| Autor: |
GABER, TIMO, HÄUPL, THOMAS, SANDIG, GRIT, TYKWINSKA, KAROLINA, FANGRADT, MONIQUE, TSCHIRSCHMANN, MIRIAM, HAHNE, MARTIN, DZIURLA, RENÉ, EREKUL, KEREM, LAUTENBACH, MARTIN, KOLAR, PAULA, BURMESTER, GERD-RÜDIGER, BUTTGEREIT, FRANK |
| Zdroj: |
Journal of Rheumatology; December 2009, Vol. 36 Issue: 12 p2655-2669, 15p |
| Abstrakt: |
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. |
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