Leishmania major infection activates NF-kappaB and interferon regulatory factors 1 and 8 in human dendritic cells.
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-kappaB transcription factors and the up-regulation and nuclear translocation of interferon regulatory factor 1 (IRF-1) and IRF-8. The inhibition of NF-kappaB 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.
Jayakumar
Asha
A
Center for Global Health and Infectious Diseases, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
Donovan
Michael J
MJ
Tripathi
Vinita
V
Ramalho-Ortigao
Marcelo
M
McDowell
Mary Ann
MA
D000818:Animals; D001665:Binding Sites; D002109:Caffeic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D018320:Leishmania major / Q000276:immunology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015854:Up-Regulation; D000099185:Interferon Regulatory Factor-8
D002109:Caffeic Acids; D004247:DNA; D007155:Immunologic Factors; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D018664:Interleukin-12; D016328:NF-kappa B; D010626:Phenylethyl Alcohol; D000099185:Interferon Regulatory Factor-8; C494257:IRF1 protein, human; C055494:caffeic acid phenethyl ester