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J Biol Chem, Vol. 273, Issue 22, 13944-13949, May 29, 1998

Modulation of Interferon--induced Macrophage Activation by Phosphotyrosine Phosphatases Inhibition
EFFECT ON MURINE LEISHMANIASIS PROGRESSION

From the ^a Centre de Recherche en Infectiologie and Département de Biologie Médicale, ⁱ Unité de Recherche en Neuroscience and Département de Médecine, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, Faculté de Médecine, Université Laval, Ste-Foy (Québec) Canada G1V 4G2, and ^h Department of Medicine, McGill University, Montréal,Canada H3A 1A1

Phagocyte functions are markedly inhibited after infection with the intracellular protozoan parasite Leishmania. This situation strongly favors the installation and propagation of this pathogen within its mammalian host. Previous findings by us and others have established that alteration of several signaling pathways (protein kinase C-, Ca²⁺- and protein-tyrosine kinases-dependent signaling events) were directly responsible for Leishmania-induced macrophage (MØ) dysfunctions. Here we report that modulation of phosphotyrosine-dependent events with a protein tyrosine phosphatases (PTP) inhibitor, the peroxovanadium (pV) compound bpV(phen) (potassium bisperoxo(1,10-phenanthroline)oxovanadate(V_i)), can control host-pathogen interactions by different mechanisms. We observed that the inhibition of parasite PTP resulted in an arrest of proliferation and death of the latter in coincidence with cyclin-dependent kinase (CDK1) tyrosine 15 phosphorylation. Moreover the treatment of MØ with bpV(phen) resulted in an increased sensitivity to interferon- stimulation, which was reflected by enhanced nitric oxide (NO) production. This enhanced IFN--induced NO generation was accompanied by a marked increase of inducible nitric oxide synthase (iNOS) mRNA gene and protein expression. Finally we have verified the in vivo potency of bpV(phen) over a 6-week period of daily administration of a sub-toxic dose. The results revealed its effectiveness in controlling the progression of visceral and cutaneous leishmaniasis. Therefore PTP inhibition of Leishmania and MØ by the pV compound bpV(phen) can differentially affect these eukaryotic cells. This strongly suggests that PTP plays an important role in the progression of Leishmania infection and pathogenesis. The apparent potency of pV compounds along with their relatively simple and versatile structure render them attractive pharmacological agents for the management of parasitic infections.

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