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Synoviocyte Innate Immune Responses: I. Differential Regulation of Interferon Responses and the JNK Pathway by MAPK Kinases¹

Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093

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-β mRNA was decreased in MKK4- or MKK7-deficient FLS. However, MKK4 and MKK7 deficiency did not affect phosphorylation of IB 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 inhibitor SP600125, indicating that JNK can directly phosphorylate IRF3. In contrast, deficiency of either MKK4 or MKK7 decreased AP-1 transcriptional activity. Therefore, JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 requires both MKK4 and MKK7, with the former activating c-Jun and the latter activating both c-Jun and IRF3 through JNK-dependent mechanisms.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI067752 and AR047825.

² Address correspondence and reprint requests to Dr. Gary S. Firestein, Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, 9500 Gilman Drive, Mail Code 0656, La Jolla, CA 92093-0656. E-mail address: gfirestein{at}ucsd.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; MMP, matrix metalloproteinase; FLS, fibroblast-like synoviocyte; PGN, peptidoglycan; siRNA, small interfering RNA; ISRE, IFN-sensitive response element; TBK1, TANK binding kinase 1; IKK, IB kinase; TANK, TRAF family member-associated NF-B activator.