Prostaglandin E₂ inhibits tumor necrosis factor-alpha RNA through PKA type I

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• 作者：Jennifer B. Stafford ; Lawrence J. Marnett
• 关键词：Raw 264.7 cells ; Inflammation ; cAMP ; Epac ; PGE₂ ; Prostacyclin ; Macrophage ; Tumor necrosis factor-alpha ; Lipopolysaccharide
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2008
• 出版时间：1 February 2008
• 年：2008
• 卷：366
• 期：1
• 页码：104-109
• 全文大小：457 K

文摘

Tumor necrosis factor-alpha (TNF-α) 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-α production. We investigated the timing and signaling pathway of prostaglandin-mediated inhibition of TNF-α production in Raw 264.7 and J774 macrophages. TNF-α mRNA levels were rapidly modulated by PGE₂ or carbaprostacylin. PGE₂ or carbaprostacyclin prevented and rapidly terminated on-going TNF-α 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-α mRNA levels. The mechanisms by which prostaglandins limit TNF-α mRNA levels may underlie endogenous regulatory mechanisms that limit inflammation, and may have important implications for understanding chronic inflammatory disease pathogenesis.