Interferon (IFN) 13 Acts Downstream of IFN-~/-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-~

Interferon (IFN) ",/, a cardinal proinflammatory cytokine, induces expression of the gene products of the class II locus of the major histocompatibility complex (MHC), whereas IFN-0t or -[3 suppresses M H C class II expression. The mechanism of IFN-13-mediated M H C class II inhibition has been unclear. Recently, a novel factor termed class II transactivator (CIITA) has been identified as essential for IFN-~/-induced M H C class II transcription. We studied the status of IFN-~/-induced CIITA messenger P, NA (mI(NA) accumulation and CIITA-driven transactivation in IFN-13-treated cells and used cell lines that had defined defects in the type I IFN response pathway to address the roles of IFN signaling components in the inhibition of M H C class II induction. IFN-~ treatment did not suppress IFN-~-induced accumulation of CIITA m R ~ A . After cells were stably transfected with CIITA, endogenous M H C class II genes were constitutively expressed, and M H C class II promoters, delivered by transfection, were actively transcribed in CIITA-expressing cells. Expression of these promoters was significantly impaired by pretreatment with IFN-[3. These results suggest that IFN-[3 acts downstream of CIITA m R N A accumulation, and acts in part by reducing the functional competence of CIITA for transactivating M H C class II promoters. IFN stimulated gene factor 3 (ISGF3) was essential for IFN-[3 to mediate inhibition of M H C class II induction, regardless of whether M H C class II transcription was stimulated by IFN-~ or directly by CIITA expression. Results of these experiments suggest that inhibition of M H C class II in IFN-[3-treated cells requires expression of gene(s) directed by the ISGF3-IFN-stimulated response element pathway, and that these gene product(s) may act by blocking CIITA-driven transcription of M H C class II promoters.