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Expression and activation of mitogen-activated protein kinase kinases-3 and -6 in rheumatoid arthritis

Martine Chabaud-Riou1, Gary S Firestein

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

The American Journal of Pathology
|December 26, 2003
PubMed

Insights

The study found that MKK3 and MKK6 kinases are activated in rheumatoid arthritis (RA) synovium, suggesting they are key regulators of p38 MAP kinase in this inflammatory disease and potential therapeutic targets.

Area of Science:

  • Immunology
  • Molecular Biology
  • Rheumatology

Background:

  • The p38 MAP kinase pathway is crucial for inflammatory cytokine production.
  • p38 kinase inhibitors show promise for rheumatoid arthritis (RA) treatment.
  • Upstream regulators of p38 activation in RA synovium are not well understood.

Purpose of the Study:

  • To investigate the role of MAP kinase kinases (MAPKKs) MKK3 and MKK6 in RA pathogenesis.
  • To evaluate the expression and activation of MKK3 and MKK6 in RA synovium and fibroblast-like synoviocytes (FLS).

Main Methods:

  • Immunohistochemistry to assess MKK3/6 expression in synovial tissue.
  • Western blot analysis to quantify phosphorylated MKK3/6 levels in RA and osteoarthritis (OA) synovium and FLS.
  • Co-immunoprecipitation assays to study protein interactions.

Main Results:

  • MKK3 and MKK6 are expressed in both RA and OA synovium, with significantly higher phosphorylated MKK3/6 in RA.
  • Phosphorylated MKK3/6 is localized to specific cell types within the RA synovium.
  • RA FLS express MKK3 and MKK6, and MKK3 activation is induced by inflammatory cytokines (IL-1, TNF-alpha).
  • Activated MKK3/6 forms complexes with p38 in FLS, leading to downstream signaling.

Conclusions:

  • MKK3 and MKK6 are activated in the RA synovium, representing the first documentation in human inflammatory disease.
  • These kinases play a significant role in regulating p38 activation in RA.
  • MKK3 and MKK6 represent potential therapeutic targets for controlling pro-inflammatory cytokine production in RA.

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