Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 366, Issue 1, Pages 104-109Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2007.11.091
Keywords
Raw 264.7 cells; inflammation; cAMP; Epac; PGE(2); prostacyclin; macrophage; tumor necrosis factor-alpha; lipopolysaccharide
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Funding
- NIGMS NIH HHS [P50 GM015431-410001, GM015431, P01 GM015431, P50 GM015431] Funding Source: Medline
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Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that may contribute to the pathogenesis of septic shock, rheumatoid arthritis, cancer, and diabetes. Prostaglandins endogenously produced by macrophages act in an autocrine fashion to limit TNF-alpha production. We investigated the timing and signaling pathway of prostaglandin-mediated inhibition of TNF-alpha production in Raw 264.7 and J774 macrophages. TNF-alpha mRNA levels were rapidly modulated by PGE(2) or carbaprostacylin. PGE2 or carbaprostacyclin prevented and rapidly terminated on-going TNF-alpha gene transcription within 15 min of prostaglandin treatment. Selective activation of PKA type I, but not PKA type II or Epac, with chemical analogs of cAMP was sufficient to inhibit LPS-induced TNF-alpha mRNA levels. The mechanisms by which prostaglandins limit TNF-alpha mRNA levels may underlie endogenous regulatory mechanisms that limit inflammation, and may have important implications for understanding chronic inflammatory disease pathogenesis. (C) 2007 Elsevier Inc. All rights reserved.
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