Protease-Activated Receptor-2 (PAR2) in Human Gastric Mucosa as Mediator of Proinflammatory Effects in Helicobacter pylori Infection

Abstract

Protease-activated receptors (PAR) are seven transmembrane receptors that are expressed throughout the gastrointestinal tract. In vitro experiments using gastric tumor cell lines, murine models and one clinical study provided evidence for a potential role of PAR2 in Helicobacter pylori-induced gastritis. To investigate PAR2 expression in H. pylori-infected patients and correlation with proinflammatory IL-8, IL-1β as well as histologic changes of the mucosa. Furthermore, PAR2 expression was studied in context to mucosal amounts of secretory leukocyte protease inhibitor (SLPI), a putative regulator of PAR2. Twenty-two H. pylori-infected patients and 72 H. pylori-negative subjects underwent upper GI endoscopy. In antrum-derived mucosal biopsies, PAR2, IL-1β, IL-8, and SLPI expression was analyzed by quantitative RT-PCR, and in part by ELISA and immunohistochemistry. Histopathologic evaluation of gastritis was performed according to the updated Sydney classification. IL-8 gene expression was 5-fold increased in the mucosa of H. pylori-infected patients compared with non-infected (p < .0001), whereas no differences for PAR2 and IL-1β mRNA amounts were observed between both groups. PAR2 gene expression correlated positively with transcript levels of IL-8, IL-1β as well mucosal SLPI levels in H. pylori-infected patients (r: 0.47-0.84; p < .0001), whereas no correlation was found with the degree of gastritis. PAR2 represents an additive pathway of IL-8 secretion and proinflammatory effects in H. pylori-induced gastritis. Reduced SLPI levels leading to higher serine protease activities in the mucosa of infected subjects might regulate PAR2 activation.