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The role of p38 mitogen-activated protein kinase in IL-1 beta transcription

J J Baldassare1, Y Bi, C J Bellone

  • 1Department of Pharmacological and Physiological Sciences, St. Louis University School of Medicine, St. Louis, MO 63104, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|May 5, 1999
PubMed

Insights

p38 mitogen-activated protein kinase (MAPK) inhibitors like SB203580 block Interleukin-1 beta (IL-1beta) gene transcription in monocytes. This study reveals p38 MAPK regulates IL-1beta via C/EBP/NFIL-6 transcription factors.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • p38 mitogen-activated protein kinase (MAPK) inhibitors block cytokine synthesis.
  • The specific role of p38 MAPK in regulating IL-1beta gene expression requires further elucidation.

Purpose of the Study:

  • To investigate the role of p38 MAPK in the transcriptional regulation of the IL-1beta cytokine gene in monocytic cell lines.
  • To identify the transcription factors involved in p38 MAPK-mediated IL-1beta regulation.

Main Methods:

  • Utilized the p38 MAPK inhibitor SB203580 in RAW264.7 and J774 monocytic cell lines stimulated with lipopolysaccharide (LPS).
  • Assessed IL-1beta protein and mRNA levels, performed nuclear run-off assays for RNA synthesis, and measured MAPKAP2 kinase activity.
  • Employed chloramphenicol acetyltransferase (CAT) reporter assays with C/EBP/NFIL-6 and NF-kappaB elements, and electrophoretic mobility shift assays (EMSA) for NF-kappaB activation.

Main Results:

  • SB203580 dose-dependently inhibited IL-1beta protein and mRNA, primarily by decreasing IL-1beta gene transcription (approx. 80% reduction).
  • SB203580 blocked LPS-stimulated p38 MAPK activity and inhibited C/EBP/NFIL-6-driven reporter activity, but only partially affected NF-kappaB-driven reporter activity.
  • LPS-stimulated NF-kappaB activation, as measured by EMSA, was not altered by SB203580, while TNF-alpha synthesis remained unaffected.

Conclusions:

  • p38 MAPK plays a critical role in the transcriptional regulation of the IL-1beta gene in monocytic cells.
  • The p38 MAPK pathway regulates IL-1beta transcription through C/EBP/NFIL-6 transcription factors.
  • NF-kappaB activation is not the primary mechanism for p38 MAPK-mediated IL-1beta regulation in this context.

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