title: Tat engagement of p38 MAP kinase and IRF7 pathways leads to activation of interferon-stimulated genes in antigen-presenting cells.
abstract: As a result of its interaction with transcription factors, HIV type 1 (HIV-1) Tat can modulate the expression of both HIV and cellular genes. In antigen-presenting cells Tat induces the expression of a subset of interferon (IFN)-stimulated genes (ISGs) in the absence of IFNs. We investigated the genome-wide Tat association with promoters in immature dendritic cells and in monocyte-derived macrophages. Among others, Tat associated with the MAP2K6, MAP2K3, and IRF7 promoters that are functionally part of IL-1 and p38 mitogen-activated protein kinase (MAPK) signaling pathways. The association correlated with their increased gene expression, increased activation of p38 MAPK and of phosphorylated signal transducer and activator of transcription 1 (STAT1), and consequent induction of ISGs. Probing these pathways with RNA interference, pharmacological p38 MAPK inhibition, and in cell lines lacking STAT1s or the type I IFN receptor chain confirmed the role of MAPKKs and IRF7 in Tat-mediated modulation of ISGs and excluded the involvement of IFNs in this modulation. Tat interaction with the 2 MAPKK and IRF7 promoters in HIV-1-infected cells and the resulting persistent activation of ISGs, which include inflammatory cytokines and chemokines, can contribute to the increased immune activation that characterizes HIV infection.
authors.affiliation: Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.forename: Sami
authors.initials: S
authors.lastname: Kukkonen
authors.forename: Maria Del Pilar
authors.initials: Mdel P
authors.lastname: Martinez-Viedma
authors.forename: Sumeet
authors.initials: S
authors.lastname: Gupta
authors.forename: Anna
authors.initials: A
authors.lastname: Aldovini
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D015696:Gene Products, tat / Q000378:metabolism* / Q000502:physiology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D007372:Interferons / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D048371:MAP Kinase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D018925:Chemokines; D015696:Gene Products, tat; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D019707:Receptors, Chemokine; D007372:Interferons; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human
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