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Despite the use of disease-modifying drugs, only about 50% of RA patients reach remission in real-world settings. We used an unbiased approach to investigate the effects of standard-of-care methotrexate (MTX) and a Janus kinase inhibitor, tofacitinib (TOFA), on gene expression in RA-FLS, in order to identify untargeted disease mediators.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Primary RA-FLS were activated by stimulation with interleukin-1\u03b2 (IL-1\u03b2) or platelet-derived growth factor\u2009+\u2009IL-1\u03b2 in the presence or absence of MTX or TOFA, with or without additional inhibitors. Co-cultures of synovial cells were performed in direct and indirect systems. Cells were collected for RNA sequencing or qPCR, and supernatants were analyzed for protein concentrations.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Six thousand three hundred fifty genes were differentially expressed, the majority being upregulated, in MTX-treated activated RA-FLS and 970 genes, the majority being downregulated, in TOFA-treated samples. Pathway analysis showed that MTX had largest effects on \u2018Molecular mechanisms of cancer\u2019 and TOFA on \u2018Interferon signaling\u2019. Targeted analysis of disease-associated genes revealed that MTX increased the expression of cell cycle-regulating genes but also of pro-inflammatory mediators like IL-1\u03b1 <jats:italic>(IL1A<\/jats:italic>) and granulocyte\u2013macrophage colony-stimulating factor, GM-CSF (<jats:italic>CSF2<\/jats:italic>)<jats:italic>.<\/jats:italic> The MTX-promoted expression of <jats:italic>CSF2<\/jats:italic> in activated RA-FLS peaked at 48\u00a0h, could be mediated via either NF-\u03baB or AP-1 transcription factors, and was abrogated by IL-1 inhibitors (IRAK4 inhibitor and anakinra). In a co-culture setting, MTX-treatment of activated RA-FLS induced <jats:italic>IL1B<\/jats:italic> expression in macrophages.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>MTX treatment induces secretion of IL-1 from activated RA-FLS which by autocrine signaling augments their release of GM-CSF. This unexpected effect of MTX might contribute to the persistence of synovitis.\n<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13075-024-03406-6","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T04:01:38Z","timestamp":1728619298000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Methotrexate promotes the release of granulocyte\u2013macrophage colony-stimulating factor from rheumatoid arthritis fibroblast-like synoviocytes via autocrine interleukin-1 signaling"],"prefix":"10.1186","volume":"26","author":[{"given":"Beatrice","family":"Bergstr\u00f6m","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilia","family":"Selld\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Bollmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattias N. 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