Sanders-Brown Center on Aging.
Aging Dis. 2010 Dec;1(3):199-211. Epub 2010 Sep 24.
Inflammation in the central nervous system (CNS) is a common feature of age-related neurodegenerative diseases. Proinflammatory cytokines, such as IL-1β and TNFα, are produced primarily by cells of the innate immune system, namely microglia in the CNS, and are believed to contribute to the neuronal damage seen in the disease. The p38 mitogen-activated protein kinase (MAPK) is one of the kinase pathways that regulate the production of IL-1β and TNFα. Importantly, small molecule inhibitors of the p38 MAPK family have been developed and show efficacy in blocking the production of IL-1β and TNFα. The p38 family consists of at least four isoforms (p38α, β, γ, δ) encoded by separate genes. Recent studies have begun to demonstrate unique functions of the different isoforms, with p38α being implicated as the key isoform involved in CNS inflammation. Interestingly, there is also emerging evidence that two downstream substrates of p38 may have opposing roles, with MK2 being pro-inflammatory and MSK1/2 being antiinflammatory. This review discusses the properties, function and regulation of the p38 MAPK family as it relates to cytokine production in the CNS.
中枢神经系统（CNS）中的炎症是与年龄相关的神经退行性疾病的共同特征。促炎细胞因子，如 IL-1β 和 TNFα，主要由先天免疫系统的细胞产生，即中枢神经系统中的小胶质细胞，据信它们有助于疾病中观察到的神经元损伤。p38 丝裂原活化蛋白激酶（MAPK）是调节 IL-1β 和 TNFα 产生的激酶途径之一。重要的是，已经开发出 p38 MAPK 家族的小分子抑制剂，并显示出阻断 IL-1β 和 TNFα 产生的功效。p38 家族由至少四个同工型（p38α、β、γ、δ）组成，由单独的基因编码。最近的研究开始证明不同同工型的独特功能，其中 p38α 被认为是涉及 CNS 炎症的关键同工型。有趣的是，也有越来越多的证据表明 p38 的两个下游底物可能具有相反的作用，MK2 具有促炎作用，而 MSK1/2 具有抗炎作用。这篇综述讨论了 p38 MAPK 家族的特性、功能和调节与其在 CNS 中细胞因子产生的关系。
