Institute of Molecular Virology (IMV), Centre for Molecular Biology of Inflammation (ZMBE), and.
Department of Pediatric Rheumatology and Immunology, Westfälische Wilhelms University, Münster, Germany;
FASEB J. 2014 Oct;28(10):4235-46. doi: 10.1096/fj.14-249599. Epub 2014 Jun 16.
MK2 and MK3 are downstream targets of p38 and ERK1/2. They control the mRNA stability of several inflammatory cytokines, including TNF-α and IL-10. Whereas MK2 is expressed ubiquitously, the expression of MK3 is restricted to muscle, liver, and heart tissues and T and NK cells. Using Mk-deficient and wild-type (WT) mice, we demonstrated an inhibitory effect of MK3, but not of MK2, on interferon (IFN)-γ expression in T and NK lymphocytes. The results provided evidence that the inhibitory effect of MK3 is based on negative feedback phosphorylation of p38 and ERK1/2, which causes decreased binding of Stat4 to the IFN-γ promoter and reduced expression of IFN-γ mRNA and protein. Consequently, all Mk3(-/-) mice challenged with the Th1-inducing influenza A virus (IAV) survived the WT LD50 virus dose. The reduced disease severity in the Mk3(-/-) mice was accompanied by a >10-fold reduction in viral lung titer and an increase in the number of activated NK cells and enhanced Th1 activation of CD4 T cells. Thus, our data describe the protein kinase MK3 as a novel regulator of the innate and adaptive immune responses.-Köther, K., Nordhoff, C., Masemann, D., Varga, G., Bream, J. H., Gaestel, M., Wixler, V., Ludwig, S. MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T-cell development upon influenza A virus infection.
MK2 和 MK3 是 p38 和 ERK1/2 的下游靶标。它们控制几种炎症细胞因子的 mRNA 稳定性，包括 TNF-α 和 IL-10。MK2 广泛表达，而 MK3 的表达局限于肌肉、肝脏和心脏组织以及 T 和 NK 细胞。使用 Mk 缺陷型和野生型（WT）小鼠，我们证明了 MK3 而非 MK2 对 T 和 NK 淋巴细胞中干扰素（IFN）-γ表达的抑制作用。结果提供了证据表明，MK3 的抑制作用基于 p38 和 ERK1/2 的负反馈磷酸化，这导致 Stat4 与 IFN-γ 启动子的结合减少和 IFN-γ mRNA 和蛋白的表达减少。因此，所有用 Th1 诱导的流感 A 病毒（IAV）挑战的 Mk3(-/-) 小鼠都存活了 WT LD50 病毒剂量。Mk3(-/-) 小鼠疾病严重程度降低伴随着病毒肺部滴度降低 10 倍以上，激活的 NK 细胞数量增加，以及 CD4 T 细胞 Th1 激活增强。因此，我们的数据将蛋白激酶 MK3 描述为先天和适应性免疫反应的新型调节剂。-Köther，K.，Nordhoff，C.，Masemann，D.，Varga，G.，Bream，J. H.，Gaestel，M.，Wixler，V.，Ludwig，S. MAPKAP 激酶 3 抑制流感 A 病毒感染时的 Ifng 基因表达，并减弱 NK 细胞细胞毒性和 Th1 CD4 T 细胞发育。
