Helicobacter pylori–dependent ceramide production may mediate increased interleukin 8 expression in human gastric cancer cell lines☆

Masamune, Atsushi; Shimosegawa, Tooru; Masamune, Osamu; Mukaida, Naofumi; Koizumi, Masaru; Toyota, Takayoshi

doi:10.1016/s0016-5085(99)70497-x

Cited by 48 publications

(37 citation statements)

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“…This finding remained significant after adjustment by the Bonferroni correction for multiple testing (P Ͻ 0.0125). This is consistent with a previous report by Masamune et al that ceramide plays a crucial role in H. pylori-induced IL-8 expression (38). We then tested whether the 3 components-TLR4, ceramide, and lipid raft integrity-were essential for IL-8 secretion in H. pylori-infected cells.…”

Section: Figsupporting

confidence: 90%

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Ceramide and Toll-Like Receptor 4 Are Mobilized into Membrane Rafts in Response to Helicobacter pylori Infection in Gastric Epithelial Cells

Chen

Yang

et al. 2012

Infect Immun

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ABSTRACTHelicobacter pyloriinfection is thought to be involved in the development of several gastric diseases. TwoH. pylorivirulence factors (vacuolating cytotoxin A and cytotoxin-associated gene A) reportedly interact with lipid rafts in gastric epithelial cells. The role of Toll-like receptor (TLR)-mediated signaling in response toH. pyloriinfection has been investigated extensively in host cells. However, the receptor molecules in lipid rafts that are involved inH. pylori-induced innate sensing have not been well characterized. This study investigated whether lipid rafts play a role inH. pylori-induced ceramide secretion and TLR4 expression and thereby contribute to inflammation in gastric epithelial cells. We observed that both TLR4 and MD-2 mRNA and protein levels were significantly higher inH. pylori-infected AGS cells than in mock-infected cells. Moreover, significantly more TLR4 protein was detected in detergent-resistant membranes extracted fromH. pylori-infected AGS cells than in those extracted from mock-infected cells. However, this effect was attenuated by the treatment of cells with cholesterol-usurping agents, suggesting thatH. pylori-induced TLR4 signaling is dependent on cholesterol-rich microdomains. Similarly, the level of cellular ceramide was elevated and ceramide was translocated into lipid rafts afterH. pyloriinfection, leading to interleukin-8 (IL-8) production. Using the sphingomyelinase inhibitor imipramine, we observed thatH. pylori-induced TLR4 expression was ceramide dependent. These results indicate the mobilization of ceramide and TLR4 into lipid rafts byH. pyloriinfection in response to inflammation in gastric epithelial cells.

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Section: Figsupporting

confidence: 90%

“…6), which has been shown to activate NF-B and IL-8 production upon H. pylori infection (38). Ceramide plays an important role in several signaling pathways by triggering a coalescence of receptor molecules in membrane rafts (19).…”

Section: Discussionmentioning

confidence: 99%

Ceramide and Toll-Like Receptor 4 Are Mobilized into Membrane Rafts in Response to Helicobacter pylori Infection in Gastric Epithelial Cells

Chen

Yang

et al. 2012

Infect Immun

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“…62 AP-1 has been known as an oxidant-sensitive or antioxidantresponsive factor depending on cell types. 63 In H. pylori-induced IL-8 gene transcription in MKN 45 cells 17 and KATO III cells, 18 the activation of both NF-kB and, to a lesser extent, AP-1 was induced for IL-8 gene transcription. Our previous study 19 demonstrated the importance of AP-1 as much as NFkB for IL-8 expression by H. pylori in AGS cells.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori in a Korean isolate activates mitogen-activated protein kinases, AP-1, and NF-κB and induces chemokine expression in gastric epithelial AGS cells

et al. 2003

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Oxidant-sensitive transcription factors, nuclear factor-jB (NF-jB), and activator protein-1 (AP-1) have been considered as the regulators of inducible genes such as chemokines. Since oxygen radicals are considered as an important regulator in the pathogenesis of Helicobacter pylori (H. pylori)-induced gastric ulceration and carcinogenesis, chemokines such as interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) may be regulated by NF-jB and/or AP-1. Ras, the upstream activator for mitogen-activated protein kinase (MAPK) and MAPK cascade regulate AP-1 activation. The present study aims to investigate whether H. pylori in a Korean isolate (HP99) induces the expression of chemokines (IL-8, MCP-1), which is regulated by Ras, MAPK, AP-1, and NF-jB in gastric epithelial AGS cells, and whether these transcriptional regulations of chemokines are inhibited by transfection with mutant genes for Ras (ras N-17), c-Jun (TAM-67), and IjBa (MAD-3) or treatment with MAPK inhibitors (U0126 for extracellular signal-regulated kinase or SB203580 for p38 kinase). In addition, virulence factors of HP99 were characterized by PCR analysis for the isolated DNA. As a result, HP99 is identified as cagA þ , vacA s1b, m2, iceA1 H. pylori strain. HP99 induced a time-dependent expression of mRNA and protein for IL-8 and MCP-1 via mediation of MAPK, AP-1, and NF-jB. Transfection with mutant genes for Ras, c-Jun, and IjBa and treatment with MAPK inhibitors suppressed H. pylori-induced activation of transcription factors (NF-jB, AP-1) and expression of chemokines (IL-8, MCP-1) in AGS cells. In conclusion, Ras and MAPK cascade may act as the upstream signaling for the activation of AP-1 and NF-jB, which induce chemokine expression in H. pylori-infected AGS cells. Specific targeting of the activation of NF-jB and AP-1 may be effective for the prevention or treatment of gastric inflammation associated with H. pylori infection.

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“…NF-B activation was not altered in ASMKO mouse embryonic fibroblasts (Zumbansen and Stoffel, 1997) or in human Niemann-Pick type A fibroblasts (Gamard et al, 1997) when compared with cells with normal ASM activities. On the other hand, a recent report links the sphingomyelin-ceramide pathway with expression of human interleukin (IL)-8, a functional analog of murine MIP-2, through NF-B activation in gastric epithelial cells (Masamune et al, 1999). It should be remembered that different cell types (and even the same cells in different compartments) may function through divergent signaling mechanisms, and further analysis of pulmonary cells in the ASMKO mice may help clarify the role of ASM and ceramide signaling in the NPD inflammatory disease process.…”

Section: Dhami Et Almentioning

confidence: 99%

Analysis of the Lung Pathology and Alveolar Macrophage Function in the Acid Sphingomyelinase–Deficient Mouse Model of Niemann-Pick Disease

Dhami

Gordon

et al. 2001

Laboratory Investigation

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SUMMARY:Types A and B Niemann-Pick disease (NPD) are lipid storage diseases caused by the deficient activity of the lysosomal enzyme, acid sphingomyelinase (ASM). Type B NPD is associated with progressive pulmonary function decline and frequent respiratory infections. ASM knock-out (ASMKO) mice are available as a model for NPD, but the lung pathology in these mice has not been adequately characterized. This study shows that by 10 weeks of age ASMKO mice have a significantly higher number of cells in their pulmonary airspaces than normal mice, consisting primarily of enlarged and often multinucleated macrophages. These mice also have much higher levels of sphingomyelin in their airspaces at 10 weeks of age, and both cell numbers and sphingomyelin concentrations remain elevated until 26 weeks of age. In these older mice an increased number of neutrophils is also seen. The alveolar cell population in the ASMKO mice produces less superoxide when stimulated, but this can be corrected by providing recombinant ASM to the culture media. Elevated levels of the chemokines macrophage inflammatory protein-2 and macrophage inflammatory protein-1␣ were also present in the bronchoalveolar lavage fluid of ASMKO mice, and this correlated with increased production of these chemokines by cultured macrophages and enhanced immunostaining in situ. Also, lung histology showed increased cellularity in the alveolar walls of ASMKO mice, but no evidence of fibrosis. Ultrastructural analysis of the lungs showed that the ASMKO mice have similar pathologic features to human NPD patients, with variable lipid storage evident in type I pneumocytes, endothelial cells, and airway ciliated epithelia. The alveolar macrophage, however, was the most dramatically affected cell type in both mice and humans. These studies indicate that the ASMKO mice can be used as a model to study the lung pathology associated with NPD, and demonstrate that the cellular and biochemical analysis of pulmonary airspaces may be a useful approach to monitoring disease progression and/or treatment. (Lab Invest 2001, 81:987-999).

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Helicobacter pylori–dependent ceramide production may mediate increased interleukin 8 expression in human gastric cancer cell lines☆

Cited by 48 publications

References 50 publications

Ceramide and Toll-Like Receptor 4 Are Mobilized into Membrane Rafts in Response to Helicobacter pylori Infection in Gastric Epithelial Cells

Ceramide and Toll-Like Receptor 4 Are Mobilized into Membrane Rafts in Response to Helicobacter pylori Infection in Gastric Epithelial Cells

Helicobacter pylori in a Korean isolate activates mitogen-activated protein kinases, AP-1, and NF-κB and induces chemokine expression in gastric epithelial AGS cells

Analysis of the Lung Pathology and Alveolar Macrophage Function in the Acid Sphingomyelinase–Deficient Mouse Model of Niemann-Pick Disease

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