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Blood. 2008 Aug 15;112(4):1290-8. doi: 10.1182/blood-2008-04-149856. Epub 2008 Jun 9.

Inhibition of TLR3 and TLR4 function and expression in human dendritic cells by helminth parasites.

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Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.


Patent lymphatic filariasis is characterized by antigen-specific T-cell unresponsiveness with diminished IFN-gamma and IL-2 production and defects in dendritic cell (DC) function. Because Toll-like receptors (TLRs) play an important role in pathogen recognition and TLR expression is diminished on B and T cells of filaria-infected individuals, we examined the effect of live microfilariae (mf) on expression and function of TLRs in human DCs. We show that mf-exposed monocyte-derived human DCs (mhDCs) demonstrate marked diminution of TLR3 and TLR4 mRNA expression compared with mf-unexposed mhDCs that translated into loss of function in response to appropriate TLR ligands. Exposure to mf significantly down-regulated production of IFN-alpha, MIP-1alpha, IL-12p70, and IL-1alpha following activation with poly I:C, and of IL-12p40 following activation with poly I:C or LPS. mRNA expression of MyD88, the adaptor molecule involved in TLR4 signaling, was significantly diminished in mhDCs after exposure to mf. Moreover, mf interfered with NF-kappaB activation (particularly p65 and p50) following stimulation with poly I:C or LPS. These data suggest that mf interfere with mhDC function by altering TLR expression and interfering with both MyD88-dependent signaling and a pathway that ultimately diminishes NF-kappaB activity. This down-regulated NF-kappaB activity impairs mhDC-produced cytokines needed for full T-cell activation.

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