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The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms.

Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, Amedei A, D'Elios MM, Telford JL, Baldari CT - J. Exp. Med. (2003)

Bottom Line: A second, channel-independent mechanism involves activation of intracellular signaling through the mitogen-activated protein kinases MKK3/6 and p38 and the Rac-specific nucleotide exchange factor, Vav.As a consequence of aberrant Rac activation, disordered actin polymerization is stimulated.The resulting defects in T cell activation may help H. pylori to prevent an effective immune response leading to chronic colonization of its gastric niche.

View Article: PubMed Central - PubMed

Affiliation: Department of Evolutionary Biology, University of Sienna, 53100 Siena, Italy.

ABSTRACT
Helicobacter pylori toxin, VacA, damages the gastric epithelium by erosion and loosening of tight junctions. Here we report that VacA also interferes with T cell activation by two different mechanisms. Formation of anion-specific channels by VacA prevents calcium influx from the extracellular milieu. The transcription factor NF-AT thus fails to translocate to the nucleus and activate key cytokine genes. A second, channel-independent mechanism involves activation of intracellular signaling through the mitogen-activated protein kinases MKK3/6 and p38 and the Rac-specific nucleotide exchange factor, Vav. As a consequence of aberrant Rac activation, disordered actin polymerization is stimulated. The resulting defects in T cell activation may help H. pylori to prevent an effective immune response leading to chronic colonization of its gastric niche.

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p38 activity is detectable in gastric biopsies of H. pylori–positive patients and in VacA-treated neutrophils and macrophages. (A) Immunohistochemistry of activated p38 in gastric mucosa of H. pylori–infected patient. Phosphorylated p38 antigens are identified by brown peroxidase staining. No staining was observed in the absence of primary antibody (not depicted). (Top) Healthy H. pylori–negative control (no positive anti–phospho-p38 staining). (Bottom) H. pylori–infected patient (positive anti–phospho-p38 staining). Original magnification 40×. (B) Immunoblot analysis with anti–phospho-p38 antibodies of postnuclear supernatants from purified human neutrophils or macrophages treated with 20 μg/ml VacA for 5 or 10 min as indicated. (C) Immunoblot analysis with anti–COX-2 antibodies of postnuclear supernatants from purified human neutrophils or macrophages treated with 20 μg/ml VacA for 24 h. Macrophages activated with 10 μg/ml LPS were used as a positive control. After stripping, all filters were reprobed with control antibodies as indicated.
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fig7: p38 activity is detectable in gastric biopsies of H. pylori–positive patients and in VacA-treated neutrophils and macrophages. (A) Immunohistochemistry of activated p38 in gastric mucosa of H. pylori–infected patient. Phosphorylated p38 antigens are identified by brown peroxidase staining. No staining was observed in the absence of primary antibody (not depicted). (Top) Healthy H. pylori–negative control (no positive anti–phospho-p38 staining). (Bottom) H. pylori–infected patient (positive anti–phospho-p38 staining). Original magnification 40×. (B) Immunoblot analysis with anti–phospho-p38 antibodies of postnuclear supernatants from purified human neutrophils or macrophages treated with 20 μg/ml VacA for 5 or 10 min as indicated. (C) Immunoblot analysis with anti–COX-2 antibodies of postnuclear supernatants from purified human neutrophils or macrophages treated with 20 μg/ml VacA for 24 h. Macrophages activated with 10 μg/ml LPS were used as a positive control. After stripping, all filters were reprobed with control antibodies as indicated.

Mentions: To assess the in vivo relevance of p38 activation, gastric sections from H. pylori–infected patients were stained for phosphorylated p38. Gastric biopsies were obtained from five H. pylori–infected subjects and five healthy H. pylori–negative volunteers. Phospho-p38 was detected in glandular epithelial and lymphomononuclear-like cells in sections from all five H. pylori–infected patients but not from any of the healthy H. pylori–noninfected subjects (Fig. 7 A).


The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms.

Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, Amedei A, D'Elios MM, Telford JL, Baldari CT - J. Exp. Med. (2003)

p38 activity is detectable in gastric biopsies of H. pylori–positive patients and in VacA-treated neutrophils and macrophages. (A) Immunohistochemistry of activated p38 in gastric mucosa of H. pylori–infected patient. Phosphorylated p38 antigens are identified by brown peroxidase staining. No staining was observed in the absence of primary antibody (not depicted). (Top) Healthy H. pylori–negative control (no positive anti–phospho-p38 staining). (Bottom) H. pylori–infected patient (positive anti–phospho-p38 staining). Original magnification 40×. (B) Immunoblot analysis with anti–phospho-p38 antibodies of postnuclear supernatants from purified human neutrophils or macrophages treated with 20 μg/ml VacA for 5 or 10 min as indicated. (C) Immunoblot analysis with anti–COX-2 antibodies of postnuclear supernatants from purified human neutrophils or macrophages treated with 20 μg/ml VacA for 24 h. Macrophages activated with 10 μg/ml LPS were used as a positive control. After stripping, all filters were reprobed with control antibodies as indicated.
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Related In: Results  -  Collection

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fig7: p38 activity is detectable in gastric biopsies of H. pylori–positive patients and in VacA-treated neutrophils and macrophages. (A) Immunohistochemistry of activated p38 in gastric mucosa of H. pylori–infected patient. Phosphorylated p38 antigens are identified by brown peroxidase staining. No staining was observed in the absence of primary antibody (not depicted). (Top) Healthy H. pylori–negative control (no positive anti–phospho-p38 staining). (Bottom) H. pylori–infected patient (positive anti–phospho-p38 staining). Original magnification 40×. (B) Immunoblot analysis with anti–phospho-p38 antibodies of postnuclear supernatants from purified human neutrophils or macrophages treated with 20 μg/ml VacA for 5 or 10 min as indicated. (C) Immunoblot analysis with anti–COX-2 antibodies of postnuclear supernatants from purified human neutrophils or macrophages treated with 20 μg/ml VacA for 24 h. Macrophages activated with 10 μg/ml LPS were used as a positive control. After stripping, all filters were reprobed with control antibodies as indicated.
Mentions: To assess the in vivo relevance of p38 activation, gastric sections from H. pylori–infected patients were stained for phosphorylated p38. Gastric biopsies were obtained from five H. pylori–infected subjects and five healthy H. pylori–negative volunteers. Phospho-p38 was detected in glandular epithelial and lymphomononuclear-like cells in sections from all five H. pylori–infected patients but not from any of the healthy H. pylori–noninfected subjects (Fig. 7 A).

Bottom Line: A second, channel-independent mechanism involves activation of intracellular signaling through the mitogen-activated protein kinases MKK3/6 and p38 and the Rac-specific nucleotide exchange factor, Vav.As a consequence of aberrant Rac activation, disordered actin polymerization is stimulated.The resulting defects in T cell activation may help H. pylori to prevent an effective immune response leading to chronic colonization of its gastric niche.

View Article: PubMed Central - PubMed

Affiliation: Department of Evolutionary Biology, University of Sienna, 53100 Siena, Italy.

ABSTRACT
Helicobacter pylori toxin, VacA, damages the gastric epithelium by erosion and loosening of tight junctions. Here we report that VacA also interferes with T cell activation by two different mechanisms. Formation of anion-specific channels by VacA prevents calcium influx from the extracellular milieu. The transcription factor NF-AT thus fails to translocate to the nucleus and activate key cytokine genes. A second, channel-independent mechanism involves activation of intracellular signaling through the mitogen-activated protein kinases MKK3/6 and p38 and the Rac-specific nucleotide exchange factor, Vav. As a consequence of aberrant Rac activation, disordered actin polymerization is stimulated. The resulting defects in T cell activation may help H. pylori to prevent an effective immune response leading to chronic colonization of its gastric niche.

Show MeSH
Related in: MedlinePlus