H. pylori Activated Signaling
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H. pylori Activated Signaling
Helicobacter pylori is a gram negative bacterium that causes chronic inflammation in essentially all hosts, a process that increases the risk of developing peptic ulceration, distal gastric adenocarcinoma, and gastric mucosal lymphoproliferative disease. This bacterium also is the most common cause of ulcers worldwide. H. pylori infection is most likely acquired by ingesting contaminated food and water and through person to person contact. The infection is more common in crowded living conditions with poor sanitation. Infected individuals usually carry the infection indefinitely unless they are treated with medications to eradicate the bacterium. One out of every six patients with H. pylori infection develops ulcers of the duodenum or stomach. H. pylori are also associated with stomach cancer and a rare type of lymphocytic tumor of the stomach called MALT (Mucosa-Associated Lymphoid Tissue) lymphoma (Ref.1).

The major virulence factors produced by H. pylori strains are VacA (Vacuolating cytotoxin-A) and products of a 40-kb genetic locus of ~31 genes termed the CagPAI (Cag Pathogenicity Island). VacA is a secreted toxin that produced multiple functional and morphological changes within gastric epithelial cells. The CagPAI encodes proteins that act to form a Type IV secretion system that is responsible for translocation of the H. pylori CagA protein into gastric cells (Ref.2). H. pylori interact with the apical membrane of the gastric epithelium and induce a number of proinflammatory cytokines or chemokines and release other toxic factors such as VacA and HP-NAP (H. pylori NAP). The subsequent infiltration of macrophages and granulocytes into the mucosa leads to gastric inflammation accompanied by epithelial degeneration. Gastric epithelial cells respond to H. pylori infection by activating NF-KappaB (Nuclear Factor kappaB), up regulating the expression of a proinflammatory gene program, which includes the chemokine IL-8, COX2 (Cyclooxygenase-2), and iNOS (inducible Nitric Oxide Synthase), and by finally undergoing apoptosis. VacA also inserts into mitochondrial membranes and induce CytoC (Cytochrome-C) release, and activate the Caspase3-dependent cell-death signaling cascade (Ref.3). Another mechanism by which H. pylori can stimulate apoptosis is by inducing expression of the cell-surface receptor Fas and FasL (Fas Ligand). The pathogen can also bind to class MHC-II (Major Histocompatibility Complex-II) molecules on the surface of gastric epithelial cells, inducing their apoptosis. H. pylori urease and porins may contribute to extravasation and chemotaxis of neutrophils. On stimulation with signaling molecules such as TNF-Alpha (Tumor Necrosis Factor-Alpha) and IL-1, phosphorylation of I-KappaB (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells) leads to the ubiquitination and proteosome-mediated degradation of phosphorylated I-KappaB, thereby liberating NF-KappaB subunits, p50 and p65 to enter the nucleus, where they regulate transcription of a variety of genes including those involved in inflammation. An upstream mediator of these events is NIK (NF-KappaB Inducing Kinase), a member of the MEKK (MAPK /ERK Kinase Kinase) family, which activate IKK (I-KappaB Kinases) through interaction with adaptor proteins associated with TNFR and IL-1R. The adaptor protein TRAF2 (TNF Receptor Associated Factor-2) and TRAF6 act as effectors for activated TNF-Alpha and IL-1R (Ref.4). H. pylori infection also elevates the abundance of classical second messenger molecules such as Ca2+, cAMP (cyclic Adenosine Monophosphate), and IP3 (Inositol trisphosphate) through the activation of G-protein-coupled PLC (Phospholipase-C) and PLA2(Phospholipase-A2). Activation of PLC leads to the formation of IP3 and DAG (Diacylglycerol), and IP3 binds to its receptor (IP3R) on an intracellular Ca2+ store to release Ca2+. The H. pylori-induced intracellular Ca2+ increase can then stimulate Ca2+-dependent PLA2to produce Arachidonic Acid regulating Ca2+ influx. The H. pylori-translocated CagA protein, which becomes phosphorylated by Src kinases also directly or indirectly control Ca2+ influx (Ref.5).

ERK (Extracellular Signal-regulated Kinases)-related signaling cascades also plays a central role in the transmission of the effects of Gastrin and oxidative stress on the hHDC (Histidine Decarboxylase) promoter in gastric cancer cells. HDC is the key enzyme involved in histamine biosynthesis and converts L-histidine into histamine in enterochromaffin-like cells of the corpus mucosa through activation of the GAS-RE-BP1 and GAS-RE-BP2 transcription factors. H. pylori-induced HDC-gene activation requires the temporally coordinated action of host cell signaling components that become activated by a small molecular mass component (~1 kDa) released independent of the PAI-encoded Type IV secretion machinery. The molecular nature of the H. pylori ~1 kDa components that induces the HDC activity is not known, but they activate heterotrimeric G-AlphaS and stimulate GPCR (G-Protein-Coupled Receptor) types (Ref.6). The activation usually involves the activity of the ERK1/2 and MEK1/2 (MAPK/ERK Kinases). The hierarchical cascade that leads to MEK/ERK activation in H. pylori-infected epithelial cells recruits BRaf, but not c-Raf. B-Raf activation depends on the activity of the Ras-like GTPase Rap1 and EPAC (Exchange Protein Activated by cAMP) and the accumulation of cAMP. The generation of cAMP in H. pylori-infected gastric epithelial cells is also involved in pepsinogen secretion. The production of cAMP requires the activity of AC (Adenylate Cyclase), which is under the control of G-AlphaS. H. pylori directly activate Rho-GTPases that subsequently stimulate PAK (p21-Activated Kinases). PAK then activates MKK4 (Mitogen-Activated Protein Kinase Kinase-4), which activates JNK (c-Jun N-terminal Kinase). Phosphorylated JNK then activates Activator protein-1, possibly by activating Elk1 which drives expression of c-Fos and c-Jun. Tyrosine phosphorylation of CagA by Src recapitulate intracellular events and bind directly to N-WASP (Neural Wiskott-Aldrich Syndrome Protein) with subsequent binding to the ARP2/3 (Actin-Related Proteins), thus stimulating actin polymerization and pedestal formation (Ref.7).

Hallmarks of H. pylori infection are the chronic inflammation of the stomach, which can be accompanied by hypochlorhydria upon sprawling of the infection to the corpus, followed by development of chronic atrophic gastritis and intestinal metaplasia, which may proceed to gastric cancer. H. pylori infection also has been associated with dyspepsia and non-ulcer dyspepsia, although this association is still unresolved. The WHO (World Health Organization) classifies this bacterium as a Type 1 carcinogen. Although H. pylori infection is minimally invasive, metaplastic gastric tissue may also spread to other parts of the alimentary tract such as the duodenum, the proximal esophagus, the distal esophagus, Meckel’s diverticulum, and the rectum. In addition, although H. pylori infection is circumscribed to the gastric mucosa, it conceivably produces lesions remote to the primary site of infection, by altering levels of systemic inflammatory mediators. Several non-gastrointestinal tract diseases associated with H. pylori infection include diabetes mellitus, thyroiditis, heart diseases, rheumatoid arthritis, dermatological disorders, hepatic encephalopathy, childhood anemia and several more (Ref.8). Although H. pylori infection may cause other diseases in addition to gastritis, there are no clinical consequences whatsoever in 60 to 70% of infected humans. H. pylori-associated disease is influenced not only by the pathogenic nature of the infecting strain but also by other factors. Genetic variability in host factors such as gender, blood group antigens, human lymphocyte antigen type, and the age of the host when the infection was acquired, may play a primary role in determining different clinical outcomes. Environmental factors may also play a role in the outcome of the infection. Socioeconomic class, which affects living conditions and sanitation, may increase the risk of exposure to the bacterium. Tobacco smoking increases the risk of duodenal ulceration for patients infected with H. pylori. All these environmental determinants may undergo synergistic or antagonistic interactions with H. pylori to render different clinical outcomes of infection. Similarly, dietary factors including high salt and low antioxidant intake are risk factors for gastric carcinoma in and of themselves. Accurate tests for the detection of H. pylori infection are available. They include blood antibody tests, UBT (Urea Breath Tests), stool antigen tests and endoscopic biopsies. H. pylori are difficult to eradicate from the stomach because it is capable of developing resistance to commonly used antibiotics. Therefore, two or more antibiotics usually are given together with a PPI (Proton Pump Inhibitors) and/or bismuth containing compounds to eradicate the bacterium (Bismuth and PPIs have anti-H.pylori effects) (Ref.1).