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In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In <jats:italic>Lrg1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated <jats:italic>LRG1<\/jats:italic> transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the <jats:italic>LRG1<\/jats:italic> promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced <jats:italic>LRG1<\/jats:italic> expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates <jats:italic>LRG1<\/jats:italic> transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility.<\/jats:p>","DOI":"10.1038\/s41598-022-08516-2","type":"journal-article","created":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T11:03:15Z","timestamp":1647946995000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Angiopathic activity of LRG1 is induced by the IL-6\/STAT3 pathway"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4225-6605","authenticated-orcid":false,"given":"Athina","family":"Dritsoula","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Dowsett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Pilotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie N.","family":"O\u2019Connor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen E.","family":"Moss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Greenwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,22]]},"reference":[{"key":"8516_CR1","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/0959-440x(95)80105-7","volume":"5","author":"B Kobe","year":"1995","unstructured":"Kobe, B. & Deisenhofer, J. 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