IL-37 Suppresses MyD88-mediated Inflammatory Responses in Human Aortic Valve Interstitial Cells

Abstract

Calcific aortic valve disease (CAVD) is common among the elderly, and aortic valve interstitial cells (AVICs) exhibit unique inflammatory and osteogenic responses to proinflammatory stimulation, which plays an important role in valvular fibrosis and calcification. Thus, suppression of AVIC proinflammatory response may have therapeutic utility for the prevention of CAVD progression. Interleukin (IL)-37, an antiinflammatory cytokine, reduces tissue inflammation. This study aimed to test the hypothesis that IL-37 suppresses human AVIC inflammatory responses to Toll-like receptor (TLR) agonists. Human AVICs were exposed to Pam3CSK4, poly(I:C) and lipopolysaccharide in the presence and absence of recombinant human IL-37. Stimulation of TLR4 increased the production of intercellular adhesion molecule-1, IL-6, IL-8 and monocyte chemoattractant protein-1. Knockdown of myeloid differentiation factor 88 (MyD88) or TIR-domain-containing adaptor-inducing interferon-β differentially affected inflammatory mediator production following TLR4 stimulation. IL-37 reduced production of these inflammatory mediators induced by TLR4. Moreover, knockdown of IL-37 enhanced induction of these mediators by TLR4. IL-37 also suppressed inflammatory mediator production induced by the MyD88-dependent TLR2, but had no effect on the inflammatory responses to the TRIF-dependent TLR3. Furthermore, IL-37 inhibited NF-κB activation induced by TLR2 or TLR4 through a mechanism dependent of IL-18 receptor α-chain. Activation of TLR2, TLR3 or TLR4 upregulates the production of inflammatory mediators in human AVICs. IL-37 suppresses MyD88-mediated responses to reduce inflammatory mediator production following stimulation of TLR2 and TLR4. This antiinflammatory cytokine may be useful for suppression of aortic valve inflammation elicited by MyD88-dependent TLR signaling.

Toll-Like Receptors, Inflammation, and Calcific Aortic Valve Disease

“…The first association of viral-derived molecules with inflammation and calcification of human VIC through TLR3 was reported using polyinosinic acid: polycytidylic acid to mimic dsRNA effects (López et al, 2012 ). Zhan et al, later confirmed dsRNA-mediated up-regulation of inflammatory mediators and pro-osteogenic activity, and further demonstrated by gene-silencing and neutralizing antibodies the involvement of TLR3-TRIF non canonical NF-κB signaling pathways as well as the ERK route (Zhan et al, 2015 , 2017 ). Moreover, recent in vivo data presented at European Society of Cardiology Congress 2017 have associated TLR3 to the onset of calcific aortic valve disease by using TLR3- and ApoE-deficient mice models (Tepekoylu et al, 2017 ).…”

Activation of mast cells mediates inflammatory response in psoriasis: Potential new therapeutic approach with IL‐37

“…IL‐1 family plays a crucial role in the regulation of immune and inflammatory responses to several antigens which can be inhibited by IL‐1 inhibitors such as IL‐37 and IL‐1 receptor antagonist (IL‐1RA), a natural inhibitor of IL‐1 (Garlanda, Dinarello, & Mantovani, ). Binding IL‐1 receptor (IL‐1R) by antigens provokes an activation of MyD88 pathway which leads to NF‐κB and, therefore, to the inflammatory cytokine gene expression (Zhan et al, ; Table ).…”

“…Receptor-activated mast cells lead to the generation of inflammatory compounds which mediate psoriasis inflammation. Cytokines IL-37, IL-10, and TGF-beta are potential inhibitors of the inflammatory response Binding IL-1 receptor (IL-1R) by antigens provokes an activation of MyD88 pathway which leads to NF-κB and, therefore, to the inflammatory cytokine gene expression (Zhan et al, 2017; Table 1).…”

Role for nuclear interleukin-37 in the suppression of innate immunity

“…In addition to studies in IL-37 transgenic mice, the extracellular function of IL-37 using recombinant IL-37 inhibits inflammation in vitro and in vivo in wild-type (WT) mice (12)(13)(14)(15)(16)(17)(18). Recombinant IL-37 improves insulin sensitivity and reduces inflammatory cytokine production in adipose tissue (13), ameliorates joint and systemic inflammation (15), limits the metabolic costs of chronic inflammation, which promotes exercise tolerance (14), and promotes intestinal immune homeostasis (19).…”