T Cell‐Mediated Cytotoxicity via Fas/Fas Ligand Signaling in <i>Helicobacter pylori</i>‐Infected Gastric Corpus

Ishihara, Shunji; Fukuda, Ryo; Kawashima, Kousaku; Moriyama, Nobuyuki; Suetsugu, Hiroshi; Ishimura, Norihisa; Kazumori, Hideaki; Kaji, Takekazu; Satō, Hiroshi; Okuyama, Toshihiko; Rumi, Karim; Adachi, Kyoichi; Watanabe, Makoto; Kinoshita, Yoshikazu

doi:10.1046/j.1523-5378.2001.00043.x

Cited by 18 publications

(11 citation statements)

References 53 publications

(66 reference statements)

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“…Specific IFN-γ-dependent induction of CD4+ T cell apoptosis may restrain inflammation (26), suggesting that IFN-γ maintains T cell homeostasis during immune responses. In H. felis -infected IFN-γ mice, apoptosis of CD4+ T cells appeared to be Fas-dependent, confirming prior reports (35, 36). Apoptosis of CD4+ T cells resulted in a reduction in Th1 and Th17 immune responses without a major change in Th2 responses, despite elevated IL-10 in H. felis infected IFN-γ mice, a cytokine milieu that has previously been shown to suppress inflammation-induced cancer in the gut (37).…”

Section: Discussionsupporting

confidence: 90%

IFN-γ Inhibits Gastric Carcinogenesis by Inducing Epithelial Cell Autophagy and T-Cell Apoptosis

et al. 2011

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Interferon-gamma (IFN-γ) mediates responses to bacterial infection and autoimmune disease but it is also an important tumor suppressor. IFN-γ is upregulated in the gastric mucosa by chronic Helicobacter infection; however, whether it plays a positive or negative role in inflammation-associated gastric carcinogenesis is unexplored. To study this question we generated an H+/K+-ATPase-IFN-γ transgenic mouse that overexpresses murine IFN-γ in the stomach mucosa. In contrast to the expected pro-inflammatory role during infection, we found that IFN-γ overexpression failed to induce gastritis and instead inhibited gastric carcinogenesis induced by IL-1beta (IL-1β) and/or Helicobacter infection. Th1 and Th17 immune responses were inhibited by IFN-γ through Fas induction and apoptosis in CD4 T cells. IFN-γ also induced autophagy in gastric epithelial cells through increased expression of Beclin-1. Lastly, in the gastric epithelium, IFN-γ also inhibited IL-1β- and Helicobacter-induced epithelial apoptosis, proliferation, and Dckl1+ cell expansion. Taken together, our results suggest that IFN-γ coordinately inhibits bacterial infection and carcinogenesis in the gastric mucosa by suppressing putative gastric progenitor cell expansion and reducing epithelial cell apoptosis via induction of an autophagic program.

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Section: Discussionsupporting

confidence: 90%

IFN-γ Inhibits Gastric Carcinogenesis by Inducing Epithelial Cell Autophagy and T-Cell Apoptosis

et al. 2011

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“…A similar correlation concerning differences in the expression of Fas ligand in the stomach wall was observed by Ishihara et al [5] As shown by their findings, positive FasL expression in the gastric mucosa associated with the presence of Helicobacter pylori infection occurs only in glandular epithelial cells, not in the lining epithelium.…”

Section: Discussionsupporting

confidence: 85%

Correlation between Fas and FasL proteins expression in normal gastric mucosa and gastric cancer

Gryko

Guzińska‐Ustymowicz²,

Pryczynicz³

et al. 2011

Folia Histochem Cytobiol.

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Abstract:The study's objective was to assess the expressions of Fas and FasL proteins in gastric cancer in correlation with chosen clinicohistological parameters. Fas and FasL expression was analyzed in 68 patients with gastric cancer, using the immunohistochemical method. The expression of Fas was found to be lower in gastric cancer cells than in healthy mucosa, both in the lining epithelium and in glandular tubes (28% vs. 48% and 44%; p < 0.001). The expression of FasL was also markedly lower in cancer cells than in glandular tubes, yet higher than in the lining epithelium (51% vs. 73% and 14%; p < 0.01). Positive expressions of FasL and Fas were lower in less advanced gastric cancer cells (T1, T2), than in more advanced tumors (T3, T4), but only in the case of FasL was this difference statistically significant (p < 0.05). Our findings seem to confirm the theory of the impact of apoptotic disorders at the level of Fas receptor and FasL protein in the process of gastric cancer formation and growth, which is manifested in the varied expressions of these proteins in gastric cancer and in the normal lining and glandular epithelium of the stomach. However, the lack of significant differences in the expressions of Fas and FasL in correlation to other clinicohistological parameters indicates the existence of mechanisms that have a greater impact on the process of differentiation of gastric cancers. This in our opinion eliminates these proteins as prognostic factors.

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“…21,22 CD8 þ T and NK cells utilize the Fas/FasL pathway to induce cellular lysis and injury in a variety of scenarios. 23,24 The indirect evidence provided by this series of studies as well as the findings in the present study provide rationale to investigate the ischemic component of CLP-induced pathology and the contributions of CD8 þ T and NK cells to this potential mechanism of injury.…”

Section: Discussionmentioning

confidence: 63%

Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

Sherwood

Enoh

Murphey

et al. 2004

Laboratory Investigation

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We previously showed that beta 2 microglobulin knockout mice depleted of NK cells by treatment with antiasialoGM1 (b2MKO/aAsGM1 mice) are resistant to sepsis caused by cecal ligation and puncture (CLP). b2MKO mice possess multiple immunological defects including depletion of CD8 þ T cells. This study was designed to determine the contribution of CD8 þ T and NK cell deficiency to the resistance of b2MKO/aAsGM1 mice to CLPinduced injury. b2MKO/aAsGM1 mice and CD8 knockout mice treated with anti-asialoGM1 (CD8KO/aAsGM1 mice) survived significantly longer than wild-type mice following CLP. Improved long-term survival was also observed in wild-type mice rendered CD8 þ T/NK cell-deficient by treatment with both anti-CD8a and antiasialoGM1. Blood gas analysis and body temperature measurements showed that CD8 þ T and NK cell-deficient mice have significantly reduced metabolic acidosis and less hypothermia compared to control mice at 18 h after CLP. CD8 þ T/NK cell-deficient mice also showed an attenuated proinflammatory response as indicated by decreased expression of mRNAs for IL-1, IL-6 and MIP-2 in spleen and heart. IL-6, KC and MIP-2 levels in blood and peritoneal fluid were also significantly decreased CD8 þ T/NK cell-deficient mice compared to controls. CD8 þ T/NK cell-deficient mice exhibited decreased bacterial concentrations in blood, but not in peritoneal fluid or lung, compared to wild-type controls. These data show that mice depleted of CD8 þ T and NK cells exhibit survival benefit, improved physiologic function and an attenuated proinflammatory response following CLP that is comparable to b2M/aAsGM1 mice. We previously demonstrated that b2 microglobulin knockout mice that were depleted of natural killer (NK) cells by treatment with anti-asialoGM1 (b2MKO/aAsGM1 mice) are resistant to systemic injury caused by cecal ligation and puncture (CLP). 1 Specifically, b2MKO/aAsGM1 mice exhibit improved survival, less metabolic acidosis, reduced hypothermia and better hemodynamic function compared to control mice following CLP. 1,2 These improvements in physiological function are associated with attenuation of the CLP-induced proinflammatory response.b2MKO/aAsGM1 mice have multiple immunological defects including an absence of CD8 þ T, natural killer (NK) and natural killer T (NKT) cells as well as deficient expression of the class I major histocompatability complex (MHC-I) and CD1 molecules. 1,3-5 One of our goals is to determine which of these immunological alterations confers resistance to the CLP-induced sepsis syndrome. We previously showed that adoptive transfer of CD8 þ T and NK cells into b2MKO/aAsGM1 mice will re-establish CLP-induced mortality. 1 In addition, we showed improved post-CLP survival in mice that are deficient of both CD8 þ T and NK cells. Based on this observation, we hypothesize that CD8 þ T and NK cell depletion contributes to the resistance of b2MKO/aAsGM1 mice to CLP-induced injury. To test this hypothesis, we directly compared CLP-induced mortality in b2MKO/aAsGM1 mice and CD8 þ T/NK cell-d...

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T Cell‐Mediated Cytotoxicity via Fas/Fas Ligand Signaling in Helicobacter pylori‐Infected Gastric Corpus

Abstract: T cell-mediated cytotoxicity via Fas/Fas-L signaling may contribute to the induction of apoptosis in gastric epithelial cells during H. pylori infection.

Cited by 18 publications

References 53 publications

IFN-γ Inhibits Gastric Carcinogenesis by Inducing Epithelial Cell Autophagy and T-Cell Apoptosis

IFN-γ Inhibits Gastric Carcinogenesis by Inducing Epithelial Cell Autophagy and T-Cell Apoptosis

Correlation between Fas and FasL proteins expression in normal gastric mucosa and gastric cancer

Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

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