Tat engagement of p38 MAP kinase and IRF7 pathways leads to activation of interferon-stimulated genes in antigen-presenting cells

Blood. 2013 May 16;121(20):4090-100. doi: 10.1182/blood-2012-10-461566. Epub 2013 Mar 27.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism*
  • Antigen-Presenting Cells / physiology
  • Cells, Cultured
  • Chemokines / genetics
  • Chemokines / metabolism
  • Gene Products, tat / metabolism*
  • Gene Products, tat / physiology
  • HIV Infections / genetics
  • HIV Infections / immunology
  • HIV-1 / physiology
  • Humans
  • Interferon Regulatory Factor-7 / genetics*
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon Regulatory Factor-7 / physiology
  • Interferons / pharmacology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / genetics
  • MAP Kinase Kinase 3 / genetics*
  • MAP Kinase Kinase 3 / metabolism
  • MAP Kinase Kinase 6 / genetics*
  • MAP Kinase Kinase 6 / metabolism
  • Promoter Regions, Genetic*
  • Protein Binding
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*
  • p38 Mitogen-Activated Protein Kinases / physiology

Substances

  • Chemokines
  • Gene Products, tat
  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • Receptors, Chemokine
  • Interferons
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 6
  • MAP2K3 protein, human
  • MAP2K6 protein, human