Impaired class II transactivator expression in mice lacking interferon regulatory factor-2

Class II transactivator (CIITA) is required for both constitutive and induc ible expression of MHC class II genes. IFN-gamma induced expression of CIIT A in various cell types is directed by CIITA type IV promoter. The two tran sactivators, STAT1 and IRF-1, mediate the IFN-gamma activation of the type IV promoter by binding to the GAS and IRF-E of the promoter, respectively. In addition to IRF-1, IRF-2, another member of the IRF family, also activat es the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to act ivate the promoter in transient transfection assays, IRF-1 and IRF-2 can co -occupy the IRF-E of the human CIITA type IV promoter. To understand the ef fect of loss of IRF-2 on the endogenous CIITA expression, we assayed for CI ITA expression in IRF-2 knock-out mice. Both basal and IFN-gamma induced CI ITA expression were reduced in IRF-2 knock-out mice. At least half of the a mount of inducible CIITA mRNA depends on IRF-2, The reduction of IFN-gamma induced CIITA mRNA in IRF-2: knock-out mice was due to the reduction of the type IV CIITA mRNA induction. The reduction of basal CIITA mRNA was appare ntly due to the reduction of CIITA mRNA originating from other promoters. T hese data indicate that IRF-2, like IRF-1, plays a critical role in the reg ulation of the endogenous CIITA gene. The implications in understanding the previously described phenotypes of IRF-2 defective mice are discussed.