title: HIV-1 gp120 activates the STAT3/interleukin-6 axis in primary human monocyte-derived dendritic cells.
abstract: Dendritic cells (DCs) are fundamental for the initiation of immune responses and are important players in AIDS immunopathogenesis. The modulation of DC functional activities represents a strategic mechanism for HIV-1 to evade immune surveillance. Impairment of DC function may result from bystander effects of HIV-1 envelope proteins independently of direct HIV-1 infection. In this study, we report that exposure of immature monocyte-derived DCs (MDDCs) to HIV-1 R5 gp120 resulted in the CCR5-dependent production of interleukin-6 (IL-6) via mitogen-activated protein kinase (MAPK)/NF-κB pathways. IL-6 in turn activated STAT3 by an autocrine loop. Concomitantly, gp120 promoted an early activation of STAT3 that further contributed to IL-6 induction. This activation paralleled a concomitant upregulation of the STAT3 inhibitor PIAS3. Notably, STAT3/IL-6 pathway activation was not affected by the CCR5-specific ligand CCL4. These results identify STAT3 as a key signaling intermediate activated by gp120 in MDDCs and highlight the existence of a virus-induced dysregulation of the IL-6/STAT3 axis. HIV-1 gp120 signaling through STAT3 may provide an explanation for the impairment of DC function observed upon HIV exposure.
  
  
  OBJECTIVE
  This study provides new evidence for the molecular mechanisms and signaling pathways triggered by HIV-1 gp120 in human DCs in the absence of productive infection, emphasizing a role of aberrant signaling in early virus-host interaction, contributing to viral pathogenesis. We identified STAT3 as a key component in the gp120-mediated signaling cascade involving MAPK and NF-κB components and ultimately leading to IL-6 secretion. STAT3 now is recognized as a key regulator of DC functions. Thus, the identification of this transcription factor as a signaling molecule mediating some of gp120's biological effects unveils a new mechanism by which HIV-1 may deregulate DC functions and contribute to AIDS pathogenesis.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Del Cornò
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Donninelli
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Varano
authors.affiliation: Gene Expression-Microarrays Laboratory, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Da Sacco
authors.affiliation: Gene Expression-Microarrays Laboratory, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Masotti
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy sandra.gessani@iss.it.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gessani
mesh_terms: D019898:Autocrine Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005786:Gene Expression Regulation; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D018832:Molecular Chaperones / Q000235:genetics / Q000276:immunology; D009000:Monocytes / Q000276:immunology / Q000821:virology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000276:immunology; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C584933:CCR5 protein, human; D054407:Chemokine CCL4; D015699:HIV Envelope Protein gp120; C508600:IL6 protein, human; D015850:Interleukin-6; D018832:Molecular Chaperones; D016328:NF-kappa B; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D019713:Receptors, CCR5; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C514793:gp120 protein, Human immunodeficiency virus 1; D020928:Mitogen-Activated Protein Kinases