title: 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 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.
  
  
  
  This study was 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, 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.
  
  
  
  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.
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.|Department of Cardiology, Nanfang hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.|Department of Cardiology, Nanfang hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Cardiology, Nanfang hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Dingli
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, CO 80045.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
mesh_terms: D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001021:Aortic Valve / Q000166:cytology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C508587:IL37 protein, human; D007375:Interleukin-1; D055666:Lipopeptides; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C508075:Pam(3)CSK(4) peptide; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; D011070:Poly I-C
keywords: IL-37; MyD88; Toll-like receptor; aortic valve interstitial cells; inflammation