Adaptation of human CD4+ T cells to pathophysiological hypoxia: a transcriptome analysis.
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.
Gaber
Timo
T
Department of Rheumatology and Clinical Immunology, Charité University Hospital, Charitéplatz 1, 10117 Berlin, Germany. gaber@drfz.de
Häupl
Thomas
T
Sandig
Grit
G
Tykwinska
Karolina
K
Fangradt
Monique
M
Tschirschmann
Miriam
M
Hahne
Martin
M
Dziurla
René
R
Erekul
Kerem
K
Lautenbach
Martin
M
Kolar
Paula
P
Burmester
Gerd-Rüdiger
GR
Buttgereit
Frank
F
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
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen