In human cells treated with interferons, there is an increase in the amount of HLA-ABC and (32-microglobulin exposed on the cell surface. We have used a cloned HLA-A,B,C cDNA probe to demonstrate by molecular hybridization that this effect of interferon is preceded by a large increase in the amount of HLA mRNA in the cell. Thiseffect was found in five different human cell lines, with purified leukocyte and fibroblast interferons. The increase in HLA mRNA is comparable in its Idnetics and dose-response to the induction of (2'-5') oligo(A) synthetase mRNA by interferons. Therefore, interferons seem to activate at least two cellular genes which have different biochemical functions. Studies on the mechanism by which interferons (IFNs) inhibit virus multiplication have led to the discovery of several enzymes, inhibitors ofprotein biosynthesis, which are induced in cells exposed to IFNs (for review, see refs. 1-3). An assay for the mRNA of one of these enzymes, (2'-5') oligoadenylate synthetase (synthetase E), was developed and it was shown that IFNs induce, within a few hours, the accumulation of specific synthetase E mRNA in the cytoplasm of treated cells (4). Inhibitors of transcription and translation block the induction of synthetase E (5-8). The same is true of the IFN-induced eukaryotic initiation factor 2 protein kinase (5) and of 5-10 other proteins which can be detected by one-or two-dimensional polyacrylamide gel electrophoresis (9-13). Induction of these proteins by IFN therefore is likely to take place at the gene level.In addition to the above effects, IFNs also cause complex changes in the plasma membranes of cells (14). These changes alter the electric charge ofthe cells (15), decrease their motility (16), and influence cell-cell recognition events involved in the immune response (14,17). Biochemically, these membrane changes affect both the lipids (18) and several surface protein antigens (19,20). Thus, human IFNs increase the amounts of HLA-A,B,C antigens and of P2-microglobulin available for interaction with specific antibodies on the surface of human cells (21,22). These changes are specific because there is no increase in HLA-DR or in many other surface antigens. We wondered whether these membrane effects of IFNs were topical modifications in the exposure ofantigens on the cell surface or involved changes in gene expression similar to those found for synthetase E.To investigate this question we used a cloned HLA cDNA probe, pHLA-1 (23), to study the HLA-A,B,C mRNA levels in IFN-treated cells. Our results show that, in five human cell lines of lymphoblastoid and fibroblastic origins, both leukocyte IFN (IFN-a), and fibroblast IFN (IFN-,B) produce a large and rapid increase in HLA-A,B,C mRNA, which often precedes the increase in synthetase E mRNA. air. All cultures were grown at 37°C in the presence of 100 units of penicillin and 100 pg of streptomycin per ml. Human IFN-a was purified (31) from Sendai virus-infected chronic myelogenous leukemic cells, obtained from Institut Merieux (Lyon, F...