p38 mitogen-activated protein kinase inhibition increases cytokine release by macrophages in vitro and during infection in vivo

B van den Blink; N P Juffermans; T ten Hove; M J Schultz; S J van Deventer; T van der Poll; M P Peppelenbosch

doi:10.4049/jimmunol.166.1.582

p38 mitogen-activated protein kinase inhibition increases cytokine release by macrophages in vitro and during infection in vivo

J Immunol. 2001 Jan 1;166(1):582-7. doi: 10.4049/jimmunol.166.1.582.

Authors

B van den Blink¹, N P Juffermans, T ten Hove, M J Schultz, S J van Deventer, T van der Poll, M P Peppelenbosch

Affiliation

¹ Department of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. [email protected]

PMID: 11123340
DOI: 10.4049/jimmunol.166.1.582

Abstract

p38 mitogen-activated protein kinase (MAPK) has been suggested as a mediator of cytokine release and is currently being targeted for anti-inflammatory therapy. However, experimental data are contradictory and lack sufficient affirmation in vivo. We tested the effect of p38 MAPK inhibition in several cell types and in different murine models of infectious disease. We observed that most cell types react to p38 MAPK inhibition with diminished cytokine release, but that this treatment induced increased cytokine release in macrophages. Furthermore, we observed increased cytokine production in mouse models of pneumococcal pneumonia and tuberculosis accompanied by severely reduced bacterial clearance. This apparent inefficacy of p38 MAPK inhibition in reducing cytokine release in infectious disease, as well as its immune-compromising action, suggest that targeting p38 MAPK may not be a suitable anti-cytokine strategy in patients with such disease or at risk for infection.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
Cells, Cultured
Cytokines / biosynthesis
Cytokines / metabolism*
Disease Models, Animal
Endotoxemia / enzymology
Endotoxemia / immunology*
Enzyme Inhibitors / administration & dosage
Female
Humans
Imidazoles / administration & dosage
Injections, Intraperitoneal
Macrophages, Peritoneal / immunology
Macrophages, Peritoneal / metabolism*
Mice
Mice, Inbred BALB C
Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Mitogen-Activated Protein Kinases / physiology
Pneumonia, Pneumococcal / enzymology
Pneumonia, Pneumococcal / immunology*
Pyridines / administration & dosage
Tuberculosis / enzymology
Tuberculosis / immunology*
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha / metabolism
Up-Regulation / drug effects
Up-Regulation / immunology
p38 Mitogen-Activated Protein Kinases

Substances

Anti-Inflammatory Agents, Non-Steroidal
Cytokines
Enzyme Inhibitors
Imidazoles
Pyridines
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
SB 203580