title: Inflammatory cytokines induce production of CHI3L1 by articular chondrocytes.
abstract: Elevated levels of CHI3L1 (chitinase-3-like protein 1) are associated with disorders exhibiting increased connective tissue turnover, such as rheumatoid arthritis, osteoarthritis, scleroderma, and cirrhosis of the liver. This secreted protein is not synthesized in young healthy cartilage, but is produced in cartilage from old donors or patients with osteoarthritis. The molecular processes governing the induction of CHI3L1 are currently unknown. To elucidate the molecular events involved in CHI3L1 synthesis, we investigated two models of articular chondrocytes: neonatal rat chondrocytes, which do not express CHI3L1, and human chondrocytes, which express CHI3L1 constitutively. In neonatal rat chondrocytes, the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 potently induced steady-state levels of CHI3L1 mRNA and protein secretion. Treatment of chondrocytes with TNF-alpha for as little as 1 h was sufficient for sustained induction up to 72 h afterward. Using inhibitors selective for the major signaling pathways implicated in mediating the effects of TNF-alpha and interleukin-1, only inhibition of NF-kappaB activation was effective in curtailing cytokine-induced expression, including after removal of the cytokine, indicating that induction and continued production of CHI3L1 are controlled mainly by this transcription factor. Inhibition of NF-kappaB signaling also abolished constitutive expression by human chondrocytes. Thus, induction and continued secretion of CHI3L1 in chondrocytes require sustained activation of NF-kappaB. Selective induction of CHI3L1 by cytokines acting through NF-kappaB coupled with the known restriction of the catabolic responses by CHI3L1 in response to these inflammatory cytokines represents a key regulatory feedback process in controlling connective tissue turnover.
authors.affiliation: Joint Diseases Laboratory, Shriners Hospital for Children, McGill University, Montreal, Quebec, Canada. arecklies@shriners.mcgill.ca
authors.forename: Anneliese D
authors.initials: AD
authors.lastname: Recklies
authors.forename: Hua
authors.initials: H
authors.lastname: Ling
authors.forename: Chantal
authors.initials: C
authors.lastname: White
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Bernier
mesh_terms: D054392:Adipokines; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002358:Cartilage, Articular / Q000378:metabolism*; D002478:Cells, Cultured; D000071451:Chitinase-3-Like Protein 1; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D003470:Culture Media / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D005269:Femur / Q000473:pathology; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism; D037102:Lectins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; C507621:CHI3L1 protein, rat; D000071451:Chitinase-3-Like Protein 1; D003470:Culture Media; D017077:Culture Media, Conditioned; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D037102:Lectins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D012313:RNA