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However, little is known about the vascular endothelial signaling pathways regulating the transcriptional profile in failing organs. Our work focused on signaling downstream of IL-6, due to its clinical importance as a biomarker for disease severity and predictor of mortality. Here, we show that loss of endothelial expression of the IL-6 pathway inhibitor SOCS3 promoted a type I IFN\u2013like (IFNI-like) gene signature in response to endotoxemia in mouse kidneys and brains. In cultured primary human endothelial cells, IL-6 induced transient IFNI-like gene expression in a noncanonical, IFN-independent fashion. We further show that STAT3, which we had previously demonstrated to control IL-6\u2013driven endothelial barrier function, was dispensable for this activity. Instead, IL-6 promoted a transient increase in cytosolic mitochondrial DNA and required STAT1, cGAS, STING, and IRF1, -3, and -4. Inhibition of this pathway in endothelial cell\u2013specific STING-KO mice or global STAT1-KO mice led to reduced the severity of the response to acute endotoxemic challenge and prevented expression of an endotoxin-induced IFNI-like gene signature. These results suggest that permeability and DNA-sensing responses are driven by parallel pathways downstream of this cytokine, provide potential insights into the complex response to acute inflammatory responses, and offer the possibility of novel therapeutic strategies for independently controlling the intracellular responses to IL-6 in order to tailor the inflammatory response.<\/jats:p>","DOI":"10.1172\/jci189570","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T16:00:22Z","timestamp":1758038422000},"source":"Crossref","is-referenced-by-count":12,"title":["Endothelial STING and STAT1 mediate IFN-independent effects of IL-6 in an endotoxemia-induced model of shock"],"prefix":"10.1172","volume":"135","author":[{"given":"Nina","family":"Martino","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York, 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