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Papers In Press, published online ahead of print November 4, 2002
Laboratoire de Biochemie du Tissu Conjonctif, 14032, Caen Cedex
Corresponding Author: flo_legendre{at}yahoo.fr
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, 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 PD98059 was without significant effect. Thus, activation of the STAT signaling pathway, 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.
J. Biol. Chem, 10.1074/jbc.M110773200
Submitted on November 9, 2001
Revised on October 29, 2002
Accepted on November 4, 2002
JAK/STAT but not ERK1/ERK2 pathway mediates IL-6/sIL-6R down-regulation of type II collagen, aggrecan core and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression
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