{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:38Z","timestamp":1787028518002,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T00:00:00Z","timestamp":1691452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Societ\u00e0 Italiana per lo Studio dell\u2019Aterosclerosi (SISA)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The impact of JAK\/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis plaque development and stability. Cultured human macrophages THP-1 were used to assess the impact of tofacitinib on cell cholesterol efflux and synthesis via radioisotopic methods, and on cholesterol uptake by measuring the cell cholesterol content with a fluorometric assay. The cholesterol acceptors and donors were either standard lipoproteins or sera from patients with juvenile idiopathic arthritis (JIA) and from control subjects. Tofacitinib significantly increased the macrophage cholesterol efflux to all acceptors; it reduced cholesterol uptake from both the normal and hypercholesterolemic sera; and it reduced cholesterol synthesis. The treatment of macrophages with tofacitinib was able to increase the cholesterol efflux and decrease cholesterol uptake when using sera from untreated JIA patients with active disease as cholesterol acceptors and donors, respectively. In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of sera from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations.<\/jats:p>","DOI":"10.3390\/ijms241612571","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T12:26:39Z","timestamp":1691497599000},"page":"12571","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Effect of the JAK\/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4810-6862","authenticated-orcid":false,"given":"Maria Pia","family":"Adorni","sequence":"first","affiliation":[{"name":"Unit of Neurosciences, Department of Medicine and Surgery, University of Parma, Via Volturno 39\/F, 43125 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Papotti","sequence":"additional","affiliation":[{"name":"Department of Food and Drug, University of Parma, Parco Area delle Scienze 27\/A, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8967-9678","authenticated-orcid":false,"given":"Maria Orietta","family":"Borghi","sequence":"additional","affiliation":[{"name":"Experimental Laboratory of Immuno-Rheumatologic Researches, IRCCS Istituto Auxologico Italiano, Cusano Milanino, Via Zucchi 18, 20095 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Raschi","sequence":"additional","affiliation":[{"name":"Experimental Laboratory of Immuno-Rheumatologic Researches, IRCCS Istituto Auxologico Italiano, Cusano Milanino, Via Zucchi 18, 20095 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6665-263X","authenticated-orcid":false,"given":"Francesca","family":"Zimetti","sequence":"additional","affiliation":[{"name":"Department of Food and Drug, University of Parma, Parco Area delle Scienze 27\/A, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Bernini","sequence":"additional","affiliation":[{"name":"Department of Food and Drug, University of Parma, Parco Area delle Scienze 27\/A, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3394-1451","authenticated-orcid":false,"given":"Pier Luigi","family":"Meroni","sequence":"additional","affiliation":[{"name":"Experimental Laboratory of Immuno-Rheumatologic Researches, IRCCS Istituto Auxologico Italiano, Cusano Milanino, Via Zucchi 18, 20095 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Ronda","sequence":"additional","affiliation":[{"name":"Department of Food and Drug, University of Parma, Parco Area delle Scienze 27\/A, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nrrheum.2011.75","article-title":"Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE","volume":"7","author":"Symmons","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1093\/ehjcvp\/pvz033","article-title":"Lipid management in rheumatoid arthritis: A position paper of the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology","volume":"6","author":"Hollan","year":"2020","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1186\/s13075-017-1439-1","article-title":"Methotrexate and anti-tumor necrosis factor treatment improves endothelial function in patients with inflammatory arthritis","volume":"19","author":"Deyab","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1080\/1744666X.2021.1899809","article-title":"Biologics and atherosclerotic cardiovascular risk in rheumatoid arthritis: A review of evidence and mechanistic insights","volume":"17","author":"Karpouzas","year":"2021","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/nrrheum.2015.167","article-title":"Type I\/II cytokines, JAKs, and new strategies for treating autoimmune diseases","volume":"12","author":"Schwartz","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"103276","DOI":"10.1016\/j.autrev.2023.103276","article-title":"JAK inhibitors and autoimmune rheumatic diseases","volume":"22","author":"Benucci","year":"2023","journal-title":"Autoimmun. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4389","DOI":"10.1093\/eurheartj\/ehab447","article-title":"The JAK-STAT pathway: An emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms","volume":"42","author":"Baldini","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1161\/ATVBAHA.108.173781","article-title":"Suppressors of cytokine signaling modulate JAK\/STAT-mediated cell responses during atherosclerosis","volume":"29","author":"Mallavia","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"796","DOI":"10.5551\/jat.6569","article-title":"AOPPs inhibits cholesterol efflux by down-regulating ABCA1 expression in a JAK\/STAT signaling pathway-dependent manner","volume":"18","author":"Mo","year":"2011","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1080\/21691401.2019.1573740","article-title":"Tofacitinib inhibits ox-LDL-induced adhesion of THP-1 monocytes to endothelial cells","volume":"47","author":"Yang","year":"2019","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.semarthrit.2016.05.014","article-title":"Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor","volume":"46","author":"Wicker","year":"2016","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1002\/art.40911","article-title":"Risk Factors for Major Adverse Cardiovascular Events in Phase III and Long-Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis","volume":"71","author":"DeMasi","year":"2019","journal-title":"Arthritis Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1136\/ard-2022-223357","article-title":"Safety of synthetic and biological DMARDs: A systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis","volume":"82","author":"Sepriano","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1056\/NEJMoa2109927","article-title":"Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis","volume":"386","author":"Ytterberg","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s10067-022-06415-5","article-title":"Cardiovascular risks associated with Janus kinase inhibitors: Peering outside the black box","volume":"42","author":"Misra","year":"2023","journal-title":"Clin. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s10067-021-06003-z","article-title":"Effect of JAK inhibitors on high- and low-density lipoprotein in patients with rheumatoid arthritis: A systematic review and network meta-analysis","volume":"41","author":"Li","year":"2022","journal-title":"Clin. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cz\u00f3kolyov\u00e1, M., Hamar, A., Pusztai, A., Tajti, G., V\u00e9gh, E., Peth\u0151, Z., Bodn\u00e1r, N., Horv\u00e1th, \u00c1., So\u00f3s, B., and Szamosi, S. (2022). Effects of One-Year Tofacitinib Therapy on Lipids and Adipokines in Association with Vascular Pathophysiology in Rheumatoid Arthritis. Biomolecules, 12.","DOI":"10.3390\/biom12101483"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.1038\/s41467-021-23361-z","article-title":"Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus","volume":"12","author":"Hasni","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1007\/s00228-022-03402-2","article-title":"JAK inhibitors and risk of major cardiovascular events or venous thromboembolism: A self-controlled case series study","volume":"78","author":"Gouverneur","year":"2022","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"116","DOI":"10.21037\/atm.2018.02.02","article-title":"Atherosclerosis as autoimmune disease","volume":"6","author":"Sima","year":"2018","journal-title":"Ann. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/jcmm.12689","article-title":"Macrophage-mediated cholesterol handling in atherosclerosis","volume":"20","author":"Chistiakov","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/978-3-319-09665-0_14","article-title":"Impact of systemic inflammation and autoimmune diseases on apoA-I and HDL plasma levels and functions","volume":"224","author":"Montecucco","year":"2015","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Adorni, M.P., Ronda, N., Bernini, F., and Zimetti, F. (2021). High Density Lipoprotein Cholesterol Efflux Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological Aspects and Pharmacological Perspectives. Cells, 10.","DOI":"10.3390\/cells10030574"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.bbrc.2017.06.020","article-title":"Tofacitinib ameliorates atherosclerosis and reduces foam cell formation in apoE deficient mice","volume":"490","author":"Wang","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1111\/bph.13932","article-title":"Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: Understanding the lipid paradox associated with rheumatoid arthritis","volume":"174","author":"Barrasa","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E474","DOI":"10.1152\/ajpendo.90369.2008","article-title":"Leptin modulates ACAT1 expression and cholesterol efflux from human macrophages","volume":"297","author":"Hongo","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"172940","DOI":"10.1016\/j.ejphar.2020.172940","article-title":"JAK-STAT-dependent regulation of scavenger receptors in LPS-activated murine macrophages","volume":"871","author":"Hashimoto","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14490","DOI":"10.1016\/S0021-9258(19)85265-1","article-title":"Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its target nucleotide sequence","volume":"268","author":"Briggs","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1242\/jcs.1985.Supplement_3.13","article-title":"The LDL receptor and the regulation of cellular cholesterol metabolism","volume":"3","author":"Goldstein","year":"1985","journal-title":"J. Cell Sci. Suppl."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0092-8674(94)90234-8","article-title":"SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis","volume":"77","author":"Wang","year":"1994","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11603","DOI":"10.1073\/pnas.90.24.11603","article-title":"SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element","volume":"90","author":"Hua","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","first-page":"999","article-title":"Inhibitory effect of JAK inhibitor on mechanical stress-induced protease expression by human articular chondrocytes","volume":"66","author":"Machida","year":"2017","journal-title":"Inflamm. Res. Off. J. Eur. Histamine Res. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e5081","DOI":"10.1002\/bmc.5081","article-title":"Identification of the metabolites of tofacitinib in liver microsomes by liquid chromatography combined with high resolution mass spectrometry","volume":"35","author":"Liu","year":"2021","journal-title":"Biomed. Chromatogr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1136\/annrheumdis-2012-202914","article-title":"Impaired serum cholesterol efflux capacity in rheumatoid arthritis and systemic lupus erythematosus","volume":"73","author":"Ronda","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1194\/jlr.P076463","article-title":"Plasma cholesterol homeostasis, HDL remodeling and function during the acute phase reaction","volume":"58","author":"Zimetti","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1007\/s00296-017-3844-9","article-title":"Tofacitinib improves atherosclerosis despite up-regulating serum cholesterol in patients with active rheumatoid arthritis: A cohort study","volume":"37","author":"Kume","year":"2017","journal-title":"Rheumatol. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1124\/jpet.113.209304","article-title":"Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis","volume":"348","author":"Dowty","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1194\/jlr.M500466-JLR200","article-title":"Measurement of cholesterol bidirectional flux between cells and lipoproteins","volume":"47","author":"Zimetti","year":"2006","journal-title":"J. Lipid Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5069","DOI":"10.1007\/s00253-013-4893-y","article-title":"A simplified diphenylamine colorimetric method for growth quantification","volume":"97","author":"Zhao","year":"2013","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1124\/jpet.105.093930","article-title":"Pitavastatin effect on ATP binding cassette A1-mediated lipid efflux from macrophages: Evidence for liver X receptor (LXR)-dependent and LXR-independent mechanisms of activation by cAMP","volume":"317","author":"Zanotti","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.55563\/clinexprheumatol\/5tckci","article-title":"Serum calprotectin (S100A8\/9), clinical and ultrasound assessment in patients with juvenile idiopathic arthritis","volume":"39","author":"Romano","year":"2021","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"329","DOI":"10.2217\/clp.10.20","article-title":"Advanced diagnostic support in lipidology project: Role for phenotypic and functional evaluation of lipoproteins in dyslipidemias","volume":"5","author":"Bernini","year":"2010","journal-title":"Clin. Lipidol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12571\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:28:05Z","timestamp":1760128085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12571"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,8]]},"references-count":42,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241612571"],"URL":"https:\/\/doi.org\/10.3390\/ijms241612571","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,8]]}}}