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Infect. Immun. doi:10.1128/IAI.01252-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Leishmania major Infection Activates NFB, IRF-1 and IRF-8 in Human Dendritic Cells

Center for Global Health and Infectious Diseases, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556

	Abstract

The salient feature of dendritic cells (DC) is the initiation of appropriate adaptive immune responses by discriminating between pathogens. Using a prototypic model of intracellular infection, we previously have shown that Leishmania major parasites prime human DC for efficient interleukin-12 (IL-12) secretion. L. major infection is associated with self-limiting cutaneous disease and powerful immunity. In stark contrast, the causative agent of visceral leishmaniasis, L. donovani, does not prime human DC for IL-12 production. Here we report DC priming by L. major infection results in the early activation of NFB transcription factors and up regulation and nuclear translocation of interferon regulatory factors (IRF) 1 and 8. Inhibition of NFB activation by pretreatment of DC with caffeic acid phenethyl ester (CAPE) blocks L. major induced IRF-1 and IRF-8 activation and IL-12 expression. We further demonstrate that IRF-1 and IRF-8 obtained from L. major-infected human DC specifically bind to their consensus binding sites on IL-12p35 promoter, indicating that L. major infection either directly stimulates a signaling cascade, or induces an autocrine pathway, that activates IRF-1 and IRF-8, ultimately resulting in IL-12 transcription.