JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression.
Signal transducers and activators of transcription (STAT) factors are cytoplasmic proteins that can be activated by Janus kinases (JAK) and that modulate gene expression in response to cytokine receptor stimulation. STAT proteins dimerize, translocate into the nucleus, and activate specific target genes. In the present study, we show for the first time that interleukin-6 (IL), in the presence of its soluble receptor (sIL-6R), induces activation of JAK1, JAK2, and STAT1/STAT3 proteins in bovine articular chondrocytes. Western blotting and mobility shift assays demonstrated that this effect is accompanied by the DNA binding of the STAT proteins. The mitogen-activated protein kinase pathway was also activated in response to IL-6/sIL-6R association, as reflected by phosphorylation of ERK1 and ERK2 proteins. In these conditions, the expression of cartilage-specific matrix genes, type II collagen, aggrecan core, and link proteins was found to be markedly down-regulated. This negative effect was abolished by addition of parthenolide, an inhibitor of the STAT activation, whereas blockade of the MAP kinases with PD098059 was without significant effect. Thus, activation of the STAT signaling pathways, but not ERK-dependent pathways, is essential for down-regulation of the major cartilage-specific matrix genes by IL-6. In addition, a parallel reduction of Sox9 expression, a key factor of chondrocyte phenotype, was found in these experimental conditions. These IL-6 effects might contribute to the phenotype loss of chondrocytes in joint diseases and the alteration of articular cartilage associated with this pathology.
Legendre
Florence
F
Laboratoire de Biochimie du Tissu Conjonctif, Faculté de Médecine, 14032 Caen Cedex, France.
Dudhia
Jayesh
J
Pujol
Jean-Pierre
JP
Bogdanowicz
Patrick
P
D053674:Aggrecans; D000818:Animals; D001483:Base Sequence; D002358:Cartilage, Articular / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000502:physiology*; D024043:Collagen Type II / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006609:High Mobility Group Proteins / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D037181:Lectins, C-Type; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D015345:Oligonucleotide Probes; D019000:Phosphotyrosine / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D011509:Proteoglycans / Q000235:genetics*; D019947:Receptors, Interleukin-6 / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D055758:SOX9 Transcription Factor; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D000099249:Proteoglycan Link Protein
D053674:Aggrecans; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D006609:High Mobility Group Proteins; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D037181:Lectins, C-Type; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D019000:Phosphotyrosine; D011506:Proteins; D011509:Proteoglycans; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D055758:SOX9 Transcription Factor; D012717:Sesquiterpenes; D014157:Transcription Factors; D000099249:Proteoglycan Link Protein; C527932:SOX9 protein, human; C002669:parthenolide