Blockade of the protease ADAM17 ameliorates experimental pancreatitis

Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalization. Despite the global health burden of pancreatitis, currently, there are no effective therapeutic agents. In this regar...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS Jg. 119; H. 42; S. e2213744119
Hauptverfasser: Saad, Mohamed I, Weng, Teresa, Lundy, Joanne, Gearing, Linden J, West, Alison C, Harpur, Christopher M, Alanazi, Mohammad, Hodges, Christopher, Croagh, Daniel, Kumar, Beena, Sagi, Irit, Rose-John, Stefan, Jenkins, Brendan J
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 18.10.2022
Schlagworte:
Acute Disease
ADAM17 Protein - genetics
ADAM17 Protein - metabolism
Animals
Carcinogens
Ceruletide - toxicity
Cytokines
Disintegrins
Endopeptidases
Fibrosis
Interleukin-6 - genetics
Interleukin-6 - metabolism
Ketones
Mice
Nicotine
Nitrosamines
Pancreatitis - drug therapy
Pancreatitis - genetics
Peptide Hydrolases
Tumor Necrosis Factor-alpha - metabolism
apoptosis
ADAM17
pancreatitis
ADAM17 prodomain inhibitor
inflammation
ISSN:1091-6490, 1091-6490
Online-Zugang:Weitere Angaben
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalization. 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 α (TNFα) 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, mice-which are homozygous for the hypomorphic allele resulting in marked reduction in ADAM17 expression-and 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 ( 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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.2213744119