title: Type I interferons and interferon regulatory factors regulate TNF-related apoptosis-inducing ligand (TRAIL) in HIV-1-infected macrophages.
abstract: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that participates in HIV-1 pathogenesis through the depletion of CD4+ T cells. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. The regulation of TRAIL in macrophages during HIV-1 infection is not completely understood. In this study, we investigated the mechanism(s) of TRAIL expression in HIV-1-infected macrophages, an important cell type in HIV-1 pathogenesis. A human monocyte-derived macrophage (MDM) culture system was infected with macrophage-tropic HIV-1(ADA), HIV-1(JR-FL), or HIV-1(BAL) strains. TRAIL, predominantly the membrane-bound form, increased following HIV-1 infection. We found that HIV-1 infection also induced interferon regulatory factor (IRF)-1, IRF-7 gene expression and signal transducers and activators of transcription 1 (STAT1) activation. Small interfering RNA knockdown of IRF-1 or IRF-7, but not IRF-3, reduced STAT1 activation and TRAIL expression. Furthermore, the upregulation of IRF-1, IRF-7, TRAIL, and the activation of STAT1 by HIV-1 infection was reduced by the treatment of type I interferon (IFN)-neutralizing antibodies. In addition, inhibition of STAT1 by fludarabine abolished IRF-1, IRF-7, and TRAIL upregulation. We conclude that IRF-1, IRF-7, type I IFNs, and STAT1 form a signaling feedback loop that is critical in regulating TRAIL expression in HIV-1-infected macrophages.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, Laboratory of Neurotoxicology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Huang
authors.forename: Angelique
authors.initials: A
authors.lastname: Walstrom
authors.forename: Luwen
authors.initials: L
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Min
authors.initials: M
authors.lastname: Cui
authors.forename: Ling
authors.initials: L
authors.lastname: Ye
authors.forename: Jialin C
authors.initials: JC
authors.lastname: Zheng
mesh_terms: D002478:Cells, Cultured; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000276:immunology; D015658:HIV Infections; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors / Q000502:physiology*; D007370:Interferon Type I / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000821:virology*; D009000:Monocytes; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand