Cag Pathogenicity Island-independent Up-regulation of Matrix Metalloproteinases-9 and -2 Secretion and Expression in Mice by Helicobacter pylori Infection

Abstract

Helicobacter pylori cag pathogenicity island (PAI) is a major determinant of gastric injury via induction of several matrix metalloproteinases (MMPs). In the present study, we examined the influence of the cag PAI on gastric infection and MMP-9 production in mice and in cultured cells. A new mouse colonizing Indian H. pylori strain (AM1) that lacks the cag PAI was used to study the cag PAI importance in inflammation. Groups of C57BL/6 mice were inoculated separately with H. pylori strains AM1 and SS1 (cag ؉ ), gastric tissues were histologically examined, and bacterial colonization was scored by quantitative culture. Mice infected with either cag ؉ or cag ؊ H. pylori strains showed gastric inflammation and elevated MMP-3 production. Significant up-regulation of pro-MMP-9 secretion and gene expression in H. pylori infected gastric tissues indicate dispensability of cag PAI for increased pro-MMP-9 secretion and synthesis in mice. In agreement, cell culture studies revealed that both AM1 and SS1 were equipotent in pro-MMP-9 induction in human gastric epithelial cells. Both strains showed moderate increase in MMP-2 activity in vivo and in vitro. In addition, increased secretion of tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, and IL-6 induced pro-MMP-9 secretion and synthesis in AM1 or SS1 strain-infected mice suggesting elicitation of pro-inflammatory cytokines by both cag ؊ and cag ؉ genotype. Moreover, tissue inhibitors of metalloproteinase-1 expression were decreased with increase in pro-MMP-9 induction. These data show that H. pylori may act through different pathways other than cag PAI-mediated for gastric inflammation and contribute to upregulation of MMP-9 via pro-inflammatory cytokines.Helicobacter pylori is a microaerophilic bacterium with an extraordinary ability to chronically infect human stomachs for years together despite gastric mucosal turnover and other host defenses (1). It colonizes more than half of all people worldwide and is still unknown why most remain asymptomatic (2). Persistent H. pylori infection is associated with chronic gastritis and gastric cancer, one of the most lethal of malignancies worldwide (2-4). It may also cause childhood malnutrition and increase the risk or severity of infection by other gastrointestinal pathogens such as Vibrio cholerae, especially in developing countries (5, 6). H. pylori appears to be one of the most genetically diverse of bacterial species and shows significant geographic differences among strains (7-11). Studies of strains from Europe and North America indicated that H. pylori genotypes can be important in colonization and disease outcome (12). Recent studies revealed that Indian H. pylori strains are genetically distinct from European and East Asian strains (9, 10). Variation in the clinical outcome of H. pylori infection seems to be multifaceted and involves a complex interplay between virulence factors, host immune responses, and other features of the H. pylori gastric mucosal niche. Prominent among the H. pylori virulence-associated determin...

Antimicrobial Activity of Curcumin against Helicobacter pylori Isolates from India and during Infections in Mice

“…Animals of both control and experimental groups were kept separately in standard conditions and were fasted for 6 h with free access to water before each inoculation. Groups of mice (12 mice per group) were inoculated with H. pylori cultures harvested in PBS twice in a period of 3 days, with about 10 8 CFU/mouse/inoculation (14). Mouse groups inoculated with SS1, AM1, or PBS (control group) were kept separately, with free access to water and food.…”

“…Two mouse-adapted H. pylori strains (one isolated from Australia [SS1] and another one from India [AM1]) were used for the animal experiment. They were revived and cultured for mouse infection (14).…”

“…Indian H. pylori strains are genetically distinct from those from east Asia and the West (4,16). Several putative virulence-associated factors, including alleles in the cag pathogenicity island (PAI) of H. pylori, contribute to its pathogenesis and augment the risk for gastric adenocarcinoma (14). As virulence markers of H. pylori are not always associated with diseases, eradication of H. pylori from infected individuals remains the best choice for an effective treatment of H. pyloriassociated diseases.…”

Matrix Metalloproteinases as Drug Targets in Infections Caused by Gram-Negative Bacteria and in Septic Shock

“…A Helicobacter pylori constituent that augments disease risk is the pathogenicity island (PAI), which encodes a secretion system that translocates bacterial effector molecules into host cells. This virulence factor selectively leads to the induction of some MMPs, such as MMP-7 (102), while other MMPs, such as MMP-9 and MMP-2, are also upregulated in strains lacking this PAI (62). Levels of MMP-9 specifically originating from macrophages are also increased in human and mouse Helicobacter-associated gastritis (7).…”

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“…The ECM of the gastric mucosa is composed of a number of macromolecules, such as collagen, laminin, proteoglycan, elastin, fibronectin and hyaluronic acid, and their degradation by MMPs plays an important role in maintaining the cellular microenvironment (Hellmig et al, 2006). MMP9 (92-kDa, type IV collagenase) located on human chromosome 20q11.1-13.1 (Fig1), is a key enzyme in the causation of gastric ulcer (Swarnakar et al, 2005;Kundu et al, 2006). MMP9 (also known as gelatinase B) can degrade collagen type IV, collagen type V and elastin as well.…”