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To date, it is not well understood what key regulator might coordinate signaling pathways to achieve inflammatory response in TNF<\/jats:styled-content>\u2010\u03b1\u2010stimulated EC<\/jats:styled-content>s. This study investigated the role of dual specificity phosphatase\u20106 (DUSP<\/jats:styled-content>6) in the regulation of endothelial inflammation. Using knockout mice, we found that DUSP<\/jats:styled-content>6 is important for TNF<\/jats:styled-content>\u2010\u03b1\u2010induced endothelial intercellular adhesion molecule\u20101 (ICAM<\/jats:styled-content>\u20101) expression in aorta and in vein. Moreover, genetic deletion of Dusp6<\/jats:italic> in pulmonary circulation significantly alleviated the susceptibility of mice to lung injury caused by neutrophil recruitment during experimental sepsis induced by TNF<\/jats:styled-content>\u2010\u03b1 or lipopolysaccharide (LPS<\/jats:styled-content>). The role of DUSP<\/jats:styled-content>6 was further investigated in primary human umbilical vein endothelial cells (HUVEC<\/jats:styled-content>s). Employing RNA<\/jats:styled-content>i approach in which endogenous DUSP<\/jats:styled-content>6 was ablated, we showed a critical function of DUSP<\/jats:styled-content>6 to facilitate TNF<\/jats:styled-content>\u2010\u03b1\u2010induced ICAM<\/jats:styled-content>\u20101 expression and endothelial leukocyte interaction. Interestingly, DUSP<\/jats:styled-content>6\u2010promoted\u00a0endothelial inflammation is independent of extracellular signaling\u2010regulated kinase (ERK<\/jats:styled-content>) signaling. On the other hand, inducible DUSP<\/jats:styled-content>6 leads to activation of canonical nuclear factor (NF<\/jats:styled-content>)\u2010\u03baB\u2010mediated transcription of ICAM<\/jats:styled-content>\u20101<\/jats:italic> gene in TNF<\/jats:styled-content>\u2010\u03b1\u2010stimulated human EC<\/jats:styled-content>s. These results are the first to demonstrate a positive role of DUSP<\/jats:styled-content>6 in endothelial inflammation\u2010mediated pathological process and the underlying mechanism through which DUSP<\/jats:styled-content>6 promotes NF<\/jats:styled-content>\u2010\u03baB signaling in the inflamed EC<\/jats:styled-content>s. Our findings suggest that manipulation of DUSP<\/jats:styled-content>6 holds great potential for the treatment of acute inflammatory diseases.<\/jats:p>","DOI":"10.1111\/febs.14425","type":"journal-article","created":{"date-parts":[[2018,3,1]],"date-time":"2018-03-01T15:41:20Z","timestamp":1519918880000},"page":"1593-1610","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Dual specificity phosphatase DUSP<\/scp>6 promotes endothelial inflammation through inducible expression of ICAM<\/scp>\u20101"],"prefix":"10.1111","volume":"285","author":[{"given":"Shu\u2010Fang","family":"Hsu","sequence":"first","affiliation":[{"name":"Institute of Biochemical Sciences National Taiwan University Taipei Taiwan"},{"name":"Institute of Biological Chemistry Academia Sinica Taipei 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