TNF induces c-fos via a novel pathway requiring conversion of arachidonic acid to a lipoxygenase metabolite.
Tumour necrosis factor (TNF), a lymphokine released by activated macrophages, has diverse effects on a wide variety of cell types. TNF exerts these effects via specific cell surface receptors; however little is known of the biochemical events that ensue. We have shown that TNF rapidly induces the proto-oncogenes c-fos and c-jun in the adipogenic TA1 cell line and have used these responses to characterize the intracellular mediators of TNF action. We find that arachidonic acid, which is released in response to TNF, induces c-fos, but not c-jun mRNA in quiescent TA1 cells. Pretreatment of the cells with lipoxygenase inhibitors abolishes the induction of c-fos by TNF, while the induction of c-jun is unaffected; in contrast, a cyclooxygenase inhibitor has no effect on either response. Finally, we have demonstrated that TNF stimulates production of lipoxygenase metabolites in TA1 cells and that one of these, 5-HPETE, induces c-fos, but not c-jun. These data suggest that TNF activates two second messenger pathways, one of which is dependent on release of arachidonic acid and its subsequent conversion to a lipoxygenase metabolite.
Haliday
E M
EM
Department of Pharmacology, School of Medicine, Stanford University, CA 94305.
Ramesha
C S
CS
Ringold
G
G
D001095:Arachidonic Acids / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008084:Lipoxygenase / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011519:Proto-Oncogenes / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D001095:Arachidonic Acids; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D008084:Lipoxygenase; D011505:Protein-Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate