Activation of p38 mitogen-activated protein kinase attenuates Leishmania donovani infection in macrophages.
Leishmania-induced macrophage dysfunctions have been correlated with altered signaling events. In this work, we report that SB203580, a specific inhibitor of p38 mitogen-activated protein kinases (MAPK), increases Leishmania donovani survival in human peripheral blood mononuclear macrophages. Consistent with this finding, activation of p38 and c-jun N-terminal kinase (JNK) MAPK signaling pathways by anisomycin significantly reduced parasite survival within these cells. However, the majority of the effect was seen in a 50% reduction in the percentage of macrophages infected, with little effect on the highly infected macrophages. The observed effect was likely to be due to the p38 MAPK pathway since SB203580 was able to completely reverse the effect of anisomycin. These findings suggest that the previously reported p38 MAPK inhibition by Leishmania infection may be partially overcome by anisomycin. Similar effects were observed in pretreated macrophages or in treatment of infected macrophages. These results suggests that p38 MAPK activation may have a potential therapeutic value in the treatment of visceral leishmaniasis.
Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Muthoni
M
Junghae
John G
JG
Raynes
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007893:Leishmania donovani / Q000187:drug effects* / Q000472:pathogenicity*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000201:enzymology / Q000469:parasitology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000469:parasitology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D000841:Anisomycin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580