Reversal of an Interferon-γ-Resistant Phenotype by Poly(I:C): Possible Role of Double-Stranded RNA-Activated Kinase in Interferon-γ Signaling

Indoleamine 2,3-dioxygenase (IDO) is induced in neoplastic cell lines by interferon-γ (IFN-γ) treatment. In ME180 cervical carcinoma cells, there is a rapid increase in IDO mRNA accumulation beginning at 4 h after IFN-γ treatment and continuing for at least 24 h. The IFN-γ-resistant mutant of ME180, IR3B6B, expresses very low levels of IDO message after IFN-γ 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-γresistant 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-γ-treated ME180 and IR3B6B cells revealed the deficiency of activation of this kinase in IR3B6B cells after IFN-γ 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-γ treatment and its activation correlates with IFN-γ-mediated induction of the IDO gene.