Activation of Activator Protein 1 and Stress Response Kinases in Epithelial Cells Colonized by Helicobacter pylori Encoding the cag Pathogenicity Island

Abstract

Helicobacter pylori interacts with the apical membrane of the gastric epithelium and induces a number of proinflammatory cytokines/chemokines. The subsequent infiltration of macrophages and granulocytes into the mucosa leads to gastric inflammation accompanied by epithelial degeneration. Gastric diseases, e.g. peptic ulcer or gastric adenocarcinoma, are more common among people infected with H. pylori strains producing VacA (vacuolating cytotoxin A) and possessing a cag (cytotoxin-associated antigen A) pathogenicity island. For the induction of the cytokine/chemokine genes in response to H. pylori, we studied the signaling leading to the nuclear activation of the early response transcription factor activator protein 1 (AP-1). We found that H. pylori strains carrying the pathogenicity island induce activation of AP-1 and nuclear factor B. In contrast to the wild type or an isogenic strain without the vacA gene, isogenic H. pylori strains with mutations in certain cag genes revealed only weak AP-1 and nuclear factor B activation. In respect to the molecular components that direct AP-1 activity, our results indicate a cascade of the cellular stress response kinases c-Jun N-terminal kinase, MAP kinase kinase 4, and p21-activated kinase, and small Rho-GTPases including Rac1 and Cdc42, which contributes to the activation of proinflammatory cytokines/chemokines induced by H. pylori encoding the cag pathogenicity island.

Helicobacter pylori adherence to gastric epithelial cells: a role for non-adhesin virulence genes

“…The cagA gene is a marker for a large 40-kb locus containing .40 genes, termed the cag pathogenicity island (cag PAI), and the majority of these genes encode membrane-associated proteins with features similar to other bacterial secretion systems, particularly the type IV system epitomised by Bordetella pertussis toxin secretion [27][28][29]. A cagE mutant induced only mild inflammation in Mongolian gerbils, whereas the wild-type strain and vacA mutants induced more severe gastritis [30].…”

“…A cagE mutant induced only mild inflammation in Mongolian gerbils, whereas the wild-type strain and vacA mutants induced more severe gastritis [30]. Mutation of cagE abolishes the ability of H. pylori to induce the cytokine interleukin-8 (IL-8), a neutrophil chemotactic factor, in Kato-3 cells [27,29,31,32]. Adherence has been shown to play a role in the induction of H. pyloriassociated IL-8 secretion [33].…”

Helicobacter pylori: recent advances in the study of its pathogenicity and prevention

“…It also induces inflammatory cytokines IL-1, IL-6 and TNF-α, which up-regulate the expression of IL-8 in epithelial cells. 67,105,113 This epithelial proinflammatory cytokine/chemokine response is particularly important because it serves to amplify and spread the primary pathogenic signal that leads to a rapid mobilization of phagocytic cells to the sites of invasion. Proinflammatory cytokine response may be protective, but when chronically activated, it also disrupts the function and the integrity of the gastric epithelium.…”

“…Cytokines produced by infiltrated mononuclear phagocytes within the mucosa produce additional stimulation that induces gastric degeneration. 113 Thereby, IL-8 appears to play a key role in the initiation of the local inflammatory and immune response that may contribute to the more serious sequels associated with H. pylori infection.…”

“…MAPK regulate cell proliferation, differentiation, inflammatory responses, stress, and programmed death, which may help induce gastroduodenal inflammation, ulceration, and neoplasia. 121 The integrity of whole cag PAI is also a prerequisite for efficient activation of early transcription factor AP-1, which is known for its immunostimulatory function 113 . Hence, these data support the view that the epithelial cytokine/chemokine response depends on multiple genes in the cag PAI of H. pylori.…”