Événements inflammatoires conduisant au développement de leishmanioses
Abstract (Summary)Secretion of prostaglandin E;! (PGE2) during the course of Leishmania uifection has been reported. The signaling mechanisms that induce PGE2 production following Leishmania infection are not well understood. Since cyciooxygenase-2 (COX-2) and cytosolic phospholipase A2 (=PLA2) are potentially involved in PGE2 syndiesis in response to various stimuli, the implication of these enzymes was evaluated in the Leishmania- infected PMA-differentiated U937 human monocytic ce11 line. Tirne-course experiments showed that PGE2 synthesis increased significantly in parallel with COX-2 mRNA and protein expression when U937 cells were incubated in the presence of Leishmania donovani promastigotes or LPS. Indomethacin, genistein, and H7, which are, respectively, inhibiton of COX-2, protein tyrosine kinase (PTK) and protein kinase C (PKC), Uihibited PGE2 production of both Leishmania donovani-infected cells and those stimulated by LPS. However, only H7 inhibited increased mRNA synthesis of COX-2, and there was a significant correlation between inhibition of PGE2 and COX-2 mRNA synthesis. Overall, our results indicate that Section of U937 by Leishmania donovani Ieads to the activation of COX-2 and generation of PGE2 in part through a PKC- dependent signaling pathway. They Mer reveal that PTK-dependent events are necessary for Leishmania-induced PGE2 generation, but not COX-2 expression. A better understanding of the mechanisms by which Leishrnania can induce PGE2 production could provide insight into the pathophysiology of Leishmania infection and may help irnprove the design of better therapeutic approaches. The parasite of the genus Leishmmia is responsible for various pathologies affecthg over 15 million of individuals worlwide, that will develop following its vector-mediated tr'ansmission encompassing cutaneous, muco-cutaneous and the deadly visceral leishmaniasis (Kala Azar) (3). Successful infection of macrophages by Leishmania is dependent upon a variev of mechanisms that make possible the survivat of this parasite in the harsh environment of those phagocytic cells (6, 26, 27, 29, 30, 39). The inability of the host to develop an effective immune response during the infection is a hallmark of the parasitic infection and rnay involve the participation of the immunosuppressive rnolecule PGE2 (2, 5, 11, 35). Tissue macrophages play a crucial role in the initiation and regulation of the infiammatory response via their capacity to elaborate biological mediators such as cytokines, growth factors and bioactive lipids (40). Macrophages are a major source of prostanoids durhg inflammation. Prostaglandins are among the best-studied mediators produced by macrophages and are products of the cyclooxygenase pathway of arachidonic acid and include thromboxane A2, PGE2, and PGI2 (40). The conversion of arachidonic acid to PGE2 is catalyzed by the enzyme cyclooxygenase (COX), which exists as two isoforms. COX-I is constitutively expressed whereas COX-2 is highly inducible in response to phorbol esters, LPS and interleukin-1 in competent cells such as endotheliai cells, fibroblasts and macrophages (2,33). Exogenous PGE2 inhibits macrophage proliferation, oxygen radical generation, accumulation of LPSinduced RIF-amRNA and cellular release of, as well as cellular responses to, various proinflammatory mediators and growth factors, thus remlting in the downregulation of inflammation, immune function and fibrogenesis (5). Furthemore, parasite-derived PGE2 may affect the severity of infection by favoring an exacerbating Th2-cell response (1 1). Notably, previous studies have reported increased PGE2 production during the course of Leishmmia infection initiated in vitro and in vivo progression (1l,35). which may favor its In the present study, we were interested to establish the signahg pathways that are involved in the induction of PGE2 production foilowing Leishmmialmacrophage interaction. A more complete knowledge of the biochemical cascades leading to this idammatory mediator may speed up the development of new anti-inflammatory molecules aimed at the ultimate reduction of the immunosuppressive state of the infected host.
Source Type:Master's Thesis
Date of Publication:01/01/2000