Helicobacter pylori CagL Activates ADAM17 to Induce Repression of the Gastric H, K-ATPase α Subunit

Abstract

Background & Aims Infection with H. pylori represses expression of the gastric H, K-ATPase α subunit (HKα), which could contribute to transient hypochlorhydria. CagL, a pilus protein component of the H. pylori type IV secretion system, binds to the integrin α5β1 to mediate translocation of virulence factors into the host cell and initiate signaling. α5β1 binds ADAM17, a metalloenzyme that catalyzes ectodomain shedding of receptor tyrosine kinase ligands. We investigated whether H. pylori-induced repression of HKα is mediated by CagL activation of ADAM17 and release of heparin-binding epidermal growth factor (HB-EGF). Methods HKα promoter and ADAM17 activity were measured in AGS gastric epithelial cells transfected with HKα promoter-reporter constructs or ADAM17-specific small interfering (si)RNAs and infected with H. pylori. HB-EGF secretion was measured by ELISA analysis and ADAM17 interaction with integrins were investigated by co-immunoprecipitation analyses. Results Infection of AGS cells with wild-type H. pylori or an H. pylori cagL-deficient isogenic mutant that also contained a wild-type version of cagL (P12ΔcagL/cagL) repressed HKα promoter-Luc reporter activity and stimulated ADAM17 activity. Both responses were inhibited by point mutations in the NF-κB binding site of HKα or by infection with P12ΔcagL. siRNA-mediated silencing of ADAM17 in AGS cells inhibited the repression of wild-type HKα promoter and reduced ADAM17 activity and HB-EGF production, compared to controls. Coimmunoprecipitation studies of AGS lysates showed that wild-type H. pylori disrupted ADAM17–α5β1 complexes. Conclusions During acute H. pylori infection, CagL dissociates ADAM17 from the integrin α5β1 and activates ADAM17-dependent, NF-κB–mediated repression of HKα. This might contribute to transient hypochlorhydria in patients with H. pylori infection.

Helicobacter pylori cagL amino acid polymorphisms and its association with gastroduodenal diseases

“…Previously, a study from Taiwan reported a higher rate of the amino acid sequence polymorphisms Y58 and E59 in GC patients (P \ 0.05) and concluded that cagL-Y58E59 isolates possibly exert stronger acid suppression during chronic infection [16]. On the other hand, the results of Saha et al [17] help in part to explain that CagL may dissociate ADAM17 of integrin a5b1 to contribute to hypochlorhydria during H. pylori infection. In the present study, different amino acid polymorphisms, D58 and K59, were significantly associated with GC.…”

Helicobacter pylori-Induced Disruption of Monolayer Permeability and Proinflammatory Cytokine Secretion in Polarized Human Gastric Epithelial Cells

“…It is the direct contact of the T4SS with the epithelial cell membrane, however, that is believed to be primarily responsible for induction of the secretion of interleukin-8 (IL-8) and other host immune response events (14)(15)(16)(17). Epithelial ␣5␤1 integrin has been implicated as one of the host receptors for this activity (18)(19)(20)(21). Expression of these integrins, however, is limited to the basolateral membranes.…”

H. pyloriacutely inhibits gastric secretion by activating CGRP sensory neurons coupled to stimulation of somatostatin and inhibition of histamine secretion

“…pylori-induced hypochlorhydria is thought to be important in establishing initial colonization within the hostile environment of the stomach. Prior studies have focused on bacterial adherence to epithelial cells and direct interactions of bacterial virulence factors using isolated parietal cells and oxyntic glands, gastric epithelial cell lines, and oxyntic biopsies in short-term culture (6,20,29,47,55,56). In isolated rabbit oxyntic glands, we show that H. pylori spent broth inhibits basal and histamine-stimulated acid secretion in a concentration-dependent manner.…”

“…In rabbit oxyntic glands, a protein produced by H. pylori was reported to inhibit histamine-stimulated acid secretion (6). In isolated rabbit parietal cells and a human gastric epithelial cell line, H. pylori interfered with the transcription and translation of H ϩ -K ϩ -ATPase as well as its insertion into the parietal cell apical membrane (20,55). Using the axonal blocker TTX and SST antibody, we provide additional evidence that the decrease in acid secretion induced by H. pylori in oxyntic glands occurs independent of neural pathways or release of SST.…”

“…To facilitate this, acute H. pylori infection produces hypochlorhydria in humans (21,25,51). The precise pathway whereby acute infection inhibits acid secretion is not known, but studies have suggested that constituents and products of H. pylori (e.g., acid-inhibitory factor, lipopolysaccharide, vacuolating cytotoxin, ammonia/ammonium, and products of the cag pathogenicity island gene) as well as proinflammatory cytokines may act directly on parietal cells (20,24,29,39,40,55,57,62). However, it is uncertain whether this explains how patchy superficial infection of the oxyntic mucosa can induce acute hypochlorhydria in intact gastric tissues.…”