression in the peripheral blood mononuclear cells (PBMCs), together with levels of IL-1β, IL-6, IL-10, TNF-α and TGF-β1 in the serum. Further, we either inhibited IL-37 expression in human PBMCs with siRNA or over-expressed the cytokine in human macrophages. Pro-inflammatory cytokine IL-1β, IL-6, and TNF-α expressions were significantly higher in the AGA group than in the NAGA or HC group (P < 0.05, respectively). However, anti-inflammatory IL-37, TGF-β1, and IL-10 were greater in the NAGA group than in the AGA and HC groups (P < 0.05, respectively). Expression of IL-37 in MSU crystal-treated macrophages inhibited the expression of pro-inflammatory cytokines, whereas the abundance of these cytokines increased with silencing of endogenous IL-37 in human blood cells. However, anti-inflammatory TGF-β1 and IL-10 expressions in these supernatants were unaffected by over-expression or knockdown of IL-37. Our study indicates that IL-37 is an important anti-inflammatory cytokine in AGA by suppressing the production of pro-inflammatory cytokines. Thus, IL-37 may provide a novel research target for the pathogenesis and therapy of GA.

Suppression of innate inflammation and immunity by interleukin‐37

“…A growing number of recent milestone reports reveal that IL‐37 plays a pivotal role in limiting innate inflammation as well as suppressing acquired immunity. Importantly, reducing endogenous IL‐37 in human cells reveals that IL‐37 limits the production of cytokines induced by IL‐1 and Toll‐like receptors (TLR) as well as urate crystals . However, unlike all members of the family, there is no IL‐37 in the mouse; therefore, establishing a role for this cytokine in IL‐37‐deficient mice is not possible.…”

What makes gouty inflammation so variable?

“…IL-37, a member of the IL-1 family, is an anti-inflammatory cytokine differentially regulated during the course of tissue inflammatory reactions, largely through expression by epithelial cells and mononuclear leukocytes [ 55 , 56 ]. IL-37 suppresses multiple innate inflammatory responses in vitro and in vivo, acting partially via inhibition of the NLRP3 inflammasome and activation of suppressor of cytokine signaling 3 [ 55 ].…”

A protective role of IL-37 in cancer: a new hope for cancer patients

“…The effects of STAT-3 activation are dependent of context because its activation by IL-10 prevents, and by IL-6 promotes, polarization of macrophages into the proinflammatory M1 phenotype [38]. The signaling pathways culminate in the inhibition of NF-kB, PI3K, MAPK, TAK1, mTOR, inflammasome assembly, TLR, and IL-1RF-mediated activation signals and the activation of PTEN, STAT-3, and AMPK [3,4,25,28,39]. It was demonstrated in murine and human macrophage cell lines and in vivo studies that SMAD-3 siRNA and SMAD-3 inhibitors cause significant reductions in the anti-inflammatory effects of human IL-37 [3,10,19].…”

“…Similar inhibitory effects are observed upon activation with other TLR ligands as well as with IL-1RF ligands. Furthermore, IL-37 also inhibits assembly and activation of inflammasomes and, hence, production and maturation of proinflammatory cytokines, such as IL-1b and IL-18 [5,39]. The down-regulation of IL-37 synthesis by siRNA in human PBMCs and macrophages leads to increased production of several proinflammatory cytokines (e.g., IL-1R antagonist, IL-1a, IL-1b, IL-18, IL-6, IL-12, IL-23, IL-17, G-CSF, GM-CSF, and TNF-a, among others) and chemokines (e.g., MIP-2/CXCL2, BLC/CXCL13, and IL-8/CXCL8, among others) [3,4,22,39].…”