J Biol Regul Homeost Agents 2014 Jan-Mar;28(1):41-52

Toll-like receptor 4 promotes control of Leishmania infantum infection through inducement of leishmanicidal activity in host macrophages: Role of Mitogen Activated Kinases

Agallou M.1, Dotsika E.1, Frydas S.2 and Karagouni E.1,*

 1Laboratory of Cellular Immunology, Department of Microbiology, Hellenic Pasteur Institute, Athens 115 21, Greece

2Laboratory of Parasitology and Parasitic Diseases, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

 

Abstract

Establishment of Leishmania infection inside macrophages requires deactivation of various signaling pathways that are dispensable for effective immune responses against the parasite. In the present study, we provide evidence that Leishmania infantum promastigotes attachment on the surface of peritoneal macrophages, internalization and transformation to amastigotes abrogated the activation of extracellular signal-regulated protein kinases (ERK) 1/2, p38 mitogen activated protein kinases (MAPK) and c-Jun NH2-terminal kinases (JNK) and the production of pro-inflammatory cytokines IL-12 and TNFα. Subsequent macrophage stimulation with lipopolysaccharide (LPS) during the first hours of exposure to parasite or infection resulted in restoration of MAPK phosphorylation. However, LPS-mediated MAPK activation required parasite internalization (uptake) since cytochalasin-D pretreated macrophages did not responded to LPS stimulation. IL-12, TNFα, and NO production was positively regulated with MAPK phosphorylation in contrast to nuclear factor-kappaB (NF-κB) which was MAPK independent. Specifically, inhibition of MAPK activation with specific inhibitors revealed that IL-12 production required p38 MAPK activation, whereas TNFαand NO production required all three MAPK. The restoration of NO production resulted in decrease of infection rates. Hence, these results suggest that in contrast tophagocytosis of L. infantum promastigotes, establishment of infection does not desensitize macrophages to subsequent stimulation with LPS, resulting in parasite elimination through MAPK and NF-κB activation and partial restoration of IL-12, TNFα and NO synthesis.

Keywords: Leishmania, macrophage, MAPK, IL-12, TNFα, NO, LPS

PMID:24750790

 

Agallou et alFigure 1. The two different forms of the parasite differentially regulate the signaling molecules involved in the TLR4 pathway.

 

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