@article{b4f602200adc4abfbde79c79ae15160c,
title = "Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals",
abstract = "p38α activation of multiple effectors may underlie the failure of global p38α inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38α activation of the proinflammatory kinase MK2 while sparing p38a activation of PRAK and ATF2. Next, the hypothesis that the p38α-MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1{\ss} expression by promoting IL-1{\ss} mRNA degradation. Thus, IL-1{\ss} is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α-MK2. CDD-450 also accelerated TNF-a and IL-6 mRNA decay, inhibited inflammation in mice with cryopyrinopathy, and was as efficacious as global p3α inhibitors in attenuating arthritis in rats and cytokine expression by cells from patients with cryopyrinopathy and rheumatoid arthritis. These findings have clinical translation implications as CDD-450 offers the potential to avoid tachyphylaxis associated with global p38α inhibitors that may result from their inhibition of non-MK2 substrates involved in antiinflammatory and housekeeping responses.",
author = "Chun Wang and Susan Hockerman and Jacobsen, {E. Jon} and Yael Alippe and Selness, {Shaun R.} and Hope, {Heidi R.} and Hirsch, {Jeffrey L.} and Mnich, {Stephen J.} and Saabye, {Matthew J.} and Hood, {William F.} and Bonar, {Sheri L.} and Yousef Abu-Amer and Ariela Haimovich and Hoffman, {Hal M.} and Monahan, {Joseph B.} and Gabriel Mbalaviele",
note = "Funding Information: We thank Dr. Evan Dick, Walter Smith, and Dr. Deborah V. Novack for critical reading of the manuscript, and we thank Dr. Can-Xin Xu for technical assistance. We also thank Washington University Musculoskeletal Research Center, National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases P30 AR057235, and National Institutes of Health/Clinical and Translational Science Awards grant UL1 TR000448. Funding Information: This work was supported by National Institutes of Health/ National Institute of Arthritis and Musculoskeletal and Skin Diseases grants AR064755 and AR068972 to G. Mbalaviele. Y. Abu-Amer is supported by National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases grants AR049192 and AR054326. Publisher Copyright: {\textcopyright} 2018 Wang et al.",
year = "2018",
month = may,
day = "1",
doi = "10.1084/jem.20172063",
language = "English",
volume = "215",
pages = "1315--1325",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
number = "5",
}