Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals
| Autor: | E. Jon Jacobsen, Matthew J. Saabye, Chun Wang, Jeffrey L. Hirsch, Sheri L. Bonar, Gabriel Mbalaviele, Shaun R. Selness, Hal M. Hoffman, Susan L. Hockerman, Yael Alippe, Joseph B. Monahan, William F. Hood, Stephen J. Mnich, Yousef Abu-Amer, Ariela Haimovich, Heidi R. Hope |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Inflammasomes medicine.medical_treatment RNA Stability Immunology Priming (immunology) Arthritis Protein Serine-Threonine Kinases Bone and Bones Proinflammatory cytokine Mitogen-Activated Protein Kinase 14 03 medical and health sciences Mice 0302 clinical medicine medicine Immunology and Allergy Animals Humans Interleukin 6 Protein Kinase Inhibitors Research Articles Inflammation biology Chemistry Kinase Brief Definitive Report Intracellular Signaling Peptides and Proteins Inflammasome medicine.disease Cell biology 030104 developmental biology Cytokine Rats Inbred Lew 030220 oncology & carcinogenesis biology.protein Cytokines Joints Signal transduction Cues medicine.drug Signal Transduction |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 |
| Popis: | A unique p38α MAPK–MK2 pathway inhibitor, CDD-450, is used to uncover the function of this protein complex in inflammasome priming signals. Importantly, CDD-450 is as efficacious as global p38α MAPK inhibitors in decreasing inflammation in disease models. 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 p38α 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-1β expression by promoting IL-1β mRNA degradation. Thus, IL-1β is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α–MK2. CDD-450 also accelerated TNF-α and IL-6 mRNA decay, inhibited inflammation in mice with cryopyrinopathy, and was as efficacious as global p38α 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. |
| Databáze: | OpenAIRE |
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