Signal transduction by interferon-alpha through arachidonic acid metabolism.
Molecular mechanisms that mediate signal transduction by growth inhibitory cytokines are poorly understood. Type I (alpha and beta) interferons (IFNs) are potent growth inhibitory cytokines whose biological activities depend on induced changes in gene expression. IFN-alpha induced the transient activation of phospholipase A2 in 3T3 fibroblasts and rapid hydrolysis of [3H]arachidonic acid (AA) from prelabeled phospholipid pools. The phospholipase inhibitor, bromophenacyl bromide (BPB), specifically blocked IFN-induced binding of nuclear factors to a conserved, IFN-regulated enhancer element, the interferon-stimulated response element (ISRE). BPB also caused a dose-dependent inhibition of IFN-alpha-induced ISRE-dependent transcription in transient transfection assays. Specific inhibition of AA oxygenation by eicosatetraynoic acid prevented IFN-alpha induction of factor binding to the ISRE. Treatment of intact cells with inhibitors of fatty acid cyclooxygenase or lipoxygenase enzymes resulted in amplification of IFN-alpha-induced ISRE binding and gene expression. Thus, IFN-alpha receptor-coupled AA hydrolysis may function in activation of latent transcription factors by IFN-alpha and provides a system for studying the role of AA metabolism in transduction of growth inhibitory signals.
Hannigan
G E
GE
Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Williams
B R
BR
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation; D007213:Indomethacin / Q000494:pharmacology; D007370:Interferon Type I / Q000502:physiology*; D016859:Lipoxygenase Inhibitors; D008244:Lysophosphatidylcholines / Q000378:metabolism; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D015290:Second Messenger Systems; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D000098:Acetophenones; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D007370:Interferon Type I; D016859:Lipoxygenase Inhibitors; D008244:Lysophosphatidylcholines; D010982:Platelet-Derived Growth Factor; D014157:Transcription Factors; D015117:5,8,11,14-Eicosatetraynoic Acid; D016718:Arachidonic Acid; D009637:Masoprocol; D010741:Phospholipases A; D054467:Phospholipases A2; C006821:4-bromophenacyl bromide; D007213:Indomethacin