Reversal of an interferon-gamma-resistant phenotype by poly(I:C): possible role of double-stranded RNA-activated kinase in interferon-gamma signaling.
Indoleamine 2,3-dioxygenase (IDO) is induced in neoplastic cell lines by interferon-gamma (IFN-gamma) treatment. In ME180 cervical carcinoma cells, there is a rapid increase in IDO mRNA accumulation beginning at 4 h after IFN-gamma treatment and continuing for at least 24 h. The IFN-gamma-resistant mutant of ME180, IR3B6B, expresses very low levels of IDO message after IFN-gamma treatment. However, pretreatment of this mutant with poly(I:C) restores normal levels of IDO mRNAs and IDO enzyme activity. Poly(I:C) mediated reversal of the IFN-gamma-resistant phenotype and induction of IDO mRNA are inhibited by 2-aminopurine. In vitro phosphorylation of calf thymus histone using the immunoprecipitated p68 kinase prepared from IFN-gamma-treated ME180 and IR3B6B cells revealed the deficiency of activation of this kinase in IR3B6B cells after IFN-gamma treatment, and treatment of this mutant cells with poly(I:C) restores p68 kinase activity. From these results, we conclude that a double-stranded RNA-dependent kinase is activated by IFN-gamma treatment and its activation correlates with IFN-gamma-mediated induction of the IDO gene.
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Department of Biology, Indiana University, Bloomington 47405.
Taylor
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D004351:Drug Resistance / Q000235:genetics; D004789:Enzyme Activation; D006657:Histones / Q000737:chemistry; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D011070:Poly I-C / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012330:RNA, Double-Stranded / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D019892:eIF-2 Kinase
D006657:Histones; D012330:RNA, Double-Stranded; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D011070:Poly I-C