title: IL37 dampens the IL1β-induced catabolic status of human OA chondrocytes.
abstract: A crucial feature of OA is cartilage degradation. This process is mediated by pro-inflammatory cytokines, among other factors, via induction of matrix-degrading enzymes. Interleukin 37 (IL37) is an anti-inflammatory cytokine and is efficient in blocking the production of pro-inflammatory cytokines during innate immune responses. We hypothesize that IL37 is therapeutic in treating the inflammatory cytokine cascade in human OA chondrocytes and can act as a counter-regulatory cytokine to reduce cartilage degradation in OA.
  
  
  
  Human OA cartilage was obtained from patients undergoing total knee or hip arthroplasty. Immunohistochemistry was applied to study IL37 protein expression in cartilage biopsies from OA patients. Induction of IL37 expression by IL1β, OA synovium-conditioned medium and TNFα was investigated in human OA chondrocytes. Adenoviral overexpression of IL37 followed by IL1β stimulation was performed to investigate the anti-inflammatory potential of IL37.
  
  
  
  IL37 expression was detected in cartilage biopsies of OA patients and induced by IL1β. After IL1β stimulation, increased IL1β, IL6 and IL8 expression was observed in OA chondrocytes. Elevated IL37 levels diminished the IL1β-induced IL1β , IL6 and IL8 gene levels and IL1β and IL8 protein levels. In addition to the reduction in pro-inflammatory cytokine expression, IL37 reduced MMP1 , MMP3 , MMP13 and disintegrin and metalloproteinase with thrombospondin motifs 5 gene levels and MMP3 and MMP13 protein levels.
  
  
  
  IL37 is induced by IL1β, and IL37 itself reduced IL1β, IL6 and IL8 production, indicating that IL37 is able to induce a counter-regulatory anti-inflammatory feedback loop in chondrocytes. In addition, IL37 dampens catabolic enzyme expression. This supports IL37 as a potential therapeutic target in OA.
authors.affiliation: Department of Rheumatology, Experimental Rheumatology.
authors.forename: Ellen W
authors.initials: EW
authors.lastname: van Geffen
authors.affiliation: Department of Rheumatology, Experimental Rheumatology.
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: van Caam
authors.affiliation: Department of Rheumatology, Experimental Rheumatology.
authors.forename: Henk M
authors.initials: HM
authors.lastname: van Beuningen
authors.affiliation: Department of Rheumatology, Experimental Rheumatology.
authors.forename: Elly L
authors.initials: EL
authors.lastname: Vitters
authors.affiliation: Department of Orthopaedics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Schreurs
authors.affiliation: Department of Rheumatology, Experimental Rheumatology.
authors.forename: Fons A
authors.initials: FA
authors.lastname: van de Loo
authors.affiliation: Department of Rheumatology, Experimental Rheumatology.
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.affiliation: Department of Rheumatology, Experimental Rheumatology.
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.affiliation: Department of Rheumatology, Experimental Rheumatology.
authors.forename: Esmeralda N
authors.initials: EN
authors.lastname: Blaney Davidson
authors.affiliation: Department of Rheumatology, Experimental Rheumatology.
authors.forename: Peter M
authors.initials: PM
authors.lastname: van der Kraan
mesh_terms: D000256:Adenoviridae; D015153:Blotting, Western; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D019483:Disintegrins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010003:Osteoarthritis; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C508606:CXCL8 protein, human; D019483:Disintegrins; C508585:IL1B protein, human; C508587:IL37 protein, human; C508600:IL6 protein, human; D007375:Interleukin-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: IL37; cartilage; cytokines; inflammation; osteoarthritis