Biol Chem. 2013 Oct;394(10):1301-15. doi: 10.1515/hsz-2013-0197.
Inflammation is normally a fast and transient response to microbial invaders or sterile damage and has to be stringently controlled. The closely-related mitogen-activated protein kinase-activated protein kinases MK2 and MK3 are involved in both up- and down-regulation of inflammation in mammals and govern the inflammatory response at different regulatory levels of gene expression and with different kinetics. In conjunction with their activator MAP kinase p38, MK2 and MK3 stimulate the transcription of immediate-early genes including that of the mRNA-binding protein tristetraprolin (TTP). TTP competes with the constitutively expressed protein human antigen R in binding to the mRNA destabilizing adenylate-uridylate -rich element. MK2 and MK3 also regulate the activity of TTP by direct phosphorylation, determine stability and stimulate the translation of cytokine mRNAs. In addition, TTP controls its own re-synthesis via stability and translation of its mRNA in a phosphorylation-dependent manner. This results in a complex scenario of gene expression and guarantees fast up-regulation and intrinsic feedback control of the inflammatory response of macrophages. Inhibition of MK2/3 by small-molecule pharmaceutical inhibitors is an emerging strategy to manipulate the inflammatory response as a therapeutic option. This strategy could display advantages over the direct inhibition of MAP kinase p38.
炎症通常是对微生物入侵或无菌损伤的快速和短暂反应，必须严格控制。与丝裂原激活的蛋白激酶激活的蛋白激酶 MK2 和 MK3 密切相关，它们参与了哺乳动物的炎症的上调和下调，并在基因表达的不同调控水平上和不同的动力学上调控炎症反应。与它们的激活剂 MAP 激酶 p38 一起，MK2 和 MK3 刺激包括 mRNA 结合蛋白 tristetraprolin (TTP) 的即时早期基因的转录。TTP 与组成型表达的蛋白人抗原 R 竞争结合 mRNA 不稳定的腺嘌呤-尿嘧啶丰富元件。MK2 和 MK3 还通过直接磷酸化调节 TTP 的活性，决定其稳定性并刺激细胞因子 mRNAs 的翻译。此外，TTP 通过其 mRNA 的稳定性和翻译以磷酸化依赖的方式控制自身的重新合成。这导致了一个复杂的基因表达场景，并保证了巨噬细胞炎症反应的快速上调和内在反馈控制。小分子药物抑制剂抑制 MK2/3 是一种操纵炎症反应的新兴策略，作为一种治疗选择。这种策略可能比直接抑制 MAP 激酶 p38 具有优势。
