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Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals

Aristides G Eliopoulos1, Calin D Dumitru, Chun-Chi Wang

  • 1Kimmel Cancer Center, Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA. ptsichlis@lifespan.org

The EMBO Journal
|September 18, 2002
PubMed

Insights

Tpl2 kinase regulates inflammatory responses to bacterial lipopolysaccharide (LPS). Tpl2 deficiency in macrophages reduces prostaglandin E2 and COX-2, key inflammatory mediators, highlighting Tpl2

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Biology

Background:

  • Macrophage activation by lipopolysaccharide (LPS) triggers pro-inflammatory cytokine and mediator release.
  • Tpl2/Cot kinase deficiency impairs TNF-alpha production and confers resistance to endotoxin shock.
  • ERK-dependent post-transcriptional defects are implicated in Tpl2-deficient responses.

Purpose of the Study:

  • To investigate the role of Tpl2 kinase in regulating prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated macrophages.
  • To elucidate the signaling pathway downstream of Tpl2 involved in COX-2 regulation.

Main Methods:

  • Bone marrow-derived macrophages from wild-type and Tpl2-deficient mice were stimulated with LPS.
  • Quantitative analysis of COX-2 and PGE2 levels.
  • Western blotting and phosphoprotein analysis to assess signaling pathways (ERK, p90Rsk, Msk1, CREB).

Main Results:

  • Tpl2(-/-) macrophages exhibited significantly lower levels of COX-2 and PGE2 compared to wild-type macrophages upon LPS stimulation.
  • Tpl2-mediated regulation of COX-2 expression was dependent on ERK signaling.
  • The pathway involved ERK activation of p90Rsk and Msk1, leading to CREB phosphorylation and subsequent COX-2 transcription.

Conclusions:

  • Prostaglandin E2 and COX-2 are identified as downstream targets of Tpl2 signaling in response to LPS.
  • Tpl2 plays a crucial role in the transcriptional regulation of COX-2 via the ERK/p90Rsk/Msk1/CREB pathway.
  • These findings implicate Tpl2 in the broader pathophysiology of inflammation beyond TNF-alpha production.

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