p38 mitogen-activated protein kinase inhibition increases cytokine release by macrophages in vitro and during infection in vivo.
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.
van den Blink
B
B
Department of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. B.vandenBlink@amc.uva.nl
Juffermans
N P
NP
ten Hove
T
T
Schultz
M J
MJ
van Deventer
S J
SJ
van der Poll
T
T
Peppelenbosch
M P
MP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000201:enzymology / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011018:Pneumonia, Pneumococcal / Q000201:enzymology / Q000276:immunology*; D011725:Pyridines / Q000008:administration & dosage; D014376:Tuberculosis / Q000201:enzymology / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580