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.
Original language | English |
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Article number | 108153 |
Journal | Pharmacology and Therapeutics |
Volume | 235 |
Early online date | 1 Feb 2022 |
DOIs | |
State | Published - Jul 2022 |
Bibliographical note
Funding Information:We wish to thank Dr. Allan Bar-Sinai for useful comments on the manuscript. Works in the laboratories of W.S.F.W. and D.E. were supported by the Singapore National Research Foundation under its HUJ-NUS partnership in the Campus for Research Excellence and Technological Enterprise (grant R-184-000-313-592 ), and by the Israel Science Foundation (grant 1463/18 ). D.E. holds a Wolfson family chair in Biochemistry. All figures were created with BioRender.com .
Funding Information:
We wish to thank Dr. Allan Bar-Sinai for useful comments on the manuscript. Works in the laboratories of W.S.F.W. and D.E. were supported by the Singapore National Research Foundation under its HUJ-NUS partnership in the Campus for Research Excellence and Technological Enterprise (grant R-184-000-313-592), and by the Israel Science Foundation (grant 1463/18). D.E. holds a Wolfson family chair in Biochemistry. All figures were created with BioRender.com.
Publisher Copyright:
© 2022
Keywords
- Chronic inflammation
- Hsp27
- MK2
- Mitogen-activated protein kinase