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Leishmania major Infection Activates NF-B and Interferon Regulatory Factors 1 and 8 in Human Dendritic Cells

Asha Jayakumar, Michael J. Donovan, Vinita Tripathi, Marcelo Ramalho-Ortigao, and Mary Ann McDowell^*

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

Received 12 September 2007/ Returned for modification 11 October 2007/ Accepted 16 February 2008

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 showed 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, Leishmania donovani, does not prime human DC for IL-12 production. Here, we report that DC priming by L. major infection results in the early activation of NF-B transcription factors and the up-regulation and nuclear translocation of interferon regulatory factor 1 (IRF-1) and IRF-8. The inhibition of NF-B activation by the pretreatment of DC with caffeic acid phenethyl ester 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 the 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.

Published ahead of print on 3 March 2008.

Editor: W. A. Petri, Jr.

Present address: Department of Epidemiology and Public Health, School of Medicine, Yale University, New Haven, CT 06520.