Protein Kinase C Activation by Helicobacter pylori in Human Gastric Epithelial Cells Limits Interleukin-8 Production Through Suppression of Extracellular Signal-Regulated Kinase

Nozawa, Yoshihisa; Nishihara, Katsushi; Akizawa, Yushiro; Orimoto, Naoki; Nakano, Masaya; Uji, Tatsuya; Ajioka, Hirofusa; Kanda, Atsuhiro; Matsuura, Naosuke; Kiniwa, Mamoru

doi:10.1254/jphs.94.233

Cited by 10 publications

(15 citation statements)

References 25 publications

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“…The induction of autonomous CAMKII activity by H. pylori has been demonstrated earlier . Thus, we examined the inhibition of CAMKII by the specific CAMKII inhibitor KN‐93 and its inactive analog KN‐92 in the H. pylori infection‐induced activation of NF‐κB.…”

Section: Resultsmentioning

confidence: 83%

Ca²⁺/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor-kappa B kinase complex activation inHelicobacter pyloriinfection

et al. 2013

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Helicobacter pylori, a class I carcinogen, induces a proinflammatory response by activating the transcription factor nuclear factor-kappa B (NF-jB) in gastric epithelial cells. This inflammatory condition could lead to chronic gastritis, which is epidemiologically and biologically linked to the development of gastric cancer. So far, there exists no clear knowledge on how H. pylori induces the NF-jB-mediated inflammatory response. In our study, we investigated the role of Ca 21 /calmodulindependent kinase II (CAMKII), calmodulin, protein kinases C (PKCs) and the CARMA3-Bcl10-MALT1 (CBM) complex in conjunction with H. pylori-induced activation of NF-jB via the inhibitor of nuclear factor-kappa B kinase (IKK) complex. We use specific inhibitors and/or RNA interference to assess the contribution of these components. Our results show that CAMKII and calmodulin contribute to IKK complex activation and thus to the induction of NF-jB in response to H. pylori infection, but not in response to TNF-a. Thus, our findings are specific for H. pylori infected cells. Neither the PKCs a, d, h, nor the CBM complex itself is involved in the activation of NF-jB by H. pylori. The contribution of CAMKII and calmodulin, but not PKCs/CBM to the induction of an inflammatory response by H. pylori infection augment the understanding of the molecular mechanism involved and provide potential new disease markers for the diagnosis of gastric inflammatory diseases including gastric cancer.

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Section: Resultsmentioning

confidence: 83%

Ca²⁺/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor-kappa B kinase complex activation inHelicobacter pyloriinfection

et al. 2013

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“…However, work from Weydig et al (2007) demonstrated that H. pylori mediates internalization of p120 found in adherens junctions at the plasma membrane, which may then be translocated to the nucleus. p120 is also phosphorylated at a number of sites by Src-and receptor tyrosine kinases (Reynolds, 2007), and multiple ligand-receptor pathways have been implicated in signaling to p120 through phosphorylation, including protein kinase C-and epidermal growth factor receptor-dependent pathways (Mariner et al, 2004;Xia et al, 2006), both of which are activated by H. pylori (Keates et al, 2001;Nozawa et al, 2004). However, our data demonstrate that H. pylori mediates a decrease in total p120 tyrosine phosphorylation, indicating a previously undescribed role for protein tyrosine phosphatases in H. pylori-mediated signaling to p120.…”

Section: Discussionmentioning

confidence: 99%

p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

Ogden

Wroblewski

Weydig

et al. 2008

MBoC

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Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, yet only a fraction of infected persons develop cancer. One H. pylori constituent that augments disease risk is the cytotoxin-associated gene (cag) pathogenicity island, which encodes a secretion system that translocates bacterial effector molecules into host cells. Matrix metalloproteinase (MMP)-7, a member of a family of enzymes with tumor-initiating properties, is overexpressed in premalignant and malignant gastric lesions, and H. pylori cag ؉ strains selectively increase MMP-7 protein levels in gastric epithelial cells in vitro and in vivo. We now report that H. pylori-mediated mmp-7 induction is transcriptionally regulated via aberrant activation of p120-catenin (p120), a component of adherens junctions. H. pylori increases mmp-7 mRNA levels in a cagand p120-dependent manner and induces translocation of p120 to the nucleus in vitro and in a novel ex vivo gastric gland culture system. Nuclear translocation of p120 in response to H. pylori relieves Kaiso-mediated transcriptional repression of mmp-7, which is implicated in tumorigenesis. These results indicate that selective and coordinated induction of mmp-7 expression by H. pylori cag ؉ isolates may explain in part the augmentation in gastric cancer risk associated with these strains. INTRODUCTIONHelicobacter pylori induces an inflammatory response in the stomach that persists for decades, and biological costs incurred by this pathogen include an increased risk for gastric adenocarcinoma and non-Hodgkins lymphoma of the stomach (Nomura et al., 1991;Parsonnet et al., 1991;Peterson, 1991;Hansson et al., 1993;Correa, 1996;Uemura et al., 2001;Peek and Blaser, 2002;Moss and Sood, 2003). However, only a fraction of colonized persons ever develop neoplasia, and enhanced cancer risk is related to strain-specific differences, aberrant host responses, and/or specific interactions between microbial and host determinants.H. pylori strains that possess the cytotoxin-associated gene (cag) pathogenicity island increase the risk for cancer compared with strains that lack this genetic locus (Peek and Blaser, 2002). The cag island encodes proteins, such as CagE, that form a type IV secretion system that translocates components of bacterial peptidoglycan and CagA, the product of the terminal gene of the island, into host cells (Asahi et al., 2000;Backert et al., 2000;Odenbreit et al., 2000;Stein et al., 2000;Selbach et al., 2002;Viala et al., 2004). After translocation, peptidoglycan initiates innate immune signaling via activation of the intracellular pattern recognition receptor, Nod-1, and the transcriptional activator nuclear factor-B (NF-B) (Viala et al., 2004). Intracellular CagA undergoes Src-dependent tyrosine phosphorylation and activates a eukaryotic phosphatase, leading to dephosphorylation of host cell proteins and cellular morphological changes (Backert et al., 2000;Higashi et al., 2002;Selbach et al., 2002;Stein et al., 2002). Recently, CagA has been shown to activate ␤-catenin and...

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“…Specifically, H‐7 was shown to inhibit the accumulation of ZO‐1 and disrupt filament formation. In fact, there is substantial data indicating that PKC is involved in both tight junction assembly and disassembly . Early studies indicated stimulation of both conventional and novel PKC isoforms led to translocation of tight junction proteins to cell borders, thus aiding in tight junction formation and epithelial resistance .…”

Section: Pkc Signaling and Tight Junction Barrier Integritymentioning

confidence: 99%

TLR4/PKC‐mediated tight junction modulation: A clinical marker of chemotherapy‐induced gut toxicity?

Wardill

Gibson

Logan

et al. 2014

Intl Journal of Cancer

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Chemotherapy‐induced gut toxicity is a major clinical and economic burden to oncology practice. The mechanisms responsible for its development are ill defined, hampering the development of therapeutic interventions. In light of newly published research foci and clinical practice guidelines in supportive care in cancer, there has been renewed interest in the role tight junctions play in the pathobiology of chemotherapy‐induced gut toxicity. Several preclinical studies have identified molecular defects in intestinal tight junctions following chemotherapy. Despite these findings, the mechanisms responsible for chemotherapy‐induced tight junction disruption remain unclear. Recent research has highlighted roles for toll‐like receptor 4 and protein kinase C signalling in the regulation of tight junctions. This critical review therefore aims to provide evidence linking toll‐like receptor 4 expression, protein kinase C activation and tight junction disruption and their relationship to clinical toxicity.

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Protein Kinase C Activation by Helicobacter pylori in Human Gastric Epithelial Cells Limits Interleukin-8 Production Through Suppression of Extracellular Signal-Regulated Kinase

Cited by 10 publications

References 25 publications

Ca²⁺/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor-kappa B kinase complex activation inHelicobacter pyloriinfection

Ca²⁺/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor-kappa B kinase complex activation inHelicobacter pyloriinfection

p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

TLR4/PKC‐mediated tight junction modulation: A clinical marker of chemotherapy‐induced gut toxicity?

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Protein Kinase C Activation by Helicobacter pylori in Human Gastric Epithelial Cells Limits Interleukin-8 Production Through Suppression of Extracellular Signal-Regulated Kinase

Cited by 10 publications

References 25 publications

Ca2+/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor-kappa B kinase complex activation inHelicobacter pyloriinfection

Ca2+/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor-kappa B kinase complex activation inHelicobacter pyloriinfection

p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

TLR4/PKC‐mediated tight junction modulation: A clinical marker of chemotherapy‐induced gut toxicity?

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Ca²⁺/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor-kappa B kinase complex activation inHelicobacter pyloriinfection

Ca²⁺/calmodulin-dependent kinase II contributes to inhibitor of nuclear factor-kappa B kinase complex activation inHelicobacter pyloriinfection