The induction of major histocompatibility complex (MHC) class II proteins by interferon gamma (IFN-γ) in macrophages play an important role during immune responses. Here we explore the signaling pathways involved in the induction by IFN-γ of the MHC II transactivator (CIIta) required for MHC II transcriptional activation. Cyclophilin A (CypA) is required for IFN-γ-dependent induction of MHC II in macrophages, but not when it is mediated by GM-CSF. The effect of CypA appears to be specific because it does not affect the expression of other molecules or genes triggered by IFN-γ, such as FcγR, NOS2, Lmp2, and Tap1. We found that CypA inhibition blocked the IFN-γ-induced expression of CIIta at the transcriptional level in two phases. In an early phase, during the first 2 h of IFN-γ treatment, STAT1 is phosphorylated at Tyrosine 701 and Serine 727, residues required for the induction of the transcription factor IRF1. In a later phase, STAT1 phosphorylation and JNK activation are required to trigger CIIta expression. CypA is needed for STAT1 phosphorylation in this last phase and to bind the CIIta promoter. Our findings demonstrate that STAT1 is required in a two-step induction of CIIta, once again highlighting the significance of cross talk between signaling pathways in macrophages.

干扰素 γ (IFN-γ) 在巨噬细胞中诱导主要组织相容性复合物 (MHC) II 类蛋白在免疫反应过程中发挥重要作用。在这里，我们探讨了 IFN-γ 诱导MHC II 转录激活所需的 MHC II 反式激活因子 ( CIIta )所涉及的信号通路。亲环蛋白 A (CypA) 是 IFN-γ 依赖性诱导巨噬细胞中 MHC II 所必需的，但当它由 GM-CSF 介导时则不需要。CypA 的作用似乎是特异性的，因为它不影响由 IFN-γ 触发的其他分子或基因的表达，例如 FcγR、NOS2、Lmp2和Tap1。我们发现 CypA 抑制阻断了 IFN-γ 诱导的CIIta表达在转录水平分两个阶段。在早期阶段，在 IFN-γ 处理的前 2 小时，STAT1 在酪氨酸 701 和丝氨酸 727 处被磷酸化，这是诱导转录因子 IRF1 所需的残基。在后期，需要 STAT1 磷酸化和 JNK 激活来触发CIIta表达。在最后一个阶段，STAT1 磷酸化需要 CypA 并结合CIIta启动子。我们的研究结果表明，在CIIta的两步诱导中需要 STAT1 ，再次强调了巨噬细胞中信号通路之间串扰的重要性。