INTERFERON SIGNALING THROUGH ARACHIDONIC-ACID DEPENDENT PATHWAYS - A CLUE TO ADJUVANT THERAPY FOR CHRONIC VIRAL-HEPATITIS

Molecular mechanisms that mediate signal transduction by growth inhibitory cytokines are poorly understood. Type I (α and β) interferons (IFNs) are potent growth inhibitory cytokines whose biological activities depend on induced changes in gene expression. IFN‐α induced 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 interferonstimulated response element (ISRE). BPB also caused a dose‐dependent inhibition of IFN‐α‐stimulated ISRE‐dependent transcription in transient transfection assays. Specific inhibition of AA oxidation by eicosatetraynoic acid prevented IFN‐α induction of factors binding to ISRE. Treatment of intact cells with inhibitors of fatty acid cyclooxygenase or lipoxygenase enzymes resulted in amplification of IFN‐α‐induced ISRE binding and gene expression. Thus, IFN‐α receptor‐coupled AA hydrolysis may function in activation of latent factors by IFN‐α and provides a system for studying the role of AA metabolism in transduction of growth inhibitory signals. Copyright © 1991 American Association for the Study of Liver Diseases