| Literature DB >> 30279516 |
Nesrine Makhezer1,2, Marwa Ben Khemis1,2, Dan Liu1,2, Yamina Khichane1,2, Viviana Marzaioli1,2, Asma Tlili1,2, Marjan Mojallali1,2, Coralie Pintard1,2, Philippe Letteron1,2, Margarita Hurtado-Nedelec1,2,3, Jamel El-Benna1,2, Jean-Claude Marie1,2, Aurélie Sannier4, Anne-Laure Pelletier5, Pham My-Chan Dang6,7.
Abstract
Inflammatory bowel disease (IBD) is characterized by severe and recurrent inflammation of the gastrointestinal tract, associated with altered patterns of cytokine synthesis, excessive reactive oxygen species (ROS) production, and high levels of the innate immune protein, lipocalin-2 (LCN-2), in the mucosa. The major source of ROS in intestinal epithelial cells is the NADPH oxidase NOX1, which consists of the transmembrane proteins, NOX1 and p22PHOX, and the cytosolic proteins, NOXO1, NOXA1, and Rac1. Here, we investigated whether NOX1 activation and ROS production induced by key inflammatory cytokines in IBD causally affects LCN-2 production in colonic epithelial cells. We found that the combination of TNFα and IL-17 induced a dramatic upregulation of NOXO1 expression that was dependent on the activation of p38MAPK and JNK1/2, and resulted into an increase of NOX1 activity and ROS production. NOX1-derived ROS drive the expression of LCN-2 by controlling the expression of IκBζ, a master inducer of LCN-2. Furthermore, LCN-2 production and colon damage were decreased in NOX1-deficient mice during TNBS-induced colitis. Finally, analyses of biopsies from patients with Crohn's disease showed increased JNK1/2 activation, and NOXO1 and LCN-2 expression. Therefore, NOX1 might play a key role in mucosal immunity and inflammation by controlling LCN-2 expression.Entities:
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Year: 2018 PMID： 30279516 DOI： 10.1038/s41385-018-0086-4
Source DB: PubMed Journal: Mucosal Immunol ISSN： 1933-0219 Impact factor: 7.313