Dept. of Pharmacology, Univ. of Illinois at Chicago, Chicago, IL 60612, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 May 1;302(9):L866-74. doi: 10.1152/ajplung.00277.2011. Epub 2012 Feb 3.
Mitogen-activated protein kinases (MAPKs) play a critical role in inflammation. Although activation of MAPK in inflammatory cells has been studied extensively, much less is known about the inactivation of these kinases. MAPK phosphatase 5 (MKP5) is a member of the dual-specificity phosphatase family that dephosphorylates activated MAPKs. Here we report that MKP5 protects sepsis-induced acute lung injury. Mice lacking MKP5 displayed severe lung tissue damage following LPS challenge, characterized with increased neutrophil infiltration and edema compared with wild-type (WT) controls. In response to LPS, MKP5-deficient macrophages produced significantly more inflammatory factors including inflammatory cytokines, nitric oxide, and superoxide. Phosphorylation of p38 MAPK, JNK, and ERK were enhanced in MKP5-deficient macrophages upon LPS stimulation. Adoptive transfer of MKP5-deficient macrophages led to more severe lung inflammation than transfer of WT macrophages, suggesting that MKP5-deficient macrophages directly contribute to acute lung injury. Taken together, these results suggest that MKP5 is crucial to homeostatic regulation of MAPK activation in inflammatory responses.
丝裂原活化蛋白激酶（MAPKs）在炎症中起着关键作用。虽然已经广泛研究了炎症细胞中 MAPK 的激活，但对这些激酶的失活知之甚少。MAPK 磷酸酶 5（MKP5）是双特异性磷酸酶家族的一员，可使活化的 MAPK 去磷酸化。本文报道 MKP5 可保护内毒素诱导的急性肺损伤。与野生型（WT）对照相比，缺乏 MKP5 的小鼠在 LPS 挑战后表现出严重的肺组织损伤，其特点是中性粒细胞浸润和水肿增加。对 LPS 的反应中，MKP5 缺陷型巨噬细胞产生的炎症因子（包括炎症细胞因子、一氧化氮和超氧化物）明显更多。LPS 刺激后，MKP5 缺陷型巨噬细胞中 p38 MAPK、JNK 和 ERK 的磷酸化增强。MKP5 缺陷型巨噬细胞的过继转移导致比 WT 巨噬细胞的转移更严重的肺炎症，表明 MKP5 缺陷型巨噬细胞直接导致急性肺损伤。总之，这些结果表明 MKP5 对炎症反应中 MAPK 激活的内稳态调节至关重要。
