Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes.
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-gamma/LPS or IFN-alpha/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.
Xin
Lijun
L
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
Li
Kui
K
Soong
Lynn
L
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000469:parasitology*; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007894:Leishmania mexicana / Q000201:enzymology / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099185:Interferon Regulatory Factor-8
D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D016753:Interleukin-10; D018664:Interleukin-12; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D050791:STAT Transcription Factors; D000099185:Interferon Regulatory Factor-8