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Activation of synovial cell p38 MAP kinase by macrophage migration inhibitory factor

Leilani L Santos1, Derek Lacey, Yuanhang Yang

  • 1Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Melbourne, Australia. lanie.santos@med.monash.edu.au

The Journal of Rheumatology
|June 2, 2004
PubMed
Abstract

Insights

Macrophage migration inhibitory factor (MIF) activates rheumatoid arthritis fibroblast-like synoviocytes via p38 MAP kinase, increasing COX-2 and IL-6. IL-8 production is independent of these pathways.

Area of Science:

  • Immunology
  • Molecular Biology
  • Rheumatology

Background:

  • Macrophage migration inhibitory factor (MIF) is a key proinflammatory cytokine in rheumatoid arthritis (RA) pathogenesis.
  • Fibroblast-like synoviocytes (FLS) play a critical role in RA joint inflammation.

Purpose of the Study:

  • To investigate the role of mitogen-activated protein (MAP) kinase pathways in MIF-induced FLS activation.
  • To determine the involvement of MAP kinases in the expression of cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), IL-6, and IL-8.

Main Methods:

  • Human RA FLS were stimulated with recombinant MIF.
  • MAP kinase activation (p38 and ERK) was assessed via Western blotting and specific inhibitors.
  • COX-2, PGE(2), IL-6, and IL-8 levels were quantified using flow cytometry, ELISA, and real-time PCR.

Main Results:

  • MIF induced p38 and ERK phosphorylation in FLS.
  • MIF significantly upregulated COX-2, IL-6, PGE(2), and IL-8.
  • Inhibition of p38 MAP kinase blocked MIF-induced COX-2, PGE(2), and IL-6.
  • ERK inhibition did not affect COX-2, PGE(2), or IL-6; neither inhibitor affected IL-8 induction.

Conclusions:

  • MIF activates COX-2 and IL-6 expression in RA FLS through p38 MAP kinase activation.
  • MIF induces IL-8 production via pathways independent of both p38 and ERK MAP kinases.

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