Selective inhibition of the p38? MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals.

ABSTRACT: p38? activation of multiple effectors may underlie the failure of global p38? inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38? activation of the proinflammatory kinase MK2 while sparing p38? activation of PRAK and ATF2. Next, the hypothesis that the p38?-MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1? expression by promoting IL-1? mRNA degradation. Thus, IL-1? is regulated not only transcriptionally by NF-?B and posttranslationally by the inflammasomes but also posttranscriptionally by p38?-MK2. CDD-450 also accelerated TNF-? and IL-6 mRNA decay, inhibited inflammation in mice with cryopyrinopathy, and was as efficacious as global p38? 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 p38? inhibitors that may result from their inhibition of non-MK2 substrates involved in antiinflammatory and housekeeping responses.

SUBMITTER: Wang C 

PROVIDER: S-EPMC5940269 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature