Inhibition of TLR3 and TLR4 function and expression in human dendritic cells by helminth parasites.
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.
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. rsemnani@niaid.nih.gov
Roshanak Tolouei
RT
Semnani
Priyanka Goel
PG
Venugopal
Cynthia A
CA
Leifer
Sven
S
Mostböck
Helen
H
Sabzevari
Thomas B
TB
Nutman
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000469:parasitology*; D015536:Down-Regulation; D006376:Helminths / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics
D016207:Cytokines; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4