Artikel
Synovial fibroblasts suppress inflammatory T cell responses by indoleamine 2,3-dioxygenase (IDO) 1 expression – implications for the pathogenesis of rheumatoid arthritis?
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Veröffentlicht: | 12. September 2014 |
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Background: The development of rheumatoid arthritis (RA) is linked to functional changes of synovial fibroblasts (SF) and a local infiltration of immune cells such as T lymphocytes. So far, little is known about the cross-talk between SF and T cells under normal and pathological conditions. Here, we analysed the influence of normal SF as well as of RASF on the activation, proliferation and cytokine production of T helper cells in vitro.
Methods: SF were isolated from synovectomy tissue of osteoarthritis (OA) and of RA patients. T cells were stimulated in the presence or absence of SF, in direct contact or separated by transwell chambers. T cell proliferation was measured by PKH-26. Cytokine secretion was quantified by ELISA. MRNA levels of matrix metalloproteases (MMPs) and indoleamine 2,3-dioxygenase (IDO) were quantified by real-time PCR. Tryptophan and kynurenine level were detected by HPLC.
Results: In a dynamic interplay SF supported the stimulation of T cells at early time points of coculture and in return the activated T cells induced the expression of IL-6, IL-8, MMPs, as well as of PGE2 and IDO1 by the SF. Finally, the stimulated SF strongly suppressed the proliferation of the cocultured CD4+ T cells and the secretion of pro-inflammatory cytokines in a cell contact-independent manner. A decrease of tryptophan and an increase of kynurenines in the culture supernatants correlated with its suppressive capacity and blockade of IDO completely abrogated the suppression of T cells, indicating that the inhibitory effect is mediated by tryptophan metabolism. Interestingly, RASF had a weaker T cell suppressive capacity compared to OASF and in contrast to Th1 cells, Th2 and Th17 cell proliferation was not affected by the SF.
Conclusion: The suppression of activated T cells by SF through tryptophan metabolism may play an important role in preventing inappropriate T cell responses under normal conditions. In RA patients, the inferior efficacy of RASF to restrict T cell proliferation may support the initiation or propagation of synovitis. Expansion of Th17 cells that escape the suppression by SF may be favoured, thereby leading to the overrepresentation of these cells in inflamed tissues.