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Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia
Judith Branger1, Bernt van den Blink, Sebastiaan Weijer
1Department of Infectious Diseases, Tropical Medicine, and AIDS, Academic Medical Center, and CLB and Laboratory for Clinical and Experimental Immunology, University of Amsterdam, Amsterdam, The Netherlands. j.branger@amc.uva.nl
Abstract:
The p38 mitogen-activated protein kinase (MAPK) participates in intracellular signaling cascades resulting in inflammatory responses. Therefore, inhibition of the p38 MAPK pathway may form the basis of a new strategy for treatment of inflammatory diseases. However, p38 MAPK activation during systemic inflammation in humans has not yet been shown, and its functional significance in vivo remains unclear. Hence, we exposed 24 healthy male subjects to an i.v. dose of LPS (4 ng/kg), preceded 3 h earlier by orally administered 600 or 50 mg BIRB 796 BS (an in vitro p38 MAPK inhibitor) or placebo. Both doses of BIRB 796 BS significantly inhibited LPS-induced p38 MAPK activation in the leukocyte fraction of the volunteers. Cytokine production (TNF-alpha, IL-6, IL-10, and IL-1R antagonist) was strongly inhibited by both low and high dose p38 MAPK inhibitor. In addition, p38 MAPK inhibition diminished leukocyte responses, including neutrophilia, release of elastase-alpha(1)-antitrypsin complexes, and up-regulation of CD11b with down-regulation of L-selectin. Finally, blocking p38 MAPK decreased C-reactive protein release. These data identify p38 MAPK as a principal mediator of the inflammatory response to LPS in humans. Furthermore, the anti-inflammatory potential of an oral p38 MAPK inhibitor in humans in vivo suggests that p38 MAPK inhibitors may provide a new therapeutic option in the treatment of inflammatory diseases.
Insights
p38 mitogen-activated protein kinase (MAPK) inhibition effectively reduced inflammatory responses in humans. This study demonstrates p38 MAPK
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- p38 mitogen-activated protein kinase (MAPK) is implicated in inflammatory signaling.
- Its role in human systemic inflammation and in vivo function requires elucidation.
- p38 MAPK pathway inhibition presents a potential therapeutic strategy for inflammatory diseases.
Purpose of the Study:
- To investigate the in vivo activation and functional significance of p38 MAPK during systemic inflammation in humans.
- To evaluate the efficacy of an oral p38 MAPK inhibitor (BIRB 796 BS) in modulating inflammatory responses.
Main Methods:
- 24 healthy males received intravenous lipopolysaccharide (LPS) with or without oral BIRB 796 BS.
- Leukocyte p38 MAPK activation, cytokine production, and inflammatory markers were assessed.
- Flow cytometry was used to analyze leukocyte surface marker expression.
Main Results:
- BIRB 796 BS significantly inhibited LPS-induced p38 MAPK activation in leukocytes.
- Both low and high doses of the inhibitor markedly reduced pro-inflammatory cytokine (TNF-alpha, IL-6, IL-10) production.
- Inhibition of p38 MAPK diminished leukocyte activation, elastase release, and C-reactive protein levels.
Conclusions:
- p38 MAPK is a key mediator of LPS-induced inflammatory responses in humans.
- Oral administration of a p38 MAPK inhibitor demonstrated significant anti-inflammatory effects in vivo.
- p38 MAPK inhibitors hold promise as a novel therapeutic approach for inflammatory diseases.
