PT - JOURNAL ARTICLE AU - Timo Gaber AU - Thomas Häupl AU - Grit Sandig AU - Karolina Tykwinska AU - Monique Fangradt AU - Miriam Tschirschmann AU - Martin Hahne AU - René Dziurla AU - Kerem Erekul AU - Martin Lautenbach AU - Paula Kolar AU - Gerd-Rüdiger Burmester AU - Frank Buttgereit TI - Adaptation of Human CD4+ T Cells to Pathophysiological Hypoxia: A Transcriptome Analysis AID - 10.3899/jrheum.090255 DP - 2009 Nov 02 TA - The Journal of Rheumatology PG - jrheum.090255 4099 - http://www.jrheum.org/content/early/2009/10/29/jrheum.090255.short 4100 - http://www.jrheum.org/content/early/2009/10/29/jrheum.090255.full 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.