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MyD88, IRAK1 and TRAF6 knockdown in human chondrocytes inhibits interleukin-1-induced matrix metalloproteinase-13 gene expression and promoter activity by impairing MAP kinase activation.
Cell Signal 2007; 19(12):2549-57CS

Abstract

Interleukin-1 (IL-1) is the major prototypic proinflammatory cytokine that stimulates degradation of cartilage in arthritis by inducing prominent collagen II-degrading matrix metalloproteinase-13 (MMP-13). Nothing is known about the involvement of adaptor proteins, MyD88, IRAK1 and TRAF6 in MMP-13 regulation. Here we investigated for the first time the role of these proteins in IL-1-regulated MMP-13 expression in chondrocytes. MyD88 homodimerization inhibitory peptide diminished the expression of MMP-13 gene, promoter activity, phosphorylation of mitogen-activated protein kinases (MAPKs), c-Jun and activating protein 1 (AP-1) activity. Knockdown of MyD88, IRAK1 and TRAF6 by RNA interference (RNAi) drastically down-regulated the expression of IL-1-induced MMP-13 mRNA and protein levels and MMP-13 promoter-driven luciferase activity. Non-specific control siRNA had no effect. Mechanisms of MMP-13 inhibition involved reduced phosphorylation of ERK, p38, JNK and c-Jun as well as AP-1 transcription factor binding activity. The genetic evidence presented here demonstrates that MyD88, IRAK1 and TRAF6 proteins are crucial early mediators for the IL-1-induced MMP-13 regulation through MAPK pathways and AP-1 activity. These proteins could constitute important therapeutic targets for arthritis-associated cartilage loss by MMP-13.

Authors+Show Affiliations

Department of Medicine, University of Montreal and Research Centre of CHUM Notre-Dame Hospital, Montreal, Quebec, Canada H2L 4M1.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17905570

Citation

Ahmad, Rasheed, et al. "MyD88, IRAK1 and TRAF6 Knockdown in Human Chondrocytes Inhibits Interleukin-1-induced Matrix Metalloproteinase-13 Gene Expression and Promoter Activity By Impairing MAP Kinase Activation." Cellular Signalling, vol. 19, no. 12, 2007, pp. 2549-57.
Ahmad R, Sylvester J, Zafarullah M. MyD88, IRAK1 and TRAF6 knockdown in human chondrocytes inhibits interleukin-1-induced matrix metalloproteinase-13 gene expression and promoter activity by impairing MAP kinase activation. Cell Signal. 2007;19(12):2549-57.
Ahmad, R., Sylvester, J., & Zafarullah, M. (2007). MyD88, IRAK1 and TRAF6 knockdown in human chondrocytes inhibits interleukin-1-induced matrix metalloproteinase-13 gene expression and promoter activity by impairing MAP kinase activation. Cellular Signalling, 19(12), pp. 2549-57.
Ahmad R, Sylvester J, Zafarullah M. MyD88, IRAK1 and TRAF6 Knockdown in Human Chondrocytes Inhibits Interleukin-1-induced Matrix Metalloproteinase-13 Gene Expression and Promoter Activity By Impairing MAP Kinase Activation. Cell Signal. 2007;19(12):2549-57. PubMed PMID: 17905570.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MyD88, IRAK1 and TRAF6 knockdown in human chondrocytes inhibits interleukin-1-induced matrix metalloproteinase-13 gene expression and promoter activity by impairing MAP kinase activation. AU - Ahmad,Rasheed, AU - Sylvester,Judith, AU - Zafarullah,Muhammad, Y1 - 2007/08/25/ PY - 2007/07/20/received PY - 2007/08/06/accepted PY - 2007/10/2/pubmed PY - 2007/12/21/medline PY - 2007/10/2/entrez SP - 2549 EP - 57 JF - Cellular signalling JO - Cell. Signal. VL - 19 IS - 12 N2 - Interleukin-1 (IL-1) is the major prototypic proinflammatory cytokine that stimulates degradation of cartilage in arthritis by inducing prominent collagen II-degrading matrix metalloproteinase-13 (MMP-13). Nothing is known about the involvement of adaptor proteins, MyD88, IRAK1 and TRAF6 in MMP-13 regulation. Here we investigated for the first time the role of these proteins in IL-1-regulated MMP-13 expression in chondrocytes. MyD88 homodimerization inhibitory peptide diminished the expression of MMP-13 gene, promoter activity, phosphorylation of mitogen-activated protein kinases (MAPKs), c-Jun and activating protein 1 (AP-1) activity. Knockdown of MyD88, IRAK1 and TRAF6 by RNA interference (RNAi) drastically down-regulated the expression of IL-1-induced MMP-13 mRNA and protein levels and MMP-13 promoter-driven luciferase activity. Non-specific control siRNA had no effect. Mechanisms of MMP-13 inhibition involved reduced phosphorylation of ERK, p38, JNK and c-Jun as well as AP-1 transcription factor binding activity. The genetic evidence presented here demonstrates that MyD88, IRAK1 and TRAF6 proteins are crucial early mediators for the IL-1-induced MMP-13 regulation through MAPK pathways and AP-1 activity. These proteins could constitute important therapeutic targets for arthritis-associated cartilage loss by MMP-13. SN - 0898-6568 UR - https://www.unboundmedicine.com/medline/citation/17905570/MyD88_IRAK1_and_TRAF6_knockdown_in_human_chondrocytes_inhibits_interleukin_1_induced_matrix_metalloproteinase_13_gene_expression_and_promoter_activity_by_impairing_MAP_kinase_activation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(07)00255-0 DB - PRIME DP - Unbound Medicine ER -