title: Adaptation of human CD4+ T cells to pathophysiological hypoxia: a transcriptome analysis.
abstract: OBJECTIVE
  Inflamed tissues are usually characterized by low oxygen levels. We investigated whether pathophysiological hypoxia (pO(2) < 1%) as found in the rheumatoid synovium modulates the transcriptome of human CD4+ T cells.
  
  
  METHODS
  We analyzed the extent to which hypoxia influences the transcriptome in the rheumatoid synovium according to a gene cluster reflecting adaptation to low oxygen levels. Hypoxia-inducible factor-1alpha (HIF-1alpha) was detected in the rheumatoid synovium using immunohistochemistry. Isolated human CD4+ T cells were exposed to hypoxia and analyzed using microarray analysis, quantitative polymerase chain reaction, and immunoblot detection.
  
  
  RESULTS
  In rheumatoid arthritis (RA) synovial tissue samples, hypoxia modulates the transcription profile. This profile is similar, but not identical, to that found in isolated CD4+ T cells incubated under hypoxic conditions. We show that HIF-1alpha is expressed in synovial tissue samples and in hypoxic CD4+ cells; and that hypoxia directly affects differential gene expression in human T cells with up to 4.8% modulation of the transcriptome. Functional genome analysis revealed substantial effects of hypoxia on immune response, transcriptional regulation, protein modification, cell growth and proliferation, and cell metabolism.
  
  
  CONCLUSIONS
  Severe hypoxia, a feature of joint inflammation, considerably modulates the transcriptome of cells found in the rheumatoid synovium. Human CD4+ T cells adapt to hypoxic conditions mainly by HIF-1-driven effects on the transcriptome reflecting a profound influence on immune functions. Thus, hypoxia must be taken into account when therapeutically targeting inflammation.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité University Hospital, Charitéplatz 1, 10117 Berlin, Germany. gaber@drfz.de
authors.forename: Timo
authors.initials: T
authors.lastname: Gaber
authors.forename: Thomas
authors.initials: T
authors.lastname: Häupl
authors.forename: Grit
authors.initials: G
authors.lastname: Sandig
authors.forename: Karolina
authors.initials: K
authors.lastname: Tykwinska
authors.forename: Monique
authors.initials: M
authors.lastname: Fangradt
authors.forename: Miriam
authors.initials: M
authors.lastname: Tschirschmann
authors.forename: Martin
authors.initials: M
authors.lastname: Hahne
authors.forename: René
authors.initials: R
authors.lastname: Dziurla
authors.forename: Kerem
authors.initials: K
authors.lastname: Erekul
authors.forename: Martin
authors.initials: M
authors.lastname: Lautenbach
authors.forename: Paula
authors.initials: P
authors.lastname: Kolar
authors.forename: Gerd-Rüdiger
authors.initials: GR
authors.lastname: Burmester
authors.forename: Frank
authors.initials: F
authors.lastname: Buttgereit
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D015687:Cell Hypoxia / Q000276:immunology; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D046228:Microarray Analysis; D010100:Oxygen / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology / Q000473:pathology
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen