Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore; Singapore-HUJ Alliance for Research and Enterprise, Molecular Mechanisms of Inflammatory Disease Program, National University of Singapore, 138602, Singapore.
Singapore-HUJ Alliance for Research and Enterprise, Molecular Mechanisms of Inflammatory Disease Program, National University of Singapore, 138602, Singapore; Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Pharmacol Ther. 2022 Jul;235:108153. doi: 10.1016/j.pharmthera.2022.108153. Epub 2022 Feb 1.
Chronic inflammatory diseases (CIDs) afflict millions worldwide and remain incurable. The mitogen-activated protein kinase (MAPK) p38α is a critical node in the intricate acute inflammatory response. It induces the production of various pro-inflammatory mediators, primarily via the MAPK-activated protein kinase 2 (MK2). This, coupled with its sustained activation in CIDs, has led to the assumption that dysregulated pro-inflammatory p38α-dependent pathways are central drivers of chronic inflammation. Inhibiting the p38α cascade thus seems a logical therapeutic strategy, leading to significant efforts towards developing p38α- and MK2-specific inhibitors. However, recent studies raise the possibility that the effects of chronic p38α activation in CIDs have been misinterpreted. In cell cultures and murine models, constitutive p38α activity causes dramatic downregulation, rather than activation, of downstream elements such as MK2, via the ubiquitin-proteasome system, and phospho-Hsp27. Perhaps, sustained p38α activity promotes CIDs by inducing degradation of essential components of the p38α pathway. If this notion is genuine, then the current pharmacological strategy, focused on the inhibition of these components, is counter-productive and may explain why no p38α or MK2 inhibitor has made it to the clinic. It could be that an appropriate strategy should involve restoring or inducing certain p38α targets instead.
慢性炎症性疾病（CIDs）困扰着全球数百万人，且目前仍然无法治愈。丝裂原活化蛋白激酶（MAPK）p38α 是复杂的急性炎症反应中的一个关键节点。它通过 MAPK 激活的蛋白激酶 2（MK2）诱导各种促炎介质的产生。再加上其在 CIDs 中的持续激活，导致人们假设失调的促炎 p38α 依赖性途径是慢性炎症的主要驱动因素。因此，抑制 p38α 级联反应似乎是一种合理的治疗策略，这导致了针对开发 p38α 和 MK2 特异性抑制剂的大量努力。然而，最近的研究提出了这样一种可能性，即 CIDs 中慢性 p38α 激活的作用可能被误解了。在细胞培养和小鼠模型中，通过泛素-蛋白酶体系统和磷酸化热休克蛋白 27（phospho-Hsp27），组成型 p38α 活性导致下游元件（如 MK2）的急剧下调，而不是激活。也许，持续的 p38α 活性通过诱导 p38α 途径的必需成分降解来促进 CIDs。如果这一观点是正确的，那么目前专注于抑制这些成分的药理学策略是适得其反的，这可能解释了为什么没有一种 p38α 或 MK2 抑制剂能够进入临床。也许适当的策略应该包括恢复或诱导某些 p38α 靶标。
