RT Journal Article SR Electronic T1 Adaptation of Human CD4+ T Cells to Pathophysiological Hypoxia: A Transcriptome Analysis JF The Journal of Rheumatology JO J Rheumatol FD The Journal of Rheumatology SP 2655 OP 2669 DO 10.3899/jrheum.090255 VO 36 IS 12 A1 TIMO GABER A1 THOMAS HÄUPL A1 GRIT SANDIG A1 KAROLINA TYKWINSKA A1 MONIQUE FANGRADT A1 MIRIAM TSCHIRSCHMANN A1 MARTIN HAHNE A1 RENÉ DZIURLA A1 KEREM EREKUL A1 MARTIN LAUTENBACH A1 PAULA KOLAR A1 GERD-RÜDIGER BURMESTER A1 FRANK BUTTGEREIT YR 2009 UL http://www.jrheum.org/content/36/12/2655.abstract AB Objective. Inflamed tissues are usually characterized by low oxygen levels. We investigated whether pathophysiological hypoxia (pO2 < 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-1α (HIF-1α) 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-1α 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.Conclusion. 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.