| First Author | Wang C | Year | 2018 |
| Journal | J Exp Med | Volume | 215 |
| Issue | 5 | Pages | 1315-1325 |
| PubMed ID | 29549113 | Mgi Jnum | J:262857 |
| Mgi Id | MGI:6155976 | Doi | 10.1084/jem.20172063 |
| Citation | Wang C, et al. (2018) Selective inhibition of the p38alpha MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals. J Exp Med 215(5):1315-1325 |
| abstractText | p38alpha activation of multiple effectors may underlie the failure of global p38alpha inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38alpha activation of the proinflammatory kinase MK2 while sparing p38alpha activation of PRAK and ATF2. Next, the hypothesis that the p38alpha-MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1beta expression by promoting IL-1beta mRNA degradation. Thus, IL-1beta is regulated not only transcriptionally by NF-kappaB and posttranslationally by the inflammasomes but also posttranscriptionally by p38alpha-MK2. CDD-450 also accelerated TNF-alpha and IL-6 mRNA decay, inhibited inflammation in mice with cryopyrinopathy, and was as efficacious as global p38alpha 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 p38alpha inhibitors that may result from their inhibition of non-MK2 substrates involved in antiinflammatory and housekeeping responses. |
