{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:41:46Z","timestamp":1790358106435,"version":"4.1.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T00:00:00Z","timestamp":1583452800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T00:00:00Z","timestamp":1583452800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Introduction<\/jats:title>\n<jats:p>The pathophysiology of systemic sclerosis (SSc) is closely linked to overactive TGF\u03b2 signaling. TGF\u03b2 is produced and circulates in latent form, making its activation crucial for signaling. This activation can be mediated via integrins. We investigated the balance between active and latent TGF\u03b2 in serum of SSc patients and investigated if this correlates with integrin expression on monocytes.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>A TGF\u03b2\/SMAD3- or BMP\/SMAD1\/5-luciferase reporter construct was expressed in primary human skin fibroblasts. Both acidified and non-acidified sera of ten SSc patients and ten healthy controls were tested on these cells to determine total and active TGF\u03b2 and BMP levels respectively. A pan-specific TGF\u03b21\/2\/3 neutralizing antibody was used to confirm TGF\u03b2 signaling. Monocytes of 20 SSc patients were isolated using CD14+ positive selection, and integrin gene expression was measured using qPCR. Integrin expression was modulated using rhTGF\u03b21 or a small molecule inhibitor of TGFBR1: SB-505124.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>SSc sera induced 50% less SMAD3-reporter activity than control sera. Serum acidification increased reporter activity, but a difference between healthy control and SSc serum was no longer observed, indicating that total TGF\u03b2 levels were not different. Addition of a pan-specific TGF\u03b21\/2\/3 neutralizing antibody fully inhibited SMAD3-reporter activity of both acidified and not-acidified control and SSc sera. Both HC and SSc sera induced similar SMAD1\/5-reporter activity, and acidification increased this, but not differently between groups. Interestingly, expression of two integrin alpha subunits <jats:italic>ITGA5<\/jats:italic> and <jats:italic>ITGAV<\/jats:italic> was significantly reduced in monocytes obtained from SSc patients. Furthermore, <jats:italic>ITGB3<\/jats:italic>, <jats:italic>ITGB5<\/jats:italic>, and <jats:italic>ITGB8<\/jats:italic> expression was also reduced in SSc monocytes. Stimulation of monocytes with TGF\u03b21 induced <jats:italic>ITGA5<\/jats:italic> and <jats:italic>ITGAV<\/jats:italic> but lowered <jats:italic>ITGB8<\/jats:italic> expression, whereas the use of the TGF\u03b2 receptor inhibitor SB-505124 had the opposite effect.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Total TGF\u03b2 serum levels are not different between SSc patients and controls, but TGF\u03b2 activity is. This coincides with a reduced expression of TGF\u03b2-activating integrins in monocytes of SSc patients. Because TGF\u03b2 regulates expression of these integrins in monocytes, a negative feedback mechanism possibly underlies these observations.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13075-020-2130-5","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T05:03:49Z","timestamp":1583471029000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["TGF\u03b2-mediated expression of TGF\u03b2-activating integrins in SSc monocytes: disturbed activation of latent TGF\u03b2?"],"prefix":"10.1186","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5473-4884","authenticated-orcid":false,"given":"A.","family":"van Caam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Aarts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"van Ee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Vitters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Koenders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"van de Loo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"van Lent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"van den Hoogen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Thurlings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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