Helicobacter pylori Membrane Vesicles Stimulate Innate Pro- and Anti-Inflammatory Responses and Induce Apoptosis in Jurkat T Cells

ABSTRACTPersistentHelicobacter pyloriinfection induces chronic inflammation in the human gastric mucosa, which is associated with development of peptic ulceration, gastric atrophy, and gastric adenocarcinoma. It has been postulated that secretion of immunomodulatory molecules byH. pylorifacilitates bacterial persistence, and membrane vesicles (MV), which have the potential to cross the gastric epithelial barrier, may mediate delivery of these molecules to host immune cells. However, bacterial MV effects on human immune cells remain largely uncharacterized to date. In the present study, we investigated the immunomodulatory effects ofH. pyloriMV with and without the vacuolating cytotoxin, VacA, which inhibits human T cell activity. We show a high degree of variability in the toxin content of vesicles between twoH. pyloristrains (SS1 and 60190). Vesicles from the more toxigenic 60190 strain contain more VacA (s1i1 type) than vesicles from the SS1 strain (s2i2 VacA), but engineering the SS1 strain to produce s1i1 VacA did not increase the toxin content of its vesicles. Vesicles from all strains tested, including a 60190 isogenic mutant null for VacA, strongly induced interleukin-10 (IL-10) and IL-6 production by human peripheral blood mononuclear cells independently of the infection status of the donor. Finally, we show thatH. pyloriMV induce T cell apoptosis and that this is enhanced by, but not completely dependent on, the carriage of VacA. Together, these findings suggest a role forH. pyloriMV in the stimulation of innate pro- and anti-inflammatory responses and in the suppression of T cell immunity.

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Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽

10.1128/mbio.01243-14 ◽

2014 ◽

Vol 5 (4) ◽

Cited By ~ 36

Author(s):

Adria Carbo ◽

Danyvid Olivares-Villagómez ◽

Raquel Hontecillas ◽

Josep Bassaganya-Riera ◽

Rupesh Chaturvedi ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

T Cell ◽

Wild Type ◽

Content Type ◽

Interleukin 21 ◽

H Pylori ◽

Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

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Helicobacter pylori VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection

mBio ◽

10.1128/mbio.00261-19 ◽

2019 ◽

Vol 10 (2) ◽

Cited By ~ 9

Author(s):

Aleksandra Altobelli ◽

Michael Bauer ◽

Karelia Velez ◽

Timothy L. Cover ◽

Anne Müller

Keyword(s):

Helicobacter Pylori ◽

T Cell ◽

Persistent Infection ◽

Myeloid Cells ◽

T Cell Responses ◽

T Cell Differentiation ◽

Content Type ◽

Effector T Cell ◽

Cell Responses ◽

H Pylori

ABSTRACT The gastric bacterium Helicobacter pylori causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the Helicobacter-host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the Helicobacter immunomodulator VacA to H. pylori-specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3+) regulatory T cells that are neuropilin negative and express RORγt. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type H. pylori but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-β expression in macrophages. Taken together, the results are consistent with the idea that H. pylori creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors H. pylori persistence, and affects immunity at distant sites. IMPORTANCE Helicobacter pylori has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all H. pylori strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during H. pylori infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.

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DC-LAMP+Dendritic Cells Are Recruited to Gastric Lymphoid Follicles in Helicobacter pylori-Infected Individuals

Infection and Immunity ◽

10.1128/iai.00801-13 ◽

2013 ◽

Vol 81 (10) ◽

pp. 3684-3692 ◽

Cited By ~ 6

Author(s):

Malin Hansson ◽

Malin Sundquist ◽

Susanne Hering ◽

B. Samuel Lundin ◽

Michael Hermansson ◽

...

Keyword(s):

Helicobacter Pylori ◽

Dendritic Cells ◽

Gastric Mucosa ◽

Human Gastric Mucosa ◽

Lymphoid Follicles ◽

Content Type ◽

Ulcer Disease ◽

Hla Dr ◽

H Pylori ◽

Antigen Presenting

ABSTRACTInfection withHelicobacter pyloriis associated with development of ulcer disease and gastrointestinal adenocarcinoma. The infection leads to a large infiltration of immune cells and the formation of organized lymphoid follicles in the human gastric mucosa. Still, the immune system fails to eradicate the bacteria, and the substantial regulatory T cell (Treg) response elicited is probably a major factor permitting bacterial persistence. Dendritic cells (DCs) are professional antigen-presenting cells that can activate naive T cells, and maturation of DCs is crucial for the initiation of primary immune responses. The aim of this study was to investigate the presence and localization of mature human DCs inH. pylori-infected gastric mucosa. Gastric antral biopsy specimens were collected from patients withH. pylori-associated gastritis and healthy volunteers, and antrum tissue was collected from patients undergoing gastric resection. Immunohistochemistry and flow cytometry showed that DCs expressing the maturation marker dendritic cell lysosome-associated membrane glycoprotein (DC-LAMP; CD208) are enriched in theH. pylori-infected gastric mucosa and that these DCs are specifically localized within or close to lymphoid follicles. Gastric DC-LAMP-positive (DC-LAMP+) DCs express CD11c and high levels of HLA-DR but little CD80, CD83, and CD86. Furthermore, immunofluorescence analyses demonstrated that DC-LAMP+DCs are in the same location as FoxP3-positive putative Tregs in the follicles. In conclusion, we show that DC-LAMP+DCs with low costimulatory capacity accumulate in the lymphoid follicles in humanH. pylori-infected gastric tissue, and our results suggest that Treg-DC interactions may promote chronic infection by rendering gastric DCs tolerogenic.

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Expression of Helicobacter pylori Virulence Factors and Associated Expression Profiles of Inflammatory Genes in the Human Gastric Mucosa

Infection and Immunity ◽

10.1128/iai.00334-07 ◽

2007 ◽

Vol 75 (11) ◽

pp. 5118-5126 ◽

Cited By ~ 17

Author(s):

Sicheng Wen ◽

Dominique Velin ◽

Christian P. Felley ◽

Likun Du ◽

Pierre Michetti ◽

...

Keyword(s):

Gene Expression ◽

Helicobacter Pylori ◽

Gastric Mucosa ◽

Virulence Factors ◽

Inflammatory Responses ◽

Expression Profiles ◽

Bacterial Colonization ◽

Expression Patterns ◽

Human Gastric Mucosa ◽

H Pylori

ABSTRACT Helicobacter pylori virulence factors have been suggested to be important in determining the outcome of infection. The H. pylori adhesion protein BabA2 is thought to play a crucial role in bacterial colonization and in induction of severe gastric inflammation, particularly in combination with expression of CagA and VacA. However, the influence of these virulence factors on the pathogenesis of H. pylori infection is still poorly understood. To address this question, the inflammatory gene expression profiles for two groups of patients infected with triple-negative strains (lacking expression of cagA, babA2, and vacAs1 but expressing vacAs2) and triple-positive strains (expressing cagA, vacAs1, and babA2 but lacking expression of vacAs2) were investigated. The gene expression patterns in the antrum gastric mucosa from patients infected with different H. pylori strains were very similar, and no differentially expressed genes could be identified by pairwise comparisons. Our data thus suggest that there is a lack of correlation between the host inflammatory responses in the gastric mucosa and expression of the babA2, cagA, and vacAs1 genes.

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Complex T Cell Interactions Contribute to Helicobacter pylori Gastritis in Mice

Infection and Immunity ◽

10.1128/iai.01269-12 ◽

2012 ◽

Vol 81 (3) ◽

pp. 740-752 ◽

Cited By ~ 31

Author(s):

Brian M. Gray ◽

Clinton A. Fontaine ◽

Sara A. Poe ◽

Kathryn A. Eaton

Keyword(s):

T Cells ◽

Helicobacter Pylori ◽

T Cell ◽

Published Data ◽

Proinflammatory Response ◽

Necrosis Factor Alpha ◽

Content Type ◽

Tnf Α ◽

Ifn Γ ◽

H Pylori

ABSTRACTDisease due to the gastric pathogenHelicobacter pylorivaries in severity from asymptomatic to peptic ulcer disease and cancer. Accumulating evidence suggests that one source of this variation is an abnormal host response. The goal of this study was to use a mouse model ofH. pylorigastritis to investigate the roles of regulatory T cells (Treg) as well as proinflammatory T cells (Th1 and Th17) in gastritis, gastric T cell engraftment, and gastric cytokine production. Our results support published data indicating that severe gastritis in T cell recipient mice is due to failure of Treg engraftment, that Treg ameliorate gastritis, and that the proinflammatory response is attributable to interactions between several cell subsets and cytokines. We confirmed that gamma interferon (IFN-γ) is essential for induction of gastritis but showed that IFN-γ-producing CD4 T cells are not necessary. Interleukin 17A (IL-17A) also contributed to gastritis, but to a lesser extent than IFN-γ. Tumor necrosis factor alpha (TNF-α) and IL-17F were also elevated in association with disease. These results indicate that whileH. pylori-specific CD4+T cells and IFN-γ are both essential for induction of gastritis due toH. pylori, IFN-γ production by T cells is not essential. It is likely that other proinflammatory cytokines, such as IL-17F and TNF-α, shown to be elevated in this model, also contribute to the induction of disease. We suggest that gastritis due toH. pyloriis associated with loss of immunoregulation and alteration of several cytokines and cell subsets and cannot be attributed to a single immune pathway.

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Role of Gastric Epithelial Cell-Derived Transforming Growth Factor β in Reduced CD4+T Cell Proliferation and Development of Regulatory T Cells during Helicobacter pylori Infection

Infection and Immunity ◽

10.1128/iai.01146-10 ◽

2011 ◽

Vol 79 (7) ◽

pp. 2737-2745 ◽

Cited By ~ 30

Author(s):

Ellen J. Beswick ◽

Iryna V. Pinchuk ◽

Rachel B. Earley ◽

David A. Schmitt ◽

Victor E. Reyes

Keyword(s):

T Cells ◽

Helicobacter Pylori ◽

T Cell ◽

Growth Factor ◽

Transforming Growth Factor ◽

T Cell Responses ◽

Transforming Growth Factor Β ◽

Content Type ◽

Cell Responses ◽

H Pylori

ABSTRACTGastric epithelial cells (GECs) express the class II major histocompatibility complex (MHC) and costimulatory molecules, enabling them to act as antigen-presenting cells (APCs) and affect local T cell responses. DuringHelicobacter pyloriinfection, GECs respond by releasing proinflammatory cytokines and by increasing the surface expression of immunologically relevant receptors, including class II MHC. The CD4+T cell response duringH. pyloriinfection is skewed toward a Th1 response, but these cells remain hyporesponsive. Activated T cells show decreased proliferation duringH. pyloriinfection, and CD4+CD25+FoxP3+regulatory T cells (Tregs) are present at the site of infection. In this study, we examined the mechanisms surrounding the CD4+T cell responses duringH. pyloriinfection and found that transforming growth factor β (TGF-β) plays a major role in these responses. GECs produced TGF-β1 and TGF-β2 in response to infection. Activated CD4+T cells in culture withH. pylori-treated GECs were decreased in proliferation but increased upon neutralization of TGF-β. Naïve CD4+T cell development into Tregs was also enhanced in the presence of GEC-derived TGF-β. Herein, we demonstrate a role for GEC-produced TGF-β in the inhibition of CD4+T cell responses seen duringH. pyloriinfection.

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Comparative Analysis of the Interaction of Helicobacter pylori with Human Dendritic Cells, Macrophages, and Monocytes

Infection and Immunity ◽

10.1128/iai.00381-12 ◽

2012 ◽

Vol 80 (8) ◽

pp. 2724-2734 ◽

Cited By ~ 51

Author(s):

Michael Fehlings ◽

Lea Drobbe ◽

Verena Moos ◽

Pablo Renner Viveros ◽

Jana Hagen ◽

...

Keyword(s):

Helicobacter Pylori ◽

Dendritic Cells ◽

Inflammatory Responses ◽

M2 Macrophages ◽

M1 Macrophages ◽

Content Type ◽

Immune Evasion Mechanism ◽

Enhanced Expression ◽

H Pylori ◽

Human Dendritic Cells

ABSTRACTHelicobacter pylorimay cause chronic gastritis, gastric cancer, or lymphoma. Myeloid antigen-presenting cells (APCs) are most likely involved in the induction and expression of the underlying inflammatory responses. To study the interaction of human APC subsets withH. pylori, we infected monocytes, monocyte-derived dendritic cells (DCs), and monocyte-derived (classically activated; M1) macrophages withH. pyloriand analyzed phenotypic alterations, cytokine secretion, phagocytosis, and immunostimulation. Since we detected CD163+(alternatively activated; M2) macrophages in gastric biopsy specimens fromH. pylori-positive patients, we also included monocyte-derived M2 macrophages in the study. UponH. pyloriinfection, monocytes secreted interleukin-1β (IL-1β), IL-6, IL-10, and IL-12p40 (partially secreted as IL-23) but not IL-12p70. Infected DCs became activated, as shown by the enhanced expression of CD25, CD80, CD83, PDL-1, and CCR7, and secreted IL-1β, IL-6, IL-10, IL-12p40, IL-12p70, and IL-23. However, infection led to significantly downregulated CD209 and suppressed the constitutive secretion of macrophage migration inhibitory factor (MIF).H. pylori-infected M1 macrophages upregulated CD14 and CD32, downregulated CD11b and HLA-DR, and secreted mainly IL-1β, IL-6, IL-10, IL-12p40, and IL-23. Activation of DCs and M1 macrophages correlated with increased capacity to induce T-cell proliferation and decreased phagocytosis of dextran. M2 macrophages upregulated CD14 and CD206 and secreted IL-10 but produced less of the proinflammatory cytokines than M1 macrophages. Thus,H. pyloriaffects the functions of human APC subsets differently, which may influence the course and the outcome ofH. pyloriinfection. The suppression of MIF in DCs constitutes a novel immune evasion mechanism exploited byH. pylori.

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Interleukin-17C in Human Helicobacter pylori Gastritis

Infection and Immunity ◽

10.1128/iai.00389-17 ◽

2017 ◽

Vol 85 (10) ◽

Cited By ~ 9

Author(s):

Shingo Tanaka ◽

Hiroyuki Nagashima ◽

Modesto Cruz ◽

Tomohisa Uchida ◽

Takahiro Uotani ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Gastric Biopsy ◽

Interleukin 17 ◽

Human Gastric Mucosa ◽

Mrna Levels ◽

Content Type ◽

Biopsy Specimens ◽

H Pylori

ABSTRACT The interleukin-17 (IL-17) family of cytokines (IL-17A to IL-17F) is involved in many inflammatory diseases. Although IL-17A is recognized as being involved in the pathophysiology of Helicobacter pylori-associated diseases, the role of other IL-17 cytokine family members remains unclear. Microarray analysis of IL-17 family cytokines was performed in H. pylori-infected and uninfected gastric biopsy specimens. IL-17C mRNA was upregulated approximately 4.5-fold in H. pylori-infected gastric biopsy specimens. This was confirmed by quantitative reverse transcriptase PCR in infected and uninfected gastric mucosa obtained from Bhutan and from the Dominican Republic. Immunohistochemical analysis showed that IL-17C expression in H. pylori-infected gastric biopsy specimens was predominantly localized to epithelial and chromogranin A-positive endocrine cells. IL-17C mRNA levels were also significantly greater among cagA-positive than cagA-negative H. pylori infections (P = 0.012). In vitro studies confirmed an increase in IL-17C mRNA and protein levels in cells infected with cagA-positive infections compared to cells infected with either cagA-negative or cag pathogenicity island (PAI) mutant. Chemical inhibition of IκB kinase (IKK), mitogen-activated protein extracellular signal-regulated kinase (MEK), and Jun N-terminal kinase (JNK) inhibited induction of IL-17C proteins in infected cells, whereas p38 inhibition had no effect on IL-17C protein secretion. In conclusion, H. pylori infection was associated with a significant increase in IL-17C expression in human gastric mucosa. The role of IL-17C in the pathogenesis of H. pylori-induced diseases remains to be determined.

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The Intermediate Region of Helicobacter pylori VacA Is a Determinant of Toxin Potency in a Jurkat T Cell Assay

Infection and Immunity ◽

10.1128/iai.00052-12 ◽

2012 ◽

Vol 80 (8) ◽

pp. 2578-2588 ◽

Cited By ~ 27

Author(s):

Christian González-Rivera ◽

Holly M. Scott Algood ◽

Jana N. Radin ◽

Mark S. McClain ◽

Timothy L. Cover

Keyword(s):

T Cells ◽

Helicobacter Pylori ◽

T Cell ◽

Gastric Lymphoma ◽

Jurkat Cells ◽

Gastric Disease ◽

Intermediate Region ◽

Content Type ◽

Increased Risk ◽

H Pylori

ABSTRACTColonization of the human stomach withHelicobacter pyloriis a risk factor for peptic ulceration, noncardia gastric adenocarcinoma, and gastric lymphoma. The secreted VacA toxin is an importantH. pylorivirulence factor that causes multiple alterations in gastric epithelial cells and T cells. Several families ofvacAalleles have been described, andH. pyloristrains containing certainvacAtypes (s1, i1, and m1) are associated with an increased risk of gastric disease, compared to strains containing othervacAtypes (s2, i2, and m2). Thus far, there has been relatively little study of the role of the VacA intermediate region (i-region) in toxin activity. In this study, we compared the ability of i1 and i2 forms of VacA to cause functional alterations in Jurkat cells. To do this, we manipulated the chromosomalvacAgene in twoH. pyloristrains to introduce alterations in the region encoding the VacA i-region. We did not detect any differences in the capacity of i1 and i2 forms of VacA to cause vacuolation of RK13 cells. In comparison to i1 forms of VacA, i2 forms of VacA had a diminished capacity to inhibit the activation of nuclear factor of activated T cells (NFAT) and suppress interleukin-2 (IL-2) production. Correspondingly, i2 forms of VacA bound to Jurkat cells less avidly than did i1 forms of VacA. These results indicate that the VacA i-region is an important determinant of VacA effects on human T cell function.

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Crude Preparations of Helicobacter pylori Outer Membrane Vesicles Induce Upregulation of Heme Oxygenase-1 via Activating Akt-Nrf2 and mTOR–IκB Kinase–NF-κB Pathways in Dendritic Cells

Infection and Immunity ◽

10.1128/iai.00190-16 ◽

2016 ◽

Vol 84 (8) ◽

pp. 2162-2174 ◽

Cited By ~ 17

Author(s):

Su Hyuk Ko ◽

Da Jeong Rho ◽

Jong Ik Jeon ◽

Young-Jeon Kim ◽

Hyun Ae Woo ◽

...

Keyword(s):

Helicobacter Pylori ◽

Dendritic Cells ◽

Outer Membrane ◽

Heme Oxygenase ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Heme Oxygenase 1 ◽

Content Type ◽

Iκb Kinase ◽

H Pylori

Helicobacter pylorisheds outer membrane vesicles (OMVs) that contain many surface elements of bacteria. Dendritic cells (DCs) play a major role in directing the nature of adaptive immune responses againstH. pylori, and heme oxygenase-1 (HO-1) has been implicated in regulating function of DCs. In addition, HO-1 is important for adaptive immunity and the stress response. AlthoughH. pylori-derived OMVs may contribute to the pathogenesis ofH. pyloriinfection, responses of DCs to OMVs have not been elucidated. In the present study, we investigated the role ofH. pylori-derived crude OMVs in modulating the expression of HO-1 in DCs. Exposure of DCs to crudeH. pyloriOMVs upregulated HO-1 expression. Crude OMVs obtained from acagA-negative isogenic mutant strain induced less HO-1 expression than OMVs obtained from a wild-type strain. CrudeH. pyloriOMVs activated signals of transcription factors such as NF-κB, AP-1, and Nrf2. Suppression of NF-κB or Nrf2 resulted in significant attenuation of crude OMV-induced HO-1 expression. Crude OMVs increased the phosphorylation of Akt and downstream target molecules of mammalian target of rapamycin (mTOR), such as S6 kinase 1 (S6K1). Suppression of Akt resulted in inhibition of crude OMV-induced Nrf2-dependent HO-1 expression. Furthermore, suppression of mTOR was associated with inhibition of IκB kinase (IKK), NF-κB, and HO-1 expression in crude OMV-exposed DCs. These results suggest thatH. pylori-derived OMVs regulate HO-1 expression through two different pathways in DCs, Akt-Nrf2 and mTOR–IKK–NF-κB signaling. Following this induction, increased HO-1 expression in DCs may modulate inflammatory responses inH. pyloriinfection.

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