Background/Purpose: B cell activating factor of the tumor necrosis factor family (BAFF) and interleukin-6 (IL-6) are cytokines important for the stimulation and survival of autoreactive B cells and plasma cells, respectively, and play a role in several autoimmune diseases, e.g. autoimmune arthritis. It is known that synovial fibroblasts (SFs) are capable of producing BAFF and IL-6 and therefore provide survival signals to autoreactive B cells and plasma cells in the joint. Therefore, we wanted to better characterize inflammatory stimuli that modulate BAFF and IL-6 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 (interferon (IFN)g and interleukin (IL)-1). BAFF was determined by ELISA. Levels of phosphorylated and total STAT1 and STAT3 were determined by western blotting.

Results: IFN in a concentration-dependent manner induced BAFF and IL-6 in RA and OA fibroblasts. Since inflammation usually leads to hypoxic conditions, we also compared IFN-g-induced cytokine production in RA and OA SFs under normoxic and hypoxic (oxygen content 2%) culture conditions.  IFN-induced BAFF was augmented in OA (p<0.001) and RA (p<0.01) SFs under hypoxic conditions, whereas there was no oxygen dependency of IFN-induced IL-6. IFN leads to a strong phosphorylation of STAT1 but to a reduction in phosphorylated STAT3 in RA and OA SFs. However, it has been suggested that concomitant phosphorylation of STAT3 further augments BAFF production. Therefore, we wanted to test if concomitant IL-1, which leads to phosphorylation of STAT3, further increases IFN-induced BAFF and/or IL-6 in SFs. However, in the presence of IL-1, INF-induced BAFF was inhibited (p>0.001), whereas IFN-induced IL-6 was increased (p<0.001) in a concentration dependent manner independent of oxygen content in both, OA and RA fibroblasts. Furthermore, inhibition of pSTAT3 resulted in further augmentation of IFN-induced BAFF (p=0.003) and decrease of IFN-induced IL-6 (p=0.04). 

Conclusion: Taken together, BAFF and IL-6 production in synovial fibroblasts are induced by IFN and reciprocally regulated by IL-1 in a STAT3 dependent manner. In contrast to IL-6, IFN-induced BAFF can be further augmented by hypoxia. These results give further insight in local regulation of the microenvironment provided for B cells in the arthritic joint.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interleukin-1-reciprocally-regulates-interferon-gamma-induced-b-cell-activating-factor-of-the-tumor-necrosis-factor-family-baff-and-interleukin-6-in-human-synovial-fibroblasts/