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

Lijun Xin, Kui Li, Lynn Soong

Research output: Contribution to journalArticle

55 Citations (Scopus)

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-γ/LPS or IFN-α/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.

Original languageEnglish (US)
Pages (from-to)3371-3382
Number of pages12
JournalMolecular Immunology
Volume45
Issue number12
DOIs
StatePublished - Jul 2008

Fingerprint

Leishmania
Dendritic Cells
Down-Regulation
Interleukin-12 Subunit p40
Parasites
Interleukin-10
Infection
Interferon Regulatory Factor-1
Cytokines
Proteasome Inhibitors
Antigen-Presenting Cells
Interleukin-12
Protease Inhibitors
Chemokines
Interleukin-6
Phosphorylation
T-Lymphocytes

Keywords

  • DC
  • Innate immune response
  • JAK/STAT
  • Leishmania
  • Protozoan parasites

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology

Cite this

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes. / Xin, Lijun; Li, Kui; Soong, Lynn.

In: Molecular Immunology, Vol. 45, No. 12, 07.2008, p. 3371-3382.

Research output: Contribution to journalArticle

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