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Despite the global health burden of pancreatitis, currently, there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumor necrosis factor \u03b1 (TNF\u03b1) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signaling. However, the role of ADAM17 in pancreatitis is unclear. To address this,\n                    <jats:italic>Adam17<\/jats:italic>\n                    <jats:sup>ex\/ex<\/jats:sup>\n                    mice\u2014which are homozygous for the hypomorphic\n                    <jats:italic>Adam17<\/jats:italic>\n                    <jats:sup>ex<\/jats:sup>\n                    allele resulting in marked reduction in ADAM17 expression\u2014and their wild-type (WT) littermates were exposed to the cerulein-induced acute pancreatitis model, and acute (1-wk) and chronic (20-wk) pancreatitis models induced by the cigarette smoke carcinogen nicotine-derived nitrosamine ketone (NNK). Our data reveal that ADAM17 expression was up-regulated in pancreatic tissues of animal models of pancreatitis. Moreover, the genetic (\n                    <jats:italic>Adam17<\/jats:italic>\n                    <jats:sup>ex\/ex<\/jats:sup>\n                    mice) and therapeutic (ADAM17 prodomain inhibitor [A17pro]) targeting of ADAM17 ameliorated experimental pancreatitis, which was associated with a reduction in the IL-6 trans-signaling\/STAT3 axis. This led to reduced inflammatory cell infiltration, including T cells and neutrophils, as well as necrosis and fibrosis in the pancreas. Furthermore, up-regulation of the ADAM17\/IL-6 trans-signaling\/STAT3 axis was a feature of pancreatitis patients. Collectively, our findings indicate that the ADAM17 protease plays a pivotal role in the pathogenesis of pancreatitis, which could pave the way for devising novel therapeutic options to be deployed against this disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2213744119","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T15:18:59Z","timestamp":1665415139000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":31,"title":["Blockade of the protease ADAM17 ameliorates experimental pancreatitis"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4855-2360","authenticated-orcid":false,"given":"Mohamed I.","family":"Saad","sequence":"first","affiliation":[{"name":"Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia"},{"name":"Centre for Innate Immunity and 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