Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes.
Interleukin (IL)-17 promotes cartilage breakdown by inducing matrix metalloproteinases (MMPs) and aggrecanases (a disintegrin and metalloproteinase with thrombospondin motif, ADAMTS) in arthritic joints. We investigated IL-17 signaling pathways inducing MMP-3, MMP-13 and ADAM-TS4 genes in bovine articular chondrocytes. IL-17 stimulated phosphorylation of extracellular signal-regulated kinase ( ERK), protein 38 ( p38) and c-Jun N-terminal kinase (JNK). ERK pathway inhibitors, PD98059 and U0126, down-regulated IL-17- induced MMP and ADAM-TS4 gene expression. Protein 38 and JNK pathway inhibitors, SB203580 and SP600125, also reduced induction of these genes. Antioxidants and activating protein-1 transcription factor inhibitors, nordihydroguaiaretic acid and N-acetyl-L-cysteine (NAC) suppressed MMP and ADAM-TS4 genes. Similarly, nuclear factor kappa B (NF-kappaB) pathways inhibitors curcumin and Bay-11-7085 also blocked their induction. Thus MMP-3, MMP-13 and ADAM-TS4 genes are coordinately up-regulated by IL-17 via MAP kinases, activating protein-1 (AP-1) and NF-kappaB mediators, which could be targeted for reducing IL-17-triggered cartilage damage.[1]References
- Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes. Sylvester, J., Liacini, A., Li, W.Q., Zafarullah, M. Cell. Signal. (2004) [Pubmed]
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