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Title: Targeting the p38α pathway in chronic inflammatory diseases: Could activation, not inhibition, be the appropriate therapeutic strategy?
Authors: Heng, CKM
Gilad, N
Darlyuk-Saadon, I
Wong, WSF 
Engelberg, D 
Keywords: Chronic inflammation
Mitogen-activated protein kinase
Inflammation Mediators
Mitogen-Activated Protein Kinase 14
Issue Date: 1-Jul-2022
Publisher: Elsevier BV
Citation: Heng, CKM, Gilad, N, Darlyuk-Saadon, I, Wong, WSF, Engelberg, D (2022-07-01). Targeting the p38α pathway in chronic inflammatory diseases: Could activation, not inhibition, be the appropriate therapeutic strategy?. Pharmacology and Therapeutics 235 : 108153-. ScholarBank@NUS Repository.
Abstract: 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.
Source Title: Pharmacology and Therapeutics
ISSN: 01637258
DOI: 10.1016/j.pharmthera.2022.108153
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