| Title | Adaptation of Human CD4+ T Cells to Pathophysiological Hypoxia: A Transcriptome Analysis. | | Author(s) | Gaber T, Häupl T, Sandig G, Tykwinska K, Fangradt M, Tschirschmann M, Hahne M, Dziurla R, Erekul K, Lautenbach M, Kolar P, Burmester GR, Buttgereit F | | Institution | From the Department of Rheumatology and Clinical Immunology, Charité University Hospital; German Rheumatism Research Center (DRFZ); Berlin-Brandenburg Center of Regenerative Therapies (BCRT); Department of Medical Biotechnology, University for Technologies Berlin; Department of Elbow-, Hand- and Microsurgery, Immanuel-Krankenhaus, Berlin, Germany. | | Source | J Rheumatol 2009 Nov 2. | | Abstract | 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-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.
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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19884271 |
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