Altered dendritic cell phenotype in response to Leishmania amazonensis amastigote infection is mediated by MAP kinase, ERK

Department of Veterinary Pathology, Iowa State University, Ames, Iowa 50011, USA.
American Journal Of Pathology (Impact Factor: 4.6). 05/2009; 174(5):1818-26. DOI: 10.2353/ajpath.2009.080905
Source: PubMed

ABSTRACT Initiation of productive immune responses against Leishmania depends on the successful transition of dendritic cells (DC) from an immature to a mature phenotype. This process is characterized by high CD40 surface expression as well as interleukin-12 production, which are frequently seen in response to L. major infection. In vivo footpad infection of C3HeB/FeJ mice for 7 days with L. amazonensis promoted an immature CD11c(+) DC phenotype characterized by both significantly low CD40 surface expression and significantly decreased interleukin-12p40 production compared with L. major infection of these same mice. In vitro infection of bone marrow-derived dendritic cells with L. amazonensis amastigotes resulted in rapid and significant phosphorylation of the mitogen activated protein kinase, extracellular signal-regulated kinase 1/2, observed within minutes of exposure to the parasite. Infection with L. amazonensis promastigotes led to increased 1/2 phosphorylation after 4 hours of infection compared with L. major infection, which correlated with promastigote transformation into amastigotes. Treatment of bone marrow-derived dendritic cells with a mitogen activated protein kinase kinase-specific inhibitor, PD98059, led to regained surface CD40 expression and interleukin-12p40 production following L. amazonensis amastigote infection compared with non-treated, infected DC. Treatment of L. amazonensis-infected mice with the highly-specific mitogen activated protein kinase kinase inhibitor, CI-1040, enhanced surface CD40 expression on CD11c(+) DC obtained from the draining lymph node. L. amazonensis amastigotes, through activation of extracellular signal-regulated kinase 1/2, inhibit the ability of DC to undergo proper maturation both in vitro and in vivo.

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Available from: Christine A Petersen, Aug 26, 2015
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    • "The suppression of host cell activation can be initiated at the stage of amastigote– host contact. On one hand, L. amazonensis amastigotes can infect human DCs through multiple receptor–ligand interactions such as antibodies/Fc receptors, complement components/component receptors, and proteoglycans/heparin-binding proteins (Bosetto and Giorgio, 2007), leading to altered DC activation and impaired responsiveness to exogenous stimuli through ERK/MAP kinasemediated mechanisms (Boggiatto et al., 2009). On the other hand, L. amazonensis amastigotes can expose phosphatidylserine (PS) on their surface, leading to enhanced parasite growth and host suppression through IL-10 and TGF-β production by host cells (Wanderley et al., 2006). "
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    • "Although first observed in Leishmania infection in macrophages, the same principle of differential CD40 signaling holds true in dendritic cells and in tumor models [36] [37] [38]. In one study it was shown that infection with L. amazonensis amastigotes inhibited the ability of DCs to undergo proper maturation in vivo characterized by significantly low CD40 surface expression and significantly decreased IL-12p40 production through activation of the MAP kinase ERK1/2 [39]. While the differential CD40 signaling and its selective manipulation by Leishmania solved the apparent paradox of inducing counteractive cytokines by CD40 stimulation, the question remained to be solved is how a single receptor induces reciprocal signaling pathways and counteractive effector functions. "
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