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Regulation of JNK by MKK-7 in fibroblast-like synoviocytes

Tomoyuki Inoue1, Deepa Hammaker, David L Boyle

  • 1Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0656, USA.

Arthritis and Rheumatism
|June 28, 2006
PubMed
Abstract

Insights

MKK-7, not MKK-4, is essential for JNK activation in fibroblast-like synoviocytes (FLS) following cytokine stimulation in rheumatoid arthritis (RA). Targeting MKK-7 may suppress RA-related FLS activation while preserving stress responses.

Area of Science:

  • Cellular and Molecular Biology
  • Immunology
  • Rheumatology

Background:

  • JNK signaling pathway is crucial for matrix metalloproteinase (MMP) gene expression and joint destruction in rheumatoid arthritis (RA).
  • Two upstream kinases, MKK-4 and MKK-7, phosphorylate JNK and are found in RA synovium.
  • The specific roles of MKK-4 and MKK-7 in fibroblast-like synoviocytes (FLS) remain unclear.

Purpose of the Study:

  • To elucidate the functional hierarchy of MKK-4 and MKK-7 in regulating JNK signaling within FLS.
  • To determine the relative contributions of MKK-4 and MKK-7 in cytokine-induced JNK activation and downstream gene expression.

Main Methods:

  • Gene knockdown of MKK-4 and/or MKK-7 in cultured FLS using small interfering RNA.
  • Stimulation of FLS with IL-1beta, TNFalpha, or anisomycin, followed by kinase assays.
  • Assessment of Activator protein 1 (AP-1) binding and transcriptional activity, and MMP-3 expression.

Main Results:

  • IL-1beta-induced JNK phosphorylation and activity were dependent solely on MKK-7.
  • Anisomycin-induced JNK activation required both MKK-4 and MKK-7.
  • MKK-7, but not MKK-4, was essential for IL-1beta-induced AP-1 activity and MMP-3 production.

Conclusions:

  • MKK-7 is the primary kinase for JNK activation in FLS stimulated by cytokines, whereas MKK-4 is involved in stress-induced JNK activation.
  • Targeting MKK-7 offers a potential therapeutic strategy to selectively inhibit cytokine-mediated FLS activation in RA, sparing other cellular stress responses.

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