Prostaglandin E2 inhibits tumor necrosis factor-alpha RNA through PKA type I.
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. PGE(2) 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.
Stafford
Jennifer B
JB
Department of Biochemistry, Vanderbilt University School of Medicine, 23rd Avenue South at Pierce, Nashville, TN 37232-0146, USA.
Marnett
Lawrence J
LJ
D000818:Animals; D002460:Cell Line; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D015232:Dinoprostone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D012313:RNA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D054743:Cyclic AMP-Dependent Protein Kinase Type I; D015232:Dinoprostone