Leishmania major infection activates NF-kappaB and interferon regulatory factors 1 and 8 in human dendritic cells

Infect Immun. 2008 May;76(5):2138-48. doi: 10.1128/IAI.01252-07. Epub 2008 Mar 3.

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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding Sites
  • Caffeic Acids / pharmacology
  • Cells, Cultured
  • DNA / metabolism
  • Dendritic Cells / immunology*
  • Gene Expression Profiling
  • Humans
  • Immunologic Factors / pharmacology
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism*
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism*
  • Interleukin-12 / biosynthesis
  • Interleukin-12 / genetics
  • Leishmania major / immunology*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Phenylethyl Alcohol / analogs & derivatives
  • Phenylethyl Alcohol / pharmacology
  • Promoter Regions, Genetic
  • Protein Binding
  • Up-Regulation

Substances

  • Caffeic Acids
  • IRF1 protein, human
  • Immunologic Factors
  • Interferon Regulatory Factor-1
  • Interferon Regulatory Factors
  • NF-kappa B
  • interferon regulatory factor-8
  • Interleukin-12
  • DNA
  • caffeic acid phenethyl ester
  • Phenylethyl Alcohol