Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose
B cell activating factor of the tumor necrosis factor family (BAFF) is a cytokine important for the stimulation and survival of autoreactive B cells and therefore might play a role in several autoimmune disease, e.g. autoimmune arthritis. In psoriasis arthritis , BAFF correlates with disease activity and inversely with testosterone, but only in male patients, suggesting a role for sex hormones in the regulation of BAFF. It is also known that synovial fibroblasts (SFs) are capable of producing BAFF following INF-γ stimulation and that SFs possess sex hormone receptors. Therefore, we wanted to better characterize inflammatory stimuli that modulate BAFF in SFs and then test the hypothesis that sex steroids directly regulate BAFF production in SFs.
Methods
Fibroblasts isolated from synovial tissue of RA (n=10) and OA (n=10) patients were cultured in the presence or absence of different stimuli (IFN-γ, interleukin (IL)-1, lipopolysaccharide (LPS), tumor necrosis factor (TNF), 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 in a concentration-dependent manner best induced BAFF in RA (p<0.001) and OA (p<0.001) fibroblasts. Since inflammation usually leads to hypoxic conditions, we also compared IFN-γ-induced BAFF production in RA (n=7) and OA (n=16) SFs under normoxic and hypoxic (oxygen content 2%) culture conditions. INF-induced BAFF is 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 produce more BAFF when exposed to the same IFN stimulation than OA SFs. IFN leads to a strong phosphorylation of STAT1 but to a reduction in phosphorylated STAT3. However, it has been suggested that concomitant phosphorylation of STAT3 further augments BAFF production. Therefore, we wanted to test if concomitant IL-1 or IL-10, which both lead to phosphorylation of STAT3, further increase IFN-induced BAFF in SFs. However, in the presence of IL-1 or IL-10, INF-induced BAFF was inhibited in a concentration dependent manner independent of oxygen content in both, OA (p<0.001) and RA (p<0.001) fibroblasts. Furthermore, inhibition of pSTAT3 resulted in further augmentation of IFN-induced BAFF. Finally, in the presence of dihydrotestosterone and estrogen, IFN-induced BAFF production in SFs was inhibited in a concentration dependent manner.
Conclusion
Taken together, BAFF production in synovial fibroblasts is induced by IFN-γ and pronounced under hypoxic conditions. STAT3 inducers like IL-1 and IL10 inhibit IFN-induced BAFF production. Also, the sex steroids dihydrotestosterone and estrogen inhibit BAFF production in OA and RA SFs. Therefore, the known correlation of endocrine factors with disease activity in arthritis might be in part mediated by regulating IFN-dependent BAFF production in SFs.
Disclosure:
G. Pongratz,
None;
M. Bäuml,
None;
T. Späth,
None;
R. Straub,
None;
T. Lowin,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sex-steroids-interleukin-1-and-interleukin-10-inhibit-interferon-gamma-ifn-%ce%b3-induced-b-cell-activating-factor-of-the-tumor-necrosis-factor-family-baff-in-human-synovial-fibroblasts/