title: Chitinase-3-like protein 1 protects skeletal muscle from TNFα-induced inflammation and insulin resistance.
abstract: CHI3L1 (chitinase-3-like protein 1) is a glycoprotein consisting of 383 amino acids with a molecular mass of 40 kDa, and its serum level is elevated in inflammatory diseases. Although CHI3L1 is described as a biomarker of inflammation, the function of this protein is not completely understood. In the present study, we examined the regulation of CHI3L1 in primary human skeletal muscle cells. Moreover, we analysed potential autocrine effects of CHI3L1. We show that myotubes express CHI3L1 in a differentiation-dependent manner. Furthermore, pro-inflammatory cytokines up-regulate CHI3L1 expression (6-fold) and release (3-fold). Importantly, CHI3L1 treatment blocked TNFα (tumour necrosis factor α)-induced inflammation by inhibiting NF-κB (nuclear factor κB) activation in skeletal muscle cells. We show that this effect is mediated via PAR2 (protease-activated receptor 2). In addition, CHI3L1 treatment diminished the TNFα-induced expression and secretion of IL (interleukin)-8, MCP1 (monocyte chemoattractant protein 1) and IL-6. In addition, impaired insulin action at the level of Akt and GSK3α/β (glycogen synthase kinase 3α/β) phosphoryl-ation and insulin-stimulated glucose uptake was normalized by CHI3L1. In conclusion, the novel myokine CHI3L1, which is induced by pro-inflammatory cytokines, can counteract TNFα-mediated inflammation and insulin resistance in human skeletal muscle cells, potentially involving an auto- and/or para-crine mechanism.
authors: *Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center, 40225 Düsseldorf, Germany.
authors: Sven W
authors: SW
authors: Görgens
authors: *Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center, 40225 Düsseldorf, Germany.
authors: Kristin
authors: K
authors: Eckardt
authors: *Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center, 40225 Düsseldorf, Germany.
authors: Manuela
authors: M
authors: Elsen
authors: †R&D Diabetes Division, Sanofi-Aventis Deutschland, 65929 Frankfurt, Germany.
authors: Norbert
authors: N
authors: Tennagels
authors: Jürgen
authors: J
authors: Eckel
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D002454:Cell Differentiation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D000071451:Chitinase-3-Like Protein 1; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D054392:Adipokines; C111835:CCL2 protein, human; C084533:CHI3L1 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D000071451:Chitinase-3-Like Protein 1; D016207:Cytokines; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D037102:Lectins; D016328:NF-kappa B; D044464:Receptor, PAR-2; D011994:Recombinant Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha