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Platelet-activating factor receptor contributes to antileishmanial function of miltefosine.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2015 Jun 15; Vol. 194 (12), pp. 5961-7. Date of Electronic Publication: 2015 May 15. - Publication Year :
- 2015
-
Abstract
- Miltefosine [hexadecylphosphocholine (HPC)] is the only orally bioavailable drug for the disease visceral leishmaniasis, which is caused by the protozoan parasite Leishmania donovani. Although miltefosine has direct leishmanicidal effects, evidence is mounting for its immune system-dependent effects. The mechanism of such indirect antileishmanial effects of miltefosine remains to be discovered. As platelet-activating factor and HPC share structural semblances and both induce killing of intracellular Leishmania, we surmised that platelet-activating factor (PAF) receptor had a significant role in the antileishmanial function of miltefosine. The proposition was supported by molecular dynamic simulation of HPC docking into PAF receptor and by comparison of its leishmanicidal function on PAF receptor-deficient macrophages and mice under HPC treatment. We observed that compared with wild-type macrophages, the PAF receptor-deficient macrophages showed 1) reduced binding of a fluorescent analog of HPC, 2) decreased TNF-α production, and 3) lower miltefosine-induced killing of L. donovani. Miltefosine exhibited significantly compromised leishmanicidal function in PAF receptor-deficient mice. An anti-PAF receptor Ab led to a significant decrease in miltefosine-induced intracellular Leishmania killing and IFN-γ production in a macrophage-T cell coculture system. These results indicate significant roles for PAF receptor in the leishmanicidal activity of HPC. The findings open new avenues for a more rational understanding of the mechanism of action of this drug as well as for improved therapeutic strategies.<br /> (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Subjects :
- Animals
Antibodies, Monoclonal pharmacology
Antigens, Protozoan immunology
Antiprotozoal Agents administration & dosage
Antiprotozoal Agents chemistry
CD4-Positive T-Lymphocytes immunology
CD4-Positive T-Lymphocytes metabolism
Gene Knockout Techniques
Interferon-gamma biosynthesis
Leishmaniasis, Visceral drug therapy
Leishmaniasis, Visceral genetics
Ligands
Macrophages drug effects
Macrophages immunology
Macrophages metabolism
Mice
Models, Molecular
Molecular Conformation
Phosphorylcholine administration & dosage
Phosphorylcholine chemistry
Phosphorylcholine pharmacology
Platelet Membrane Glycoproteins antagonists & inhibitors
Platelet Membrane Glycoproteins chemistry
Platelet Membrane Glycoproteins deficiency
Protein Binding
Receptors, G-Protein-Coupled antagonists & inhibitors
Receptors, G-Protein-Coupled chemistry
Receptors, G-Protein-Coupled deficiency
Antiprotozoal Agents pharmacology
Leishmania donovani immunology
Leishmaniasis, Visceral immunology
Leishmaniasis, Visceral metabolism
Phosphorylcholine analogs & derivatives
Platelet Membrane Glycoproteins metabolism
Receptors, G-Protein-Coupled metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 194
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 25980013
- Full Text :
- https://doi.org/10.4049/jimmunol.1401890