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IL-37 suppresses MyD88-mediated inflammatory responses in human aortic valve interstitial cells
Qiong Zhan1,2, Qingchun Zeng1,2, Rui Song1
1Department of Surgery, University of Colorado Denver, Aurora, CO 80045.
Insights
Interleukin-37 (IL-37) effectively suppresses inflammation in human aortic valve cells by inhibiting key signaling pathways. This finding suggests IL-37 could be a therapeutic target for calcific aortic valve disease.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Calcific aortic valve disease (CAVD) is a prevalent condition in the elderly, characterized by inflammation and calcification of the aortic valve.
- Aortic valve interstitial cells (AVICs) play a crucial role in CAVD pathogenesis through inflammatory and osteogenic responses.
- Interleukin-37 (IL-37), an anti-inflammatory cytokine, shows potential for mitigating tissue inflammation.
Purpose of the Study:
- To investigate the hypothesis that IL-37 can suppress inflammatory responses in human AVICs stimulated by Toll-like receptor (TLR) agonists.
- To explore the therapeutic potential of IL-37 in preventing the progression of CAVD.
Main Methods:
- Human AVICs were treated with TLR agonists (Pam3CSK4, poly(I:C), lipopolysaccharide) in the presence or absence of recombinant human IL-37.
- The study assessed the production of inflammatory mediators, including intercellular adhesion molecule-1, IL-6, IL-8, and monocyte chemoattractant protein-1.
- Gene knockdown of MyD88 and TRIF was employed to elucidate TLR signaling pathways, and NF-κB activation was analyzed.
Main Results:
- TLR4 stimulation significantly increased the production of inflammatory mediators in human AVICs.
- IL-37 treatment reduced the production of these TLR4-induced inflammatory mediators.
- IL-37 suppressed inflammatory responses mediated by MyD88-dependent TLR2 and TLR4 signaling, but not TRIF-dependent TLR3 signaling, and inhibited NF-κB activation.
Conclusions:
- TLR activation significantly contributes to inflammatory mediator production in human AVICs.
- IL-37 demonstrates potent anti-inflammatory effects by suppressing MyD88-dependent TLR signaling pathways (TLR2 and TLR4).
- IL-37 holds promise as a therapeutic agent for managing aortic valve inflammation in CAVD.
Background:
Calcific aortic valve disease (CAVD) is common among the elderly, and aortic valve interstitial cells (AVICs) exhibit unique inflammatory and osteogenic responses to pro-inflammatory stimulation which play an important role in valvular fibrosis and calcification. Thus, suppression of AVIC pro-inflammatory response may have therapeutic utility for prevention of CAVD progression. Interleukin (IL)-37, an anti-inflammatory cytokine, reduces tissue inflammation.
Objective:
This study was to test the hypothesis that IL-37 suppresses human AVIC inflammatory responses to Toll-like receptor (TLR) agonists.
Methods And Results:
Human AVICs were exposed to Pam3CSK4, poly(I:C) and lipopolysaccharide, respectively, 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 (TRIF) differentially affected inflammatory mediator production following TLR4 stimulation. IL-37 reduced the production of these inflammatory mediators induced by TLR4. Moreover, knockdown of IL-37 enhanced the 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.
Conclusion:
Activation of TLR2, TLR3 or TLR4 up-regulates 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 anti-inflammatory cytokine may be useful for suppression of aortic valve inflammation elicited by MyD88-dependent TLR signaling.