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Anti-inflammatory roles of p38α MAPK in macrophages are context dependent and require IL-10

Abbas Raza1, Jessica W Crothers2, Mahalia M McGill3

  • 1Division of Immunobiology, Department of Medicine, College of Medicine, University of Vermont, Burlington, Vermont, USA.

Journal of Leukocyte Biology
|September 8, 2017
PubMed

Insights

The p38 mitogen-activated protein kinase (MAPK) pathway has dual roles in inflammation. Inhibiting this pathway may require targeting its anti-inflammatory functions, like Interleukin-10 (IL-10) production, for therapeutic benefit.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • The p38 MAPK pathway is a key regulator of inflammatory responses in myeloid cells.
  • Despite preclinical promise, p38 inhibitors have failed in clinical trials for inflammatory diseases.
  • Potential reasons for failure include the pathway's complex roles and inhibitor selectivity.

Purpose of the Study:

  • To investigate the dual pro- and anti-inflammatory functions of p38α signaling in macrophages.
  • To understand how different inhibition methods affect p38α activity and inflammatory outcomes.
  • To explore strategies for enhancing the therapeutic efficacy of p38 inhibitors.

Main Methods:

  • In vivo and in vitro experiments using macrophages.
  • Comparison of genetic versus pharmacologic inhibition of p38α.
  • Assessment of cytokine production, including Interleukin-10 (IL-10).
  • Evaluation in a spontaneous model of colitis.

Main Results:

  • p38α signaling exhibits both pro- and anti-inflammatory functions, dependent on stimulus and inhibition method.
  • Second-generation p38 inhibitors show increased specificity but can block anti-inflammatory actions.
  • Anti-inflammatory roles of p38α are linked to IL-10 production.
  • Inhibition of p38α is protective in a colitis model when IL-10 is absent.

Conclusions:

  • The complex roles of p38α signaling contribute to the limited clinical success of p38 inhibitors.
  • Targeting p38 MAPK may require strategies that account for its anti-inflammatory functions.
  • Simultaneous modulation of p38-dependent mediators like IL-10 could improve therapeutic outcomes.
Keywords:
IBDautoimmunitycolitisdrugpharmacologic inhibitor

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