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However, the influence of these pro-inflammatory cytokines on other receptors\/ligands of the TNF superfamily or associated cytokine receptors in SF has not been investigated yet. Here we show the differential regulation of BAFF (CD257), Fn14 (CD266), TACI (CD267), BAFF-R (CD268), BCMA (CD269), CD40 ligand (CD40L, CD154), IFN-\u03b3R (CD119), Leptin receptor (ObR, CD295), VCAM-1 (CD106) and membrane TGF-\u03b2 in isolated SF and the impact of IFN-\u03b3\/TNF co-incubation on proliferation, IL-6 and IL-8 production. In addition, the impact of differentially stimulated SF on B cell survival in co-cultures was assessed. Surface cytokines and cytokine receptors were detected by flow cytometry. Soluble cytokine receptors and cytokines were quantified by ELISA. Proliferation was assessed by cell titer blue. Murine B cell survival in fibroblast\/ B cell co-cultures was determined by annexin V\/propidium iodide staining and flow cytometry. IFN-\u03b3 together with TNF synergistically and significantly increased the cell surface levels of BAFF, Fn14, TACI, BAFF-R, BCMA, CD40L, ObR and IFN-\u03b3R in rheumatoid arthritis SF after 72\u2009h incubation. Soluble BAFF was only induced by IFN-\u03b3 and inhibited by TNF. Addition of TWEAK had no influence on proliferation or IL-8 production but decreased TNF-induced IL-6 production, whereas APRIL, BAFF and leptin did not modulate TNF or TNF\/IFN-\u03b3-induced proliferation or cytokine production. Proliferation was increased by TNF and further enhanced by the addition of IFN-\u03b3. In co-culture experiments, SF stimulated with TNF\/IFN but not TNF or IFN-\u03b3 alone increased shedding of VCAM-1 and expression of membrane TGF\u03b2, which was associated with reduced survival of murine B cells. IFN-\u03b3 and TNF regulate the expression of TNF family member cytokines and associated receptors. Ligation of IFN-\u03b3R and Fn14 under pro-inflammatory conditions modulated IL-6\/IL-8 production and proliferation. In B cell\/SF co-cultures, the combination of TNF\/IFN reduced B cell survival possibly via enhanced VCAM-1 shedding and\/or increased TGF-\u03b2 production. IFN-\u03b3 is necessary for the observed effects on B cell survival and SF cytokine production and emphasizes its anti-inflammatory role in rheumatoid arthritis.<\/jats:p>","DOI":"10.1038\/s41598-020-57772-7","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T11:04:29Z","timestamp":1579604669000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Positive and negative cooperativity of TNF and Interferon-\u03b3 in regulating synovial fibroblast function and B cell survival in fibroblast\/B cell co-cultures"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7368-2776","authenticated-orcid":false,"given":"Torsten","family":"Lowin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tareq M.","family":"Anssar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"B\u00e4uml","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Classen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Pongratz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,21]]},"reference":[{"key":"57772_CR1","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1111\/j.1365-2249.1996.tb08288.x","volume":"103","author":"A Bucht","year":"1996","unstructured":"Bucht, A. et al. Expression of interferon-gamma (IFN-gamma), IL-10, IL-12 and transforming growth factor-beta (TGF-beta) mRNA in synovial fluid cells from patients in the early and late phases of rheumatoid arthritis (RA). Clin. Exp. Immunol. 103, 357\u2013367 (1996).","journal-title":"Clin. Exp. Immunol."},{"key":"57772_CR2","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/BF00286766","volume":"15","author":"S Sakito","year":"1995","unstructured":"Sakito, S. et al. Serum cytokines in patients with rheumatoid arthritis. Correlation of interferon gamma and tumor necrosis factor alpha with the characteristics of peripheral blood mononuclear cells. Rheumatol Int. 15, 31\u201337 (1995).","journal-title":"Rheumatol Int."},{"key":"57772_CR3","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1189\/jlb.1003524","volume":"75","author":"P Proost","year":"2004","unstructured":"Proost, P. et al. 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