scholarly journals The Degree of Helicobacter pylori Infection Affects the State of Macrophage Polarization through Crosstalk between ROS and HIF-1α

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Ying Lu ◽  
Jianfang Rong ◽  
Yongkang Lai ◽  
Li Tao ◽  
Xiaogang Yuan ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Macrophage Polarization ◽  
Polarization State ◽  
Hypoxia Inducible Factor ◽  
Mtor Pathway ◽  
Raw 264.7 Cells ◽  
Gastric Lesions ◽  
M1 Phenotype ◽  
H Pylori ◽  
M2 Phenotype

Background and Objective. Helicobacter pylori (H. pylori) is involved in macrophage polarization, but the specific mechanism is not well understood. Therefore, this study is aimed at investigating the effects of the degree of H. pylori infection on the macrophage polarization state and the crosstalk between reactive oxygen species (ROS) and hypoxia-inducible factor 1 α (HIF-1α) in this process. Methods. The expression of CD86, CD206, and HIF-1α in the gastric mucosa was evaluated through immunohistochemistry. RAW 264.7 cells were cocultured with H. pylori at various multiplicities of infection (MOIs), and iNOS, CD86, Arg-1, CD206, and HIF-1α expression was detected by Western blot, PCR, and ELISA analyses. ROS expression was detected with the fluorescent probe DCFH-DA. Macrophages were also treated with the ROS inhibitor NAC or HIF-1α inhibitor YC-1. Results. Immunohistochemical staining revealed that the macrophage polarization state was associated with the progression of gastric lesions and state of H. pylori infection. The MOI of H. pylori affected macrophage polarization, and H. pylori enhanced the expression of ROS and HIF-1α in macrophages. A low MOI of H. pylori promoted both the M1 and M2 phenotypes, while a high MOI suppressed the M2 phenotype. Furthermore, ROS inhibition attenuated HIF-1α expression and switched macrophage polarization from M1 to M2. However, HIF-1α inhibition suppressed ROS expression and inhibited both the M1 phenotype and the M2 phenotype. Inhibition of ROS or HIF-1α also suppressed the activation of the Akt/mTOR pathway, which was implicated in H. pylori-induced macrophage polarization. Conclusions. Macrophage polarization is associated with the progression of gastric lesions and state of H. pylori infection. The MOI of H. pylori influences the macrophage polarization state. Crosstalk between ROS and HIF-1α regulates H. pylori-induced macrophage polarization via the Akt/mTOR pathway.

Abstract 11059: Role of Sirtuin 6 in Macrophage Polarization and Cardiac Repair in Diabetes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rajarajan A Thandavarayan ◽  
Darukeshwara Joladarashi ◽  
Sahana S Babu ◽  
Garikipati V Srikanth ◽  
Alexander R Mackie ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Experimental Studies ◽  
Peritoneal Macrophages ◽  
Left Ventricular ◽  
Cardiac Repair ◽  
Raw 264.7 Cells ◽  
Mouse Bone Marrow ◽  
Macrophage Phenotype ◽  
Intramyocardial Injection ◽  
M2 Phenotype

Clinical and experimental studies provide evidence that metabolic and inflammatory pathways are functionally interconnected to cardiovascular diseases. Dynamic changes in macrophage activation [classical M1 activation (promote inflammation) or alternative M2 activation (promote wound healing)], in response to various stress signals, modulate cardiac physiopathology in diabetes. Sirtuin 6 (SIRT6), a NAD-dependent nuclear deacetylase plays an important role in genomic stability, cellular metabolism, stress response and aging. However, the mechanism by which SIRT6 activity affects macrophage phenotype and cardiac function in diabetes is still unexplored. Mouse bone marrow-derived macrophages (BMM) exposed to high glucose (HG, 25mM D-glucose) showed reduced expression of SIRT6 as compared to low glucose (LG, 5mM D-glucose)- and osmotic control (OC, 5mM D-glucose+20mM D-mannitol)-treated cells, associated with increased expression of proinflammatory cytokine and transcription factors (NFkb, c-JUN, FOXO, SP1 and STAT1). In addition, SIRT6 level was reduced in peritoneal macrophages of both diabetic models (streptozotocin-induced and db/db mice) as compared to non-diabetic mice. SIRT6 knockdown in RAW 264.7 cells exaggerated inflammatory response when exposed to HG. In contrast, IL-4-induced increase in mRNA expression of macrophage M2 phenotype markers like Arg1, Chi4l4, Retnla and IRS-2, but not IRS-1 expression was repressed suggesting that alternative macrophage (M2) phenotype was defective in SIRT6 deficient BM-macrophages under HG condition. SIRT6 protein expression was low in myocardial infarction-induced (MI) and diabetes-affected hearts. Interestingly, mice receiving intramyocardial injection of SIRT6-deficient macrophages showed further deterioration in left ventricular function, post-MI. Taken together, these data highlight a role for SIRT6 in regulating the balance of M1/M2 polarization, therefore, modulate macrophage mediated cardiac repair and regeneration in numerous inflammatory disease states including diabetes

scholarly journals Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease.

1994 ◽  
Vol 179 (5) ◽  
pp. 1653-1658 ◽  
Author(s):  
J L Telford ◽  
P Ghiara ◽  
M Dell'Orco ◽  
M Comanducci ◽  
D Burroni ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Peptic Ulcer ◽  
Gastric Mucosa ◽  
Chronic Infection ◽  
Gastric Disease ◽  
Human Gastric Mucosa ◽  
Gastric Lesions ◽  
Gram Negative ◽  
H Pylori ◽  
Cytotoxin Gene

The gram negative, microaerophilic bacterium Helicobacter pylori colonizes the human gastric mucosa and establishes a chronic infection that is tightly associated with atrophic gastritis, peptic ulcer, and gastric carcinoma. Cloning of the H. pylori cytotoxin gene shows that the protein is synthesized as a 140-kD precursor that is processed to a 94-kD fully active toxin. Oral administration to mice of the purified 94-kD protein caused ulceration and gastric lesions that bear some similarities to the pathology observed in humans. The cloning of the cytotoxin gene and the development of a mouse model of human gastric disease will provide the basis for the understanding of H. pylori pathogenesis and the development of therapeutics and vaccines.

scholarly journals Precancerous Gastric Lesions with Helicobacter pylori vacA+/babA2+/oipA+ Genotype Increase the Risk of Gastric Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Theeraya Simawaranon Bartpho ◽  
Wareeporn Wattanawongdon ◽  
Taweesak Tongtawee ◽  
Chatchanok Paoin ◽  
Kokiet Kangwantas ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Clinical Outcomes ◽  
Chronic Gastritis ◽  
Virulence Genes ◽  
Gastric Lesions ◽  
Precancerous Gastric Lesions ◽  
Increased Risk ◽  
H Pylori ◽  
Gastric Cancer Patients

Objective. The clinical outcomes of gastric diseases such as chronic gastritis, peptic ulcer, and gastric cancer have been attributed to the interplay of virulence factors of Helicobacter pylori (H. pylori), host genetic susceptibility, and host immune responses. This study investigated the presence of cagA, vacA, iceA2, babA2, and oipA genes and their association with clinical outcomes. Methods. Chronic gastritis, atrophic gastritis, and intestinal metaplasia specimens were obtained from patients who underwent endoscopy and surgical resection between January 2017 and December 2018; specimens from gastric cancer patients treated between January 2014 and December 2018 were also added. H. pylori infection and virulence genes (cagA, vacA, iceA2, babA2, and oipA) were determined using real-time PCR. The association between H. pylori genotypes and clinical outcomes were evaluated using multivariate regression model analysis. The overall survival of gastric cancer patients was compared between genotype combinations. Results. H. pylori was positive in 166 patients with chronic gastritis, precancerous gastric lesions, and gastric cancer. The genes vacA, babA2, and oipA were most prevalent in chronic gastritis (73%), precancerous gastric lesions (62%), and gastric cancer (91%), respectively. The vacA, babA2, and oipA genes were associated with increased risk of gastric cancer (OR = 1.23; 95% CI = 1.13–3.32; P=0.033, OR = 2.64; 95% CI = 1.44–4.82, P=0.024, and OR = 2.79; 95% CI = 1.58–5.41; P=0.031, respectively). Interestingly, H. pylori vacA+/babA2+/oipA+ genotype infection was associated with increased risk of gastric cancer (OR = 3.85, 95% CI = 1.67–5.77, P=0.014). Conclusion. In this present study, we reported on the virulence genes of H. pylori infection to reveal their association with increased risk of chronic gastritis, precancerous gastric lesions, and gastric cancer. Precancerous gastric lesions with H. pylori vacA+/babA2+/oipA+ genotype increased the risk of gastric cancer.

scholarly journals Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial

Gut ◽  
2017 ◽  
Vol 67 (7) ◽  
pp. 1239-1246 ◽  
Author(s):  
Robertino M Mera ◽  
Luis E Bravo ◽  
M Constanza Camargo ◽  
Juan C Bravo ◽  
Alberto G Delgado ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Linear Models ◽  
Precancerous Lesions ◽  
Gastric Lesions ◽  
Logistic Regression Models ◽  
Risk Of Progression ◽  
H Pylori ◽  
Cumulative Time

ObjectiveTo evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions.Design795 adults with precancerous gastric lesions were randomised to receive anti-H. pylori treatment at baseline. Gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. A total of 456 individuals attended the 16-year visit. Cumulative time of H. pylori exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (IM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1–6). The score difference between baseline and 16 years was modelled by generalised linear models.ResultsIndividuals who were continuously infected with H. pylori for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4). The average histopathology score increased by 0.20 units/year (95% CI 0.12 to 0.28) among individuals continuously infected with H. pylori. The effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without IM) than for individuals with IM (p<0.001).ConclusionsLong-term exposure to H. pylori infection was associated with progression of precancerous lesions. Individuals infected with H. pylori with these lesions may benefit from eradication, particularly those with atrophic gastritis without IM. Incomplete-type IM may be a useful marker for the identification of individuals at higher risk for cancer.

scholarly journals Melatonin Maintains Macrophage M1 Phenotype to Reverse LPS-stimulated Tumor Immune Tolerance

2020 ◽  
Author(s):  
Yukun Lin ◽  
Mengdi Zhang ◽  
Lin Zhou ◽  
Yuehua Wang ◽  
Mengqi Wang ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Immune Tolerance ◽  
Bacterial Infections ◽  
Macrophage Polarization ◽  
Surface Lipid ◽  
Lps Challenge ◽  
Stat3 Signaling ◽  
M1 Phenotype ◽  
M2 Phenotype

Abstract Background: Lipopolysaccharide (LPS) is a potent trigger of macrophage-mediated inflammation and its repeated stimulation results in immune tolerance. This study is to explore the cellular mechanisms of LPS-mediated tumor immune tolerance and to investigate whether melatonin can reverse this tolerance. Methods: The effect of melatonin and LPS on macrophages was assessed by cell proliferation, morphological changes, phagocytosis and autophagy in vitro. The tumor-preventing effect of melatonin and LPS were evaluated in the urethane-induced lung carcinoma model and in the H22 liver cancer allograft model. Immunofluorescence, immunohistochemistry and ELISA were used to examine protein expression. The related targets and pathways of melatonin were predicted by comprehensive bioinformatics, and the clinical association of bacterial infections and survival was evaluated in cancer patients by meta-analysis.Results: In vitro，Raw264.7 macrophages were polarized toward the M1 phenotype by single LPS administration but toward the M2 phenotype by repeated LPS administration. Interestingly, combination treatment with repeated LPS and 10 µM melatonin prevented macrophage polarization toward the M2-like phenotype and exerted lasting antitumor efficacy. In the urethane-induced lung carcinoma model, repeated LPS administration stimulated macrophage polarization toward the M2 phenotype and promoted lung carcinogenesis, which was abrogated by macrophage depletion, while melatonin alone or in combination with repeated LPS challenge restored M1-like macrophages and prevented carcinogenesis. In the H22 liver cancer allograft model, melatonin maintained the macrophage phenotype and promoted the tumor-suppressing effect of repeated LPS challenge. Furthermore, we found that macrophages repeatedly stimulated with LPS had a high level of surface lipid rafts that mediated PI3K/AKT and JAK2/STAT3 signaling and prevented both LPS sensitivity and immune response by self-expression of PD-L1 and surface expression of PD-1 receptor on NK cells, whereas melatonin decreased surface lipid rafts and PI3K/AKT and JAK2/STAT3 signaling. Finally, we conducted a comprehensive bioinformatics analysis of melatonin-relevant targets and pathways involved in M2 macrophage polarization and evaluated the clinical associations of bacterial infections and survival in cancer patients. Conclusions: This study suggests a function of melatonin in regulating macrophage polarization to maintain LPS-stimulated tumor immune surveillance.

scholarly journals Helicobacter Pylori UreB Upregulates the Expression of PD-L1 through Myh9 /mTOR Pathway and Inhibits the Activation of CD8+ T Cells

2020 ◽  
Author(s):  
Jian Wu ◽  
Honghao Wang ◽  
Xia Guo ◽  
Qinzhen Cai ◽  
Tian Xiang ◽  
...  
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
Cd8 T Cells ◽  
Mtor Inhibitor ◽  
Mtor Pathway ◽  
Host Cells ◽  
Regulation Mechanism ◽  
Inhibitory Effects ◽  
Culture Model ◽  
H Pylori

Abstract Objectives: Immune regulation mechanism of how Helicobacter pylori urease disrupting the homeostasis of host cells remains unknown.Methods: We thus detected the effect of Helicobacter pylori UreB on macrophage PD-L1 expression with recombinant protein and defective strains. The influence of UreB induced PD-L1 on CD8+ T cells’ proliferation and perforin and granzyme expression were assessed through co-culture model. Results: Urease subset B (UreB) significantly promoted PD-L1 expression in Bone marrow-derived macrophages (BMDMs) and thus blocked the proliferation and activity of H. pylori-primed CD8+ T cells. Myosin heavy chain 9 (Myh9) works as the receptor for UreB. The interaction between UreB and Myh9 promoted amino acid anabolism, activated mTOR pathway and induced PD-L1 expression in BMDMs. mTOR inhibitor Temsirolimus reversed UreB-induced PD-L1 expression and the inhibitory effects on CD8+ T cells. Conclusion: Our study reveals a hitherto-unknown immunosuppressive mechanism of UreB during H. pylori infection, provides clues for the development of H. pylori vaccine.

scholarly journals Mechanism of hypoxia-inducible factor 1α-mediated Mcl1 regulation in Helicobacter pylori-infected human gastric epithelium

2010 ◽  
Vol 299 (5) ◽  
pp. G1177-G1186 ◽  
Author(s):  
Asima Bhattacharyya ◽  
Ranajoy Chattopadhyay ◽  
Emily H. Hall ◽  
Semret T. Mebrahtu ◽  
Peter B. Ernst ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Cell Fate ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Cellular Growth ◽  
Gastric Epithelium ◽  
Α Subunit ◽  
Bcl2 Family ◽  
Inducible Protein ◽  
H Pylori

Hypoxia-inducible factor 1 (HIF1) consists of a hypoxia-inducible α subunit and a constitutively expressed β subunit. Reactive oxygen species (ROS) induced by Helicobacter pylori stabilize HIF1α in the human gastric epithelium in normoxia. HIF1α plays crucial role in carcinogenesis and has been associated with malignant progression of gastric cancer. Several genes contain functional hypoxia-response elements (HREs) in their promoters including Bcl2 family member, Mcl1. Cellular ratios of antiapoptotic oncogenic protein, Mcl1, and tumor suppressor proapoptotic protein, Noxa, determine cell fate by regulating normal cellular growth, cell death and oncogenic processes. The aim of the present study was to examine the mechanism of HIF1α induction in the H. pylori -infected gastric epithelium to better understand disease pathogenesis by H. pylori relevant to gastric carcinogenesis. Our data showed that the dose-dependent increase in HIF1α in H. pylori -infected gastric epithelia is mediated by induction of a ROS-inducible protein, apurinic/apyrimidinic endonuclease 1 (APE1), and an enhanced interaction of APE1 with the transcriptional coactivator p300. Surprisingly, with accumulation of HIF1α, further transcriptional activation of mcl1 was not observed. We identified a HIF-binding site (HBS) in the hif1α promoter and showed that increased HIF1α expression, whether H. pylori -induced or hypoxia-mimetic agent, CoCl2-induced, resulted in enhanced HIF1α binding to its own promoter. This resulted in a transcriptionally inactive hif1α promoter since hif1α HBS lacks HIF ancillary sequence (HAS) required for HIF1 transcriptional activity. We conclude that enhanced binding of “nonfunctional” HIF1α to hif1α promoter and limiting availability of p300 in the cell serves as checkpoints for uncontrolled HIF1α activity.

Real-time diagnostic yield of white light endoscopy, chromoendoscopy and magnifying endoscopy with narrow band imaging in the undiagnosed gastric lesions after Helicobacter pylori eradication

2019 ◽  
Author(s):  
Tomomitsu Tahara ◽  
Noriyuki Horiguchi ◽  
Tsuyoshi Terada ◽  
Dai Yoshida ◽  
Masaaki Okubo ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Real Time ◽  
Narrow Band ◽  
Narrow Band Imaging ◽  
Diagnostic Yield ◽  
Consensus Meeting ◽  
Magnifying Endoscopy ◽  
Gastric Lesions ◽  
White Light Endoscopy ◽  
H Pylori

Abstract Background: Early-stage gastric cancer (EGC) after Helicobacter pylori (H. pylori) often confuse endoscopic diagnosis. We prospectively evaluated the real-time diagnostic yield of combining white light endoscopy (WLE), chromoendoscopy (CE), and magnifying endoscopy with narrow band imaging (ME-NBI) for undiagnosed gastric lesions after H. pylori eradication. Methods: Using a retrospective data set, we conducted a consensus meeting to learn ME-NBI features of EGC after H. pylori eradication associated with diagnostic difficulty. Then, we prospectively evaluated the real-time diagnostic yield of WL, followed by CE, and ME-NBI in the diagnosis of 166 newly identified gastric lesions from 219 patients after H. pylori eradication. Results: A consensus meeting characterized ME-NBI feature of EGC with diagnostic difficulty, as having irregular vessel patterns in only tiny area of the lesion. Among 166 undiagnosed gastric lesions in the prospective study, 22 neoplastic lesions (18 adenocarcinomas and 4 adenomas) were identified. In these lesions, diagnosed case was dramatically increased when combined with ME-NBI (98%) compared to WLE alone (54%) and CE with WLE (63%) (WLE+CE+ME-NBI vs. others, all P<0.0001). In the diagnosed cases, the diagnostic accuracy was also improved when combined with ME-NBI (99.4%) compared to WLE alone (92.2%: P=0.004) and CE with WLE (95.1%: P=0.03). Conclusions: WLE combined with ME-NBI can improve the diagnostic yield of EGC in patients after H. pylori eradication. For precise diagnosis of EGC by ME-NBI, it is essential to detect irregular vessels.

Sirt1 ameliorates monosodium urate crystal–induced inflammation by altering macrophage polarization via the PI3K/Akt/STAT6 pathway

Rheumatology ◽  
2019 ◽  
Vol 58 (9) ◽  
pp. 1674-1683 ◽  
Author(s):  
Lei Liu ◽  
Xiaoxia Zhu ◽  
Tianyi Zhao ◽  
Yiyun Yu ◽  
Yu Xue ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Macrophage Polarization ◽  
Polarization State ◽  
Underlying Mechanism ◽  
Joint Fluid ◽  
Raw 264.7 Cells ◽  
Acute Gout ◽  
Peripheral Blood Mononuclear ◽  
Sirt1 Expression ◽  
Msu Crystals

Abstract Objectives Acute gout is an inflammatory response to MSU crystals. In our previous research, Sirt1 was shown to have an effect in preventing acute gouty inflammation. In the current study, we aimed to investigate the underlying mechanism involving Sirt1 in acute gout. Methods The cytological changes and Sirt1 expression in the synovium were observed in patients with acute or intermittent gout. The effect of Sirt1 and its mechanism in gout were studied in macrophages, C57BL/6 mice and Sirt1+/− mice. Results Sirt1 expression was increased in the peripheral blood mononuclear cells (PBMCs) of patients with acute gout but not in the chronic tophus tissue. The arthritis score and numbers of inflammatory cells in injured paw tissue from murine gout models were upregulated in Sirt1+/− mice compared with wild-type mice. A PCR array of the paw tissue from murine gout models indicated that Sirt1 activation might attenuate MSU-induced inflammation by altering the polarization state of macrophages. Furthermore, in patients with acute gout, the phagocytosis of MSU crystals by a macrophage was found in a smear of the joint fluid and large amounts of macrophages were also found in the synovium. The activation of Sirt1 in gouty mice actually decreased the tendency toward M1 polarization. The inhibition of PI3K/Akt partially blocked the anti-inflammatory effect of Sirt1 and the translocation of STAT6, and phosphorylated STAT6 expression was decreased in RAW 264.7 cells treated with MSU crystals. Conclusion Our studies revealed that Sirt1 ameliorates MSU-induced inflammation by altering macrophage polarization via the PI3K/Akt/STAT6 pathway.

scholarly journals Helicobacter pylori Induces Apoptosis of Macrophages in Association with Alterations in the Mitochondrial Pathway

2004 ◽  
Vol 72 (5) ◽  
pp. 2889-2898 ◽  
Author(s):  
Rena J. Menaker ◽  
Peter J. M. Ceponis ◽  
Nicola L. Jones
Keyword(s):  
Helicobacter Pylori ◽  
Immune Responses ◽  
Annexin V ◽  
Mitochondrial Pathway ◽  
Time Dependent ◽  
Raw 264.7 Cells ◽  
Cell Protein ◽  
Host Immune Responses ◽  
H Pylori

ABSTRACT Helicobacter pylori is a gastric bacterial pathogen that evades host immune responses in vivo and is associated with the development of gastritis, peptic ulcer disease, and gastric cancers. Induction of macrophage apoptosis is a method employed by multiple pathogens to escape host immune responses. Therefore, we hypothesized that H. pylori induces apoptosis of infected macrophages. RAW 264.7 cells were infected with H. pylori strain 60190, and apoptosis was assessed. Transmission electron microscopy and fluorescence microscopy showed that infected macrophages displayed morphological features characteristic of apoptosis. Quantification by acridine orange-ethidium bromide fluorescent-dye staining showed that apoptosis was dose and time dependent, and apoptosis was further confirmed by increased binding of annexin V-fluorescein isothiocyanate (FITC) to externalized phosphatidylserine of infected but not of control macrophages. Macrophages infected with isogenic mutants of H. pylori strain 60190 deficient in either cagA or vacA induced significantly less apoptosis than the parental strain, as assessed by increased binding of annexin V-FITC. Western blot analysis of whole-cell protein lysates revealed that infection with strain 60190 induced a time-dependent increase in cleavage of procaspase 8 and disappearance of full-length Bid compared with uninfected cells. Furthermore, pharmacological inhibition of caspase 8 caused a decrease in levels of apoptosis. Finally, infection caused a time-dependent increase in mitochondrial-membrane permeability and release of cytochrome c into the cytosol. These results suggest that H. pylori induces apoptosis of macrophages in association with alterations in the mitochondrial pathway. Elimination of this key immunomodulatory cell may represent a mechanism employed by the bacterium to evade host immune responses.

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