title: Induction of TRAIL- and TNF-alpha-dependent apoptosis in human monocyte-derived dendritic cells by microfilariae of Brugia malayi.
abstract: Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that circulates in blood and is responsible for most immune dysregulation in filarial infections. DC exposed to mf for 24-96 h showed a marked increase in cell death and caspase-positive cells compared with unexposed DC, whereas mf exposure did not induce apoptosis in macrophages. Interestingly, 48-h exposure of DC to mf induced mRNA expression of the proapoptotic gene TRAIL and both mRNA and protein expression of TNF-alpha. mAb to TRAIL-R2, TNF-R1, or TNF-alpha partially reversed mf-induced cell death in DC, as did knocking down the receptor for TRAIL-R2 using small interfering RNA. The mf also induced gene expression of BH3-interacting domain death agonist and protein expression of cytochrome c in DC; mf-induced cleavage of BH3-interacting domain death agonist could be shown to induce release of cytochrome c, leading to activation of caspase 9. Our data suggest that mf induce DC apoptosis in a TRAIL- and TNF-alpha-dependent fashion.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20872, USA. rsemnani@niaid.nih.gov
authors.forename: Roshanak Tolouei
authors.initials: RT
authors.lastname: Semnani
authors.forename: Priyanka Goel
authors.initials: PG
authors.lastname: Venugopal
authors.forename: Lily
authors.initials: L
authors.lastname: Mahapatra
authors.forename: Jason A
authors.initials: JA
authors.lastname: Skinner
authors.forename: Francoise
authors.initials: F
authors.lastname: Meylan
authors.forename: Daniel
authors.initials: D
authors.lastname: Chien
authors.forename: David W
authors.initials: DW
authors.lastname: Dorward
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Nutman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis; D017178:Brugia malayi / Q000276:immunology; D045304:Cytochromes c / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005368:Filariasis / Q000276:immunology*; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D008264:Macrophages / Q000276:immunology; D008842:Microfilariae / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c