Article
Sex steroids and interleukin-1 inhibit interferon-gamma induced B cell activating factor of the tumor necrosis factor family (BAFF) in human synovial fibroblasts
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Authors
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Georg Pongratz
- Universitätsklinikum Regensburg, Klinik und Poliklinik für Innere Medizin I, Regensburg
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Marina Bäuml
- University Hospital Regensburg, Dpt. of Internal Medicine I, Laboratory for Experimental Rheumatology and Neuroendokrinoimmunology, Regensburg
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Rainer H. Straub
- Innere Med I, Universitätsklinikum Regensburg, Regensburg
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Torsten Lowin
- Innere Med I, Universitätsklinikum Regensburg, Regensburg
| Published: | September 1, 2015 |
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Outline
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Introduction: BAFF, a cytokine important for B cell survival, plays a role in several autoimmune diseases. In psoriasis arthritis, BAFF correlates with disease activity and inversely with testosterone, suggesting a role for sex hormones in BAFF regulation. Synovial fibroblasts (SFs) produce BAFF upon IFN-γ stimulation and express sex hormone receptors. Therefore, we wanted to characterize inflammatory stimuli that modulate BAFF and test if sex steroids directly regulate BAFF production in SFs.
Methods: SFs from synovial tissue of RA (n=10) and OA (n=10) patients were cultured under normoxic and hypoxic conditions in the presence or absence of different stimuli (IFN-γ, IL-1, LPS, TNF, and cortisol, dihydrotestosterone, and estradiol). BAFF was determined by ELISA. Levels of phosphorylated and total STAT1 and STAT3 were determined by western blotting.
Results: IFN-γ induced BAFF in a concentration-dependent manner in RA (p<0.001) and OA (p<0.001) fibroblasts. Since joint-inflammation takes place under hypoxic conditions, we compared IFN-γ-induced BAFF production in RA (n=7) and OA (n=16) SFs under normoxic and hypoxic (O2 2%) culture conditions. INF-induced BAFF was increased in hypoxic conditions in RA SFs (p=0.015) but not OA SFs (p=0.362) as compared to the normoxic situation. In hypoxic (p=0.005) but not normoxic conditions (p=0.471), RA SFs produced more BAFF than OA SFs. IFN led to a strong phosphorylation of STAT1 but reduces phosphorylated STAT3. However, since phosphorylation of STAT3 has been suggested to further augment BAFF, we additionally stimulated SFs with IL-1, which leads to phosphorylation of STAT3. However, in the presence of IL-1, INF-induced BAFF was independent of oxygen content in both, OA (p<0.001) and RA (p<0.001) fibroblasts. Furthermore, inhibition of pSTAT3 further augmentated IFN-γ induced BAFF. Dihydrotestosterone and estrogen, inhibited IFN-induced BAFF production in synovial SFs.
Conclusion: Taken together, BAFF is induced by IFN-γ and further augmented under hypoxic conditions in RA SFs. In contrast to known mechanisms, additional STAT3 dependent signaling inhibited IFN-induced BAFF production. Also, the sex steroids dihydrotestosterone and estrogen inhibited BAFF production in OA and RA SFs. Therefore, the known correlation of sex steroids with disease activity in arthritis might be in part mediated by direct regulation of IFN-dependent BAFF production.
