MODULATION OF INTERFERON-GAMMA-INDUCED MACROPHAGE ACTIVATION BY PHOSPHOTYROSINE PHOSPHATASES INHIBITION - EFFECT ON MURINE LEISHMANIASIS PROGRESSION

Phagocyte functions are markedly inhibited after infection with the in tracellular protozoan parasite Leishmania. This situation strongly fav ors the installation and propagation of this pathogen within its mamma lian host. Previous findings by us and others have established that al teration of several signaling pathways (protein kinase C-, Ca2+- and p rotein-tyrosine kinases-dependent signaling events) were directly resp onsible for Leishmania-induced macrophage (MO) dysfunctions, Here we r eport that modulation of phosphotyrosine-dependent events with a prote in tyrosine phosphatases (PTP) inhibitor, the peroxovanadium (pV) comp ound bpV(phen) (potassium bisperoxo(1,10-phenanthroline)oxovanadate(V- i)), can control host-pathogen interactions by different mechanisms. W e observed that the inhibition of parasite PTP resulted in an arrest o f proliferation and death of the latter in coincidence with cyclin-dep endent kinase (CDK1) tyrosine 15 phosphorylation. Moreover the treatme nt of MO with bpV(phen) resulted in an increased sensitivity to interf eron-gamma- stimulation, which was reflected by enhanced nitric oxide (NO) production. This enhanced LFN-gamma-induced NO generation was acc ompanied by a marked increase of inducible nitric oxide synthase (iNOS ) mRNA gene and protein expression. Finally we have verified the in vi vo potency of bpV(phen) over a B-week period of daily administration o f a sub-toxic dose. The results revealed its effectiveness in controll ing the progression of visceral and cutaneous leishmaniasis. Therefore PTP inhibition of Leishmania and MO by the pV compound bpV(phen) can differentially affect these eukaryotic cells. This strongly suggests t hat PTP plays an important role in the progression of Leishmania infec tion and pathogenesis. The apparent potency of pV compounds along with their relatively simple and versatile structure render them attractiv e pharmacological agents for the management of parasitic infections.