Involvement of an Inducible Factor in Interferon-γ-Mediated Accumulation of HLA Gene Transcripts

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Abstract
Earlier studies with a cDNA clone (C5-4) complementary to an interferon (IFN)-.gamma.-inducible mRNA showed that in human fibroblasts (FS-4). IFN-.gamma. induced the transcription of the cognate gene, but it required new protein synthesis (Caplen and Gupta, J. Biol. Chem. 263, 332-339, 1988). To determine whether such a strategy is used for the regulation of other cellular genes by IFN-.gamma., the regulation of the HLA class I and class II genes and another cellular gene for which a cDNA clone was isolated (C13) was studied. The results indicate that: (i) HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-.gamma. and IFN-.alpha.2, and it did not require new protein synthesis. (ii) In contrast, the transcription of the HLA-DR.alpha., was activated by IFN-.gamma. (and not by IFN-.alpha.2), but the accumulation of -DR.alpha. gene transcripts was strongly inhibited by cycloheximide or anisomycin, which indicated that there was a requirement for some newly synthesized protein factor(s) in this process, apparently at a step subsequent to transcriptional activation. We obtained evidence indicating that the putative protein factor(s) required is actually induced by IFN-.gamma.. (iii) IFN-.gamma.-induced transcription of the HLA-B gene was not inhibited by anisomycin or cycloheximide, but the accumulation of HLA-B transcripts plateauned sooner. This latter effect was not due to any toxicity of these inhibitors because it was observed if cycloheximide was added together with IFN-.gamma., but not if it was added a few hours later. Furthermore, if cycloheximide was added 24 h after IFN-.gamma., it actually caused a superinduction of HLA-B transcripts. The results suggest that some newly synthesized protein factor(s) may be required also for maximal accumulation of HLA-B gene transcripts following treatment with IFN-.gamma.. The results indicate a dual regulation of HLA class I and class II genes by IFN-.gamma., and involvement of multiple mechanisms in the regulation of cellular gene expression by IFN-.gamma.