INTERFERON (IFN)-BETA ACTS DOWNSTREAM OF IFN-GAMMA-INDUCED CLASS-II TRANSACTIVATOR MESSENGER-RNA ACCUMULATION TO BLOCK MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II GENE-EXPRESSION AND REQUIRES THE 48-KD DNA-BINDING PROTEIN, ISGF3-GAMMA

Interferon (IFN) gamma, a cardinal proinflammatory cytokine, induces e xpression of the gene products of the class II locus of the major hist ocompatibility complex (MHC), whereas IFN-alpha or -beta suppresses MH C class II expression. The mechanism of IFN-beta-mediated MHC class II inhibition has been unclear. Recently, a novel factor termed class II transactivator (CIITA) has been identified as essential for IFN-gamma -induced MHC class II transcription. We studied the status of IFN-gamm a-induced CIITA messenger RNA (mRNA) accumulation and CIITA-driven tra nsactivation in IFN-beta-treated cells and used cell lines that had de fined defects in the type I IFN response pathway to address the roles of IFN signaling components in the inhibition of MHC class II inductio n. IFN-beta treatment did not suppress IFN-gamma-induced accumulation of CIITA mRNA. After cells were stably transfected with CIITA, endogen ous MHC class II genes were constitutively expressed, and MHC class II promoters, delivered by transfection, were actively transcribed in CI ITA-expressing cells. Expression of these promoters was significantly impaired by pretreatment with IFN-beta. These results suggest that IFN -beta acts downstream of CIITA mRNA accumulation, and acts in part by reducing the functional competence of CIITA for transactivating MHC cl ass II promoters. IFN stimulated gene factor 3 (ISGFS) gamma was essen tial for IFN-beta to mediate inhibition of MHC class II induction, reg ardless of whether MHC class II transcription was stimulated by IFN-ga mma or directly by CIITA expression. Results of these experiments sugg est that inhibition of MHC class II in IFN-beta-treated cells requires expression of gene(s) directed by the ISGF3-IFN-stimulated response e lement pathway, and that these gene product(s) may act by blocking CII TA-driven transcription of MHC class II promoters.