Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinases.

The Journal of Immunology : Official Journal of the American Association of Immunologists
Toshio YoshizawaGary S Firestein

Abstract

JNK is a key regulator of matrix metalloproteinase production in rheumatoid arthritis. It is regulated by two upstream kinases known as MKK4 and MKK7. Previous studies demonstrated that only MKK7 is required for cytokine-mediated JNK activation and matrix metalloproteinase expression in cultured fibroblast-like synoviocytes (FLS). However, the functions of MKK4 and MKK7 in synoviocyte innate immune responses have not been determined. TNF, peptidoglycan (PGN), and LPS stimulation led to higher and more prolonged MKK7 phosphorylation compared with MKK4 in FLS. However, this pattern was reversed in poly(I-C) stimulated cells. siRNA knockdown studies showed that TNF, PGN, and LPS-induced JNK and c-Jun phosphorylation are MKK7 dependent, while poly(I-C) responses require both MKK4 and MKK7. Poly(I-C)-induced expression of IP-10, RANTES, and IFN-beta mRNA was decreased in MKK4- or MKK7-deficient FLS. However, MKK4 and MKK7 deficiency did not affect phosphorylation of IkappaB kinase-related kinases in the TLR3 signaling pathway. MKK7, but not MKK4 deficiency, significantly decreased poly(I-C)-mediated IRF3 dimerization, DNA binding, and IFN-sensitive response element-mediated gene transcription. These results were mimicked by the JNK ...Continue Reading

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Mar 3, 2010·Immunological Reviews·Beatrix Bartok, Gary S Firestein
Aug 5, 2017·Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology·Taiji WatanabeYoshiki Ishii
Oct 31, 2009·Arthritis and Rheumatism·Camilla I SvenssonGary S Firestein
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Oct 26, 2020·Cellular Microbiology·Gayan BamunuarachchiLin Liu

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