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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Sahoo, Ganesh Chandra Das, Sushmita Rabidas, Vidyanand Rani, Mukta Pandey, Krishna Das, Pradeep |
| Description | Author Affiliation: Das S ( Department of Molecular Parasitology, Rajendra Memorial Research Institute of Medical Sciences, Indian Council of Medical Research, Bihar, India.) |
| Abstract | BACKGROUND AND PURPOSE: The combination of paromomycin-miltefosine is a successful anti-leishmanial therapy in visceral leishmaniasis (VL). This encouraged us to study its effect on Toll-like receptor (TLR)-mediated immunomodulation of dendritic cells (DC), as DC maturation and activation is crucial for anti-leishmanial activity. EXPERIMENTAL APPROACH: In silico protein-ligand interaction and biophysical characterization of TLR9-drug interaction was performed. Interaction assays of HEK293 cells with different concentrations of miltefosine and/or paromomycin were performed, and NF-κB promoter activity measured. The role of TLR9 and MyD88 in paromomycin/miltefosine-induced maturation and activation of DCs was evaluated through RNA interference techniques. The effect of drugs on DCs was measured in terms of counter-regulatory production of IL-12 over IL-10, and characterized by chromatin immunoprecipitation assay at the molecular level. KEY RESULTS: Computational and biophysical studies revealed that paromomycin/miltefosine interact with TLR9. Both drugs, as a monotherapy/combination, induced TLR9-dependent NF-κB promoter activity through MyD88. Moreover, the drug combination induced TLR9/MyD88-dependent functional maturation of DCs, evident as an up-regulation of co-stimulatory markers, enhanced antigen presentation by increasing MHC II expression, and increased stimulation of naive T-cells to produce IFN-γ. Both drugs, by modifying histone H3 at the promoter level, increased the release of IL-12, but down-regulated IL-10 in a TLR9-dependent manner. CONCLUSIONS AND IMPLICATIONS: These results provide the first evidence that the combination of paromomycin-miltefosine critically modifies the maturation, activation and development of host DCs through a mechanism dependent on TLR9 and MyD88. This has implications for evaluating the success of other combination anti-leishmanial therapies that act by targeting host DCs. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 5 |
| Volume Number | 171 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2014-03-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Antiprotozoal Agents Pharmacology Dendritic Cells Drug Effects Leishmaniasis, Visceral Metabolism Myeloid Differentiation Factor 88 Paromomycin Phosphorylcholine Analogs & Derivatives Toll-Like Receptor 9 Therapeutic Use Cells, Cultured Cytology Microbiology Drug Combinations HEK293 Cells Interleukin-10 Genetics Interleukin-12 Drug Therapy Controlled Clinical Trial Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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