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Regulation of c-Jun phosphorylation by the I kappa B kinase-epsilon complex in fibroblast-like synoviocytes

Susan E Sweeney1, Deepa Hammaker, David L Boyle

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

Journal of Immunology (Baltimore, Md. : 1950)
|May 10, 2005
PubMed

Insights

The IkappaB kinase-epsilon (IKKepsilon) enzyme plays a key role in rheumatoid arthritis (RA) pathogenesis. Targeting IKKepsilon may reduce synovial inflammation and extracellular matrix destruction in RA.

Area of Science:

  • Immunology
  • Molecular Biology
  • Rheumatology

Background:

  • Rheumatoid arthritis (RA) involves joint destruction and disability due to inflammatory polyarthritis.
  • Cytokine and enzyme production pathways are implicated in RA pathogenesis and are potential therapeutic targets.
  • IKKepsilon, an IKK-related kinase, regulates antiviral genes and is present in RA synovial cells.

Purpose of the Study:

  • To investigate the role of IKKepsilon in the pathogenesis of RA.
  • To determine if IKKepsilon is expressed in human RA and osteoarthritis synovium.
  • To explore the substrates and functional relevance of IKKepsilon in RA synovial cells.

Main Methods:

  • Immunohistochemical analysis of IKKepsilon in human synovium.
  • Functional studies using cultured fibroblast-like synoviocytes (FLS) from wild-type and IKKepsilon knockout mice.
  • Analysis of cytokine-induced IkappaB phosphorylation and NF-kappaB activation.
  • Assessment of c-Jun phosphorylation and matrix metalloproteinase (MMP) induction.

Main Results:

  • IKKepsilon protein is expressed in RA and osteoarthritis synovium, primarily in the synovial intimal lining.
  • IKKepsilon kinase activity is induced by cytokines in FLS, with less IkappaB phosphorylation compared to IKK2.
  • c-Jun is an efficient substrate for IKKepsilon in human FLS, independent of JNK.
  • Induction of MMP3 and MMP13 by IL-1, TNF-alpha, and LPS is significantly decreased in IKKepsilon knockout FLS.

Conclusions:

  • IKKepsilon is expressed in the synovium and its activity is modulated by inflammatory cytokines.
  • IKKepsilon phosphorylates c-Jun, suggesting a role beyond NF-kappaB activation.
  • IKKepsilon deficiency reduces the induction of matrix-degrading enzymes in FLS.
  • These findings indicate a novel role for IKKepsilon in RA synovial inflammation and extracellular matrix destruction.

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