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Antimicrob. Agents Chemother. doi:10.1128/AAC.01183-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Modulation of gene expression in human macrophages treated with the anti-Leishmania pentavalent antimonial drug Pentostam

Centre de Recherche en Infectiologie du Centre de Recherche du CHUL and Division de Microbiologie, Faculté de Médecine, Université Laval, Québec, Canada

^* To whom correspondence should be addressed. Email: marc.ouellette{at}crchul.ulaval.ca.

	Abstract

Within the mammalian host, Leishmania donovani is an obligatory intracellular protozoa that resides and multiplies exclusively in the phagolysosomes of macrophages. Leishmania control relies primarily on chemotherapy, with the mainstay being pentavalent antimony (SbV) complexed to carbohydrates in the form of sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime). The mode of action of SbV is still not known precisely. To explore the effect of SbV on macrophage gene expression, a microarray analysis was performed using Affymetrix Focus arrays to compare gene expression profiles in non-infected and L. donovani-infected THP-1 monocytic cells treated or not by Pentostam. Under our experimental conditions, SbV changed the expression of few host genes and this was independent of whether cells were infected or not with Leishmania. Leishmania infection had a greater effect in the modulation of host gene expression. Statistical analyses have indicated that the expression of 8 genes were modified by at least 2-fold upon SbV treatment with 6 genes up-regulated and 2 genes down-regulated. One gene whose expression was affected by SbV was the heme oxygenase HMOX-1 and this was observed in both the monocytic cell line THP-1 and primary human monocyte-derived macrophages. Another pathway that was affected was the glutathione biosynthesis pathway where the expression of glutamate-cysteine ligase modifier subunit was increased upon SbV treatment. Our analysis has suggested that under our experimental conditions the expression of few genes is altered upon SbV treatment, some of which may be implicated in the yet to be defined mode of action of SbV.