INRS-Institut Armand-Frappier, Laval, QC, Canada.
Immunology. 2009 Sep;128(1 Suppl):e652-60. doi: 10.1111/j.1365-2567.2009.03055.x. Epub 2009 Jan 23.
Members of the protein kinase C (PKC) family are activated by interferon-gamma (IFN-gamma) and modulate IFN-gamma-induced cellular responses by regulating the activity of transcription factors. We previously reported that PKC-alpha enhances the ability of IFN regulatory factor-1 to transactivate the class II transactivator (CIITA) promoter IV in IFN-gamma-stimulated macrophages. In addition, we showed that IFN-gamma induces the nuclear translocation of PKC-alpha but the mechanisms for this remain to be elucidated. In this study, we sought to identify signalling pathways involved in IFN-gamma-induced activation of PKC-alpha and to characterize their potential roles in modulating IFN-gamma-induced responses in macrophages. IFN-gamma-mediated nuclear translocation of PKC-alpha was a Janus activated kinase 2 (JAK2)-independent process, which required phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase (MAPK). However, PKC-alpha phosphorylation was independent of PI3K and p38 MAPK, indicating that IFN-gamma-induced phosphorylation and nuclear translocation of PKC-alpha are mediated by distinct mechanisms. In addition, inhibition of PI3K, but not of p38 MAPK, strongly impaired IFN-gamma-induced CIITA and MHC II gene expression. Finally, PKC-alpha associated with signal transducer and activator of transcription 1 (STAT1) and was required for the phosphorylation of STAT1 on serine 727 in IFN-gamma-stimulated macrophages. Taken together, our data indicate that PI3K and p38 MAPK modulate IFN-gamma-stimulated PKC-alpha nuclear translocation independently of JAK2 activity and that both PI3K and PKC-alpha are required for type IV CIITA and MHC II gene expression in IFN-gamma-stimulated macrophages.
蛋白激酶 C（PKC）家族成员可被干扰素-γ（IFN-γ）激活，并通过调节转录因子的活性来调节 IFN-γ 诱导的细胞反应。我们之前报道过 PKC-α 增强 IFN 调节因子-1 激活 IFN-γ 刺激的巨噬细胞中 II 类转录激活物（CIITA）启动子 IV 的能力。此外，我们还表明 IFN-γ 诱导 PKC-α 的核转位，但这一机制仍有待阐明。在这项研究中，我们试图确定 IFN-γ 诱导的 PKC-α 激活所涉及的信号通路，并描述它们在调节 IFN-γ 诱导的巨噬细胞反应中的潜在作用。IFN-γ 介导的 PKC-α 核转位是一种 Janus 激活激酶 2（JAK2）非依赖性过程，需要磷脂酰肌醇 3-激酶（PI3K）和 p38 丝裂原活化蛋白激酶（p38 MAPK）。然而，PKC-α 的磷酸化不依赖于 PI3K 和 p38 MAPK，表明 IFN-γ 诱导的 PKC-α 磷酸化和核转位是由不同的机制介导的。此外，抑制 PI3K，但不抑制 p38 MAPK，强烈抑制 IFN-γ 诱导的 CIITA 和 MHC II 基因表达。最后，PKC-α 与信号转导和转录激活因子 1（STAT1）相关，并在 IFN-γ 刺激的巨噬细胞中 STAT1 丝氨酸 727 的磷酸化中起作用。总之，我们的数据表明，PI3K 和 p38 MAPK 独立于 JAK2 活性调节 IFN-γ 刺激的 PKC-α 核转位，PI3K 和 PKC-α 均是 IFN-γ 刺激的巨噬细胞中 IV 型 CIITA 和 MHC II 基因表达所必需的。
