title: Inflammatory cytokines drive CD4+ T-cell cycling and impaired responsiveness to interleukin 7: implications for immune failure in HIV disease.
abstract: BACKGROUND
  Systemic inflammation has been linked to a failure to normalize CD4(+) T-cell numbers in treated human immunodeficiency virus (HIV) infection. Although inflammatory cytokines such as interleukin 6 (IL-6) are predictors of disease progression in treated HIV infection, it is not clear how or whether inflammatory mediators contribute to immune restoration failure.
  
  
  METHODS
  We examined the in vitro effects of IL-6 and interleukin 1β (IL-1β) on peripheral blood T-cell cycling and CD127 surface expression.
  
  
  RESULTS
  The proinflammatory cytokine IL-1β induces cell cycling and turnover of memory CD4(+) T cells, and IL-6 can induce low-level cycling of naive T cells. Both IL-1β and IL-6 can decrease T-cell surface expression and RNA levels of CD127, the interleukin 7 receptor α chain (IL-7Rα). Preexposure of healthy peripheral blood mononuclear cells (PBMCs) to IL-6 or IL-1β attenuates IL-7-induced Stat5 phosphorylation and induction of the prosurvival factor Bcl-2 and the gut homing integrin α4β7. We found elevated expression of IL-1β in the lymphoid tissues of patients with HIV infection that did not normalize with antiretroviral therapy.
  
  
  CONCLUSIONS
  Induction of CD4(+) T-cell turnover and diminished T-cell responsiveness to IL-7 by IL-1β and IL-6 exposure may contribute to the lack of CD4(+) T-cell reconstitution in treated HIV-infected subjects.
authors.affiliation: Center for AIDS Research, Case Western Reserve University.
authors.forename: Carey L
authors.initials: CL
authors.lastname: Shive
authors.affiliation: Center for AIDS Research, Case Western Reserve University.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Mudd
authors.affiliation: Center for AIDS Research, Case Western Reserve University School of Health and Rehabilitation Sciences, The Ohio State University, Columbus, Ohio.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Funderburg
authors.affiliation: Center for AIDS Research, Case Western Reserve University.
authors.forename: Scott F
authors.initials: SF
authors.lastname: Sieg
authors.affiliation: Center for AIDS Research, Case Western Reserve University.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kyi
authors.affiliation: Center for AIDS Research, Case Western Reserve University.
authors.forename: Doug A
authors.initials: DA
authors.lastname: Bazdar
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Mangioni
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gori
authors.affiliation: Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Jacobson
authors.affiliation: Endocrine and Oncologic Surgery, Pennsylvania Hospital, Philadelphia, Pennsylvania.
authors.forename: Ari D
authors.initials: AD
authors.lastname: Brooks
authors.affiliation: University Hospitals/Case Medical Center, Cleveland.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hardacre
authors.affiliation: University Hospitals/Case Medical Center, Cleveland.
authors.forename: John
authors.initials: J
authors.lastname: Ammori
authors.affiliation: AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, SAIC-Frederick, Maryland.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.affiliation: University of Minnesota, Minneapolis.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Schacker
authors.affiliation: Center for AIDS Research, Case Western Reserve University.
authors.forename: Benigno
authors.initials: B
authors.lastname: Rodriguez
authors.affiliation: Center for AIDS Research, Case Western Reserve University.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
mesh_terms: D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002453:Cell Cycle / Q000276:immunology; D002478:Cells, Cultured; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain
keywords: HIV; immune failure; inflammation; interleukin 1 beta; interleukin 6; interleukin 7