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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.

Abstract
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.
AuthorsFlorence Legendre, Jayesh Dudhia, Jean-Pierre Pujol, Patrick Bogdanowicz
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 5 Pg. 2903-12 (Jan 31 2003) ISSN: 0021-9258 [Print] United States
PMID12419823 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Aggrecans
  • Collagen Type II
  • Extracellular Matrix Proteins
  • High Mobility Group Proteins
  • Interleukin-6
  • Lectins, C-Type
  • NF-kappa B
  • Oligonucleotide Probes
  • Proteins
  • Proteoglycans
  • Receptors, Interleukin-6
  • Recombinant Proteins
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Sesquiterpenes
  • Transcription Factors
  • link protein
  • Phosphotyrosine
  • parthenolide
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
Topics
  • Aggrecans
  • Animals
  • Base Sequence
  • Cartilage, Articular (physiology)
  • Cattle
  • Cells, Cultured
  • Chondrocytes (physiology)
  • Collagen Type II (genetics)
  • Extracellular Matrix Proteins (genetics)
  • Gene Expression Regulation (drug effects)
  • High Mobility Group Proteins (genetics)
  • Humans
  • Interleukin-6 (pharmacology, physiology)
  • JNK Mitogen-Activated Protein Kinases
  • Kinetics
  • Lectins, C-Type
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases (metabolism)
  • NF-kappa B (antagonists & inhibitors)
  • Oligonucleotide Probes
  • Phosphotyrosine (metabolism)
  • Proteins (genetics)
  • Proteoglycans (genetics)
  • Receptors, Interleukin-6 (physiology)
  • Recombinant Proteins (pharmacology)
  • SOX9 Transcription Factor
  • Sesquiterpenes (pharmacology)
  • Signal Transduction
  • Transcription Factors (genetics, metabolism)
  • Transcription, Genetic (drug effects)

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