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Mol Immunol. 2008 Jul;45(12):3371-82. doi: 10.1016/j.molimm.2008.04.018. Epub 2008 Jun 5.

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes.

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1
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.

Abstract

We have previously reported a link between a deficient Th1 response to Leishmania amazonensis (La) parasites and profound impairments in the cytokine/chemokine network at early stages of the infection. To define the molecular basis of these deficiencies, we focused on early and intracellular events in La-infected dendritic cells (DCs) in this study. La amastigote-infected DCs were less mature and less potent antigen-presenting cells (APC) than their promastigote-infected counterparts, as judged by the lower expression of CD40 and CD83, suppressed cytokine expression (IL-12p40 and IL-10), reduced effectiveness for priming CD4+ T cells from naïve or infected mice. Infection with La promastigotes, but not amastigotes, triggered transient expression of IL-12p40 by DC. Both forms of parasites markedly suppressed IL-12p40, IL-12p70, and IL-6 production and increased IL-10 production when DCs were treated with LPS, IFN-gamma/LPS or IFN-alpha/LPS as positive stimuli. Of note, pre-infection of DCs with live amastigotes resulted in multiple alterations in innate signaling pathways, including degradation of STAT2, decreased phosphorylation of STAT1, 2, 3 and ERK1/2, and markedly reduced expression of interferon regulatory factor-1 (IRF-1) and IRF-8, some of which were partially reversed by pretreatment of parasites with proteasome or protease inhibitors. The impaired IL-12 production in infected DCs was not attributed to increased IL-10 production. Together, our data suggest that La parasites, especially in their intracellular forms, have evolved unique strategies to actively down-regulate early innate signaling events, resulting in impaired DC function and Th1 activation.

PMID:
18538399
PMCID:
PMC2583126
DOI:
10.1016/j.molimm.2008.04.018
[Indexed for MEDLINE]
Free PMC Article
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