Selective Inhibition of the p38α MAPK-MK2 Axis Inhibits Inflammatory Cues Including Inflammasome Priming Signals

J Exp Med. 2018 May 7;215(5):1315-1325. doi: 10.1084/jem.20172063. Epub 2018 Mar 16.

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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arthritis / pathology
  • Bone and Bones / pathology
  • Cytokines / biosynthesis
  • Humans
  • Inflammasomes / metabolism*
  • Inflammation / pathology*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Joints / pathology
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Stability
  • Rats, Inbred Lew
  • Signal Transduction*

Substances

  • Cytokines
  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 14