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Treatment with VTN (but not fibrinogen, fibronectin, laminin-111 or collagen-I) substantially increased LIF and IL-6 within 4\u2005h in C6-astroglioma cells, while VTN\u2212\/\u2212 mouse plasma was less effective than that from wild-type mice. LIF and IL-6 were induced by intracerebral injection of recombinant human (rh)VTN in mice, but induction seen upon intracerebral hemorrhage was less in VTN\u2212\/\u2212 mice than in wild-type littermates. In vitro, VTN effects were inhibited by RGD, \u03b1v\u03b23 and \u03b1v\u03b25 integrin-blocking peptides and antibodies. VTN activated focal adhesion kinase (FAK; also known as PTK2), whereas pharmacological- or siRNA-mediated inhibition of FAK, but not PYK2, reduced the expression of LIF and IL-6 in C6 and endothelial cells and after traumatic cell injury. Dominant-negative FAK (Y397F) reduced the amount of injury-induced LIF and IL-6. Pharmacological inhibition or knockdown of uPAR (also known as PLAUR), which binds VTN, also reduced cytokine expression, possibly through a common target of uPAR and integrins. We propose that VTN leakage into tissues promotes inflammation. Integrin\u2013FAK signaling is therefore a novel IL-6 and LIF regulation mechanism relevant to the inflammation and stem cell fields.<\/jats:p>","DOI":"10.1242\/jcs.202580","type":"journal-article","created":{"date-parts":[[2017,12,9]],"date-time":"2017-12-09T01:10:25Z","timestamp":1512781825000},"source":"Crossref","is-referenced-by-count":31,"title":["Blood vitronectin is a major activator of LIF and IL-6 in the brain through integrin\u2013FAK and uPAR signaling"],"prefix":"10.1242","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1236-3840","authenticated-orcid":false,"given":"Matthew P.","family":"Keasey","sequence":"first","affiliation":[{"name":"Quillen College of Medicine, East Tennessee State University 1 Department of Biomedical Sciences , , Johnson City, TN 37614 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9693-0012","authenticated-orcid":false,"given":"Cuihong","family":"Jia","sequence":"additional","affiliation":[{"name":"Quillen College of Medicine, East Tennessee State University 1 Department of Biomedical Sciences , , Johnson City, TN 37614 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1467-7624","authenticated-orcid":false,"given":"Lylyan F.","family":"Pimentel","sequence":"additional","affiliation":[{"name":"Quillen College of Medicine, East Tennessee State University 1 Department of Biomedical Sciences , , Johnson City, TN 37614 , USA"},{"name":"Universidade Federal de Pernambuco, Recife, PE, Brasil 2 Keizo Asami Laboratory (LIKA) ,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9517-0752","authenticated-orcid":false,"given":"Richard R.","family":"Sante","sequence":"additional","affiliation":[{"name":"Quillen College of Medicine, East Tennessee State University 1 Department of Biomedical Sciences , , Johnson City, TN 37614 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiharu","family":"Lovins","sequence":"additional","affiliation":[{"name":"Quillen College of Medicine, East Tennessee State University 1 Department of Biomedical Sciences , , Johnson City, TN 37614 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo","family":"Hagg","sequence":"additional","affiliation":[{"name":"Quillen College of Medicine, East Tennessee State University 1 Department of Biomedical Sciences , , Johnson City, TN 37614 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2018,2,2]]},"reference":[{"key":"2024061317265134000_JCS202580C1","doi-asserted-by":"publisher","first-page":"2513","DOI":"10.1038\/sj.onc.1205342","article-title":"Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo","volume":"21","author":"Aguirre Ghiso","year":"2002","journal-title":"Oncogene"},{"key":"2024061317265134000_JCS202580C2","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1002\/jcp.22356","article-title":"\u03b1V\u03b23 integrin regulates macrophage inflammatory responses via PI3 kinase\/Akt-dependent NF-\u03baB activation","volume":"226","author":"Antonov","year":"2011","journal-title":"J. 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