Syk: a new target for attenuation of Helicobacter pylori-induced gastric mucosal inflammatory responses.

The magnitude of gastric mucosal inflammatory response to H. pylori relies primarily on the extent of its key endotoxin, LPS, engagement of Toll-like receptor-4 (TLR4) and the initiation of signal transduction events converging on mitogen-activated protein kinase (MAPK) and IκB complex (IKK) cascades. These cascades, in turn, exert their control over the assembly of transcription factors, NFκB and AP1, implicated in the induction of the expression of iNOS and COX-2 proinflammatory genes.

Helicobacter pylori LPS-induced gastric mucosal spleen tyrosine kinase (Syk) recruitment to TLR4 and activation occurs with the involvement of protein kinase Cδ.

Spleen tyrosine kinase (Syk) has emerged recently as a major effector of proinflammatory genes expression induced by LPS-elicited TLR4 activation, and manifested by the up-amplification in the production of inflammatory mediators, including PGE2 and NO. Here, we investigated the nature of factors involved in the recruitment and interaction of Syk with TLR4 in gastric mucosa in response to H. pylori LPS.

Role of LPS-elicited signaling in triggering gastric mucosal inflammatory responses to H. pylori: modulatory effect of ghrelin.

Infection with Helicobacter pylori is a primary culprit in the etiology of gastric disease, and its cell-wall lipopolysaccharide (LPS) is recognized as a potent endotoxin responsible for triggering a pattern of the mucosal inflammatory responses. The engagement by the LPS of gastric mucosal Toll-like receptor 4 (TLR4) leads to initiation of signal transduction events characterized by the activation of mitogen-activated protein kinase (MAPK) cascade, induction of phosphoinositide-specific phospholipase C (PLC)/protein kinase C (PKC)/phosphatidylinositol 3-kinase (PI3K) pathway, and up-regulation in Src/Akt. These signaling events in turn exert their influence over H.

Helicobacter pylori-induced changes in microtubule dynamics conferred by α-tubulin phosphorylation on Ser/Tyr mediate gastric mucosal secretion of matrix metalloproteinase-9 (MMP-9) and its modulation by ghrelin.

Regulation of matrix metalloproteinase-9 (MMP-9) secretion in response to proinflammatory challenge remains under a strict control of factors that affect the stability dynamics of the major cytoskeleton polymeric structures, microtubules (MTs). In this study, we report that H. pylori LPS-elicited induction gastric mucosal MMP-9 secretion is accompanied by the enhancement in MT stabilization as evidenced by the increase in α-tubulin acetylation and detyrosination while the modulatory influence of hormone, ghrelin, is associated with MT destabilization and reflected in a decrease in α-tubulin acetylation and detyrosination.

Role of protein kinase D2 phosphorylation on Tyr in modulation by ghrelin of Helicobacter pylori-induced up-regulation in gastric mucosal matrix metalloproteinase-9 (MMP-9) secretion.

Matrix metalloproteinas-9 (MMP-9) is a glycosylated endopeptidase associated with host reaction to microbial endotoxins and also characterizes gastric mucosal inflammatory response to H. pylori infection. Here, we report on the factors involved in gastric mucosal MMP-9 secretion in response to H.

Helicobacter pylori-elicited induction in gastric mucosal matrix metalloproteinase-9 (MMP-9) release involves ERK-dependent cPLA2 activation and its recruitment to the membrane-localized Rac1/p38 complex.

Matrix metalloproteinases (MMPs) are a family of endopeptidases implicated in a wide rage of degenerative and inflammatory diseases, including Helicobacter pylori-associated gastritis, and gastric and duodenal ulcer. As gastric mucosal inflammatory responses to H. pylori are characterized by the rise in MMP-9 production, as well as the induction in mitogen-activated protein kinase (MAPK) and Rac1 activation, we investigated the role of Rac1/MAPK in the processes associated with the release of MMP-9.

Helicobacter pylori-induced gastric mucosal TGF-α ectodomain shedding and EGFR transactivation involves Rac1/p38 MAPK-dependent TACE activation.

Infection of gastric mucosa by H. pylori triggers a pattern of inflammatory responses characterized by the rise in proinflammatory cytokine production, up-regulation in mitogen-activated protein kinase (MAPK) cascade, and the induction in epidermal growth factor receptor (EGFR) activation. In this study, we report on the role of MAPK/p38 and Rac1 in the regulation of H.

Regulatory role of guanine nucleotide exchange factor (GEF) Dock180 phosphorylation on Tyr/Ser in mediation of gastric mucosal Rac1 activation in response to Helicobacter pylori and ghrelin.

A small GTPase, Rac1, is recognized as an important modulator of the inflammatory responses to bacterial lipopolysaccharide (LPS) by affecting the processes of phospholipase C activation. The activation of Rac1 involves the exchange of GDP for GTP and is catalyzed by the guanine nucleotide exchange factors (GEFs). Here, we report on the gastric mucosal GEF, Dock180, activation in response to H.

Mechanism of Rac1-induced amplification in gastric mucosal phospholipase Cγ2 activation in response to Helicobacter pylori: modulatory effect of ghrelin.

Membrane recruitment followed by targeted phosphorylation of specific Tyr and Ser residues and the interaction with Rac GTPases are the crucial parts of an elaborate mechanism of PLCγ2 activation essential for its role in linking the specific receptor responses to a variety of hormones and bacterial endotoxins with the intended intracellular targets. Here, we explored the involvement of Rac in mediation of PLCγ2 activation associated with gastric mucosal inflammatory responses to H. pylori LPS and the hormone, ghrelin.

Role of amplification in phospholipase Cγ2 activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori: effect of ghrelin.

Phosphoinositide-specific phospholipase C (PLC) enzymes are crucial elements of signal transduction pathways that provide a common link of communication integrating specific receptor responses to a variety of hormones, growth factors, and bacterial endotoxins with the intended intracellular targets. Here, we examined the involvement of PLC in modulation of gastric mucosal inflammatory responses to Helicobacter pylori LPS by peptide hormone, ghrelin. We show that stimulation of gastric mucosal cells with the LPS leads to the activation and membrane translocation of the γ2 isoform of PLC, phosphorylated on Tyr as well as Ser, while the effect of ghrelin is reflected in the translocation and phosphorylation of membrane-associated PLCγ2 on Tyr mainly.

Modulation of gastric mucosal inflammatory responses to Helicobacter pylori via ghrelin-induced protein kinase Cδ tyrosine phosphorylation.

A peptide hormone, ghrelin, plays a key role in modulation of gastric mucosal inflammatory responses to Helicobacter pylori by controlling the activation of constitutive nitric oxide synthase via Src/Akt-dependent phosphorylation that requires phosphatidylinositol 3-kinase (PI3K) participation. Here, we examined the relationship among PI3K; its upstream effector, protein kinase C (PKC); and cSrc. We show that stimulation of gastric mucosal cells with H.

Role of ghrelin-induced phosphatidylinositol 3-kinase activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori.

A peptide hormone, ghrelin, is recognized as an important modulator of gastric mucosal inflammatory responses to Helicobacter pylori through the regulation of Src/Akt-dependent activation of constitutive nitric oxide synthase (cNOS) by phosphorylation. In this study, we report on the role of phosphatidylinositol 3-kinase (PI3K) in the processes of Src/Akt activation in gastric mucosal cells exposed to H. pylori LPS.

Induction in gastric mucosal prostaglandin and nitric oxide by Helicobacter pylori is dependent on MAPK/ERK-mediated activation of IKK-β and cPLA2: modulatory effect of ghrelin.

Among the key factors defining the extent of gastric mucosal inflammatory involvement in response to Helicobacter pylori is the excessive generation of prostaglandin (PGE2) and nitric oxide (NO), caused by the overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), and triggered by the activation of mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase, p38 and ERK, and nuclear translocation of the cognate transcription factors. In this study, we report on the role of MAPK/ERK in the regulation of H. pylori LPS-induced gastric mucosal expression of COX-2 and iNOS.

Involvement of p38 MAPK-dependent activator protein (AP-1) activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori by ghrelin.

A peptide hormone, ghrelin, plays an important role in modulation of gastric mucosal inflammatory responses to Helicobacter pylori infection by controlling the cross-talk between nitric oxide synthase (NOS) and cyclooxygenase (COX) enzyme systems. In this study, we report that H. pylori LPS-elicited induction in gastric mucosal COX-2 and inducible (i) iNOS protein expression, and the impairment in constitutive (c) cNOS phosphorylation, was associated with mitogen-activated protein kinase, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase and p38 activation, and occurred with the involvement of transcription factors, CCATT/enhancer-binding protein (C/EBP) δ, cAMP response element-binding protein, activator protein-1 (AP-1), and NF-κB.

Helicobacter pylori Induces Disturbances in Gastric Mucosal Akt Activation through Inducible Nitric Oxide Synthase-Dependent S-Nitrosylation: Effect of Ghrelin.

Gastric mucosal inflammatory response to H. pylori and its key virulence factor, lipopolysaccharide (LPS), are characterized by a massive rise in apoptosis and the disturbances in NO signaling pathways. Here, we report that H.

Ghrelin Protects against the Detrimental Consequences of Porphyromonas gingivalis-Induced Akt Inactivation through S-Nitrosylation on Salivary Mucin Synthesis.

Disturbances in nitric oxide synthase isozyme system and the impairment in salivary mucin synthesis are well-recognized features associated with oral mucosal inflammatory responses to periodontopathic bacterium, P. gingivalis. In this study, using rat sublingual gland acinar cells, we report that P.

Role of ghrelin-induced cSrc activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori.

A peptide hormone, ghrelin, is recognized as an important modulator of gastric mucosal inflammatory responses to H. pylori through the regulation of nitric oxide synthase (NOS) system. As cSrc kinase plays a major role in transduction of signals that regulate the activity of NOS isozyme system, we investigated the influence of H.

Ghrelin suppression of Helicobacter pylori-induced S-nitrosylation-dependent Akt inactivation exerts modulatory influence on gastric mucin synthesis.

Loss of mucus coat integrity and the impairment in its mucin component as well as the disturbance in nitric oxide (NO) generation are well-recognized features of gastric disease associated with H. pylori infection. As ghrelin plays a major role in the regulation of nitric oxide synthase system, we investigated the influence of this hormone on H.

Mechanism of Cytosolic Phospholipase A(2) Activation in Ghrelin Protection of Salivary Gland Acinar Cells against Ethanol Cytotoxicity.

Ghrelin, a peptide hormone, newly identified in oral mucosal tissues, has emerged recently as an important mediator of the processes of mucosal defense. Here, we report on the mechanism of ghrelin protection against ethanol cytotoxicity in rat sublingual salivary gland cells. The protective effect of ghrelin was associated with the increase in NO and PGE2, and upregulation in cytosolic phospholipase A(2) (cPLA(2)) activity and arachidonic acid (AA) release.

Role of constitutive nitric oxide synthase S-nitrosylation in Helicobacter pylori-induced gastric mucosal cell apoptosis: effect of ghrelin.

Infection with H. pylori is a primary factor in the etiology of gastric disease, and the excessive NO generation and a massive rise in apoptosis are well recognized features that characterize the mucosal inflammatory responses to the bacterium and its lipopolysaccharide (LPS). Here, we report that H.

Ghrelin protection against lipopolysaccharide-induced gastric mucosal cell apoptosis involves constitutive nitric oxide synthase-mediated caspase-3 S-nitrosylation.

Ghrelin, a peptide hormone produced mainly in the stomach, has emerged as an important modulator of the inflammatory responses that are of significance to the maintenance of gastric mucosal integrity. Here, we report on the role of ghrelin in controlling the apoptotic processes induced in gastric mucosal cells by H. pylori lipopolysaccharide (LPS).

Ghrelin Protection against Cytotoxic Effect of Ethanol on Rat Salivary Mucin Synthesis involves Cytosolic Phospholipase A2 Activation through S-Nitrosylation.

Recent advances in identifying the salivary constituents of significance to the maintenance of soft oral tissue integrity have brought to focus the importance of a 28-amino acid peptide hormone, ghrelin. Here, we report on the role of ghrelin in countering the disturbances in salivary mucin synthesis caused by ethanol cytotoxicity in rat sublingual gland acinar cells. We show that the countering effect of ghrelin on mucin synthesis was associated with the increase in NO and PGE2 production, and the enhancement in cytosolic phospholipase A2 (cPLA2) activity.

Constitutive nitric oxide synthase-mediated caspase-3 S-nitrosylation in ghrelin protection against Porphyromonas gingivalis-induced salivary gland acinar cell apoptosis.

Recent advances in identifying the salivary constituents capable of influencing the oral mucosal inflammatory responses have brought to focus the importance of a peptide hormone, ghrelin. Here, we report on the involvement of ghrelin in controlling the apoptotic processes induced in sublingual salivary gland acinar cells by the lipopolysaccharide (LPS) of a periodontopathic bacterium, Porphyromonas gingivalis. We show that the countering effect of ghrelin on the LPS-induced acinar cell apoptosis was associated with the increase in constitutive nitric oxide synthase (cNOS) activity, and the reduction in caspase-3 and inducible nitric oxide synthase (iNOS).

Suppression by Ghrelin of Porphyromonas gingivalis-Induced Constitutive Nitric Oxide Synthase S-Nitrosylation and Apoptosis in Salivary Gland Acinar Cells.

Oral mucosal inflammatory responses to periodontopathic bacterium, P. gingivalis, and its key virulence factor, LPS, are characterized by a massive rise in epithelial cell apoptosis and the disturbances in NO signaling pathways. Here, we report that the LPS-induced enhancement in rat sublingual salivary gland acinar cell apoptosis and NO generation was associated with the suppression in constitutive nitric oxide synthase (cNOS) activity and a marked increase in the activity of inducible nitric oxide synthase (iNOS).

Involvement of constitutive nitric oxide synthase in ghrelin-induced cytosolic phospholipase A(2) activation in gastric mucosal cell protection against ethanol cytotoxicity.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is an important regulator of nitric oxide synthase (NOS) and cyclooxygenase (COX) enzyme systems, the products of which are of major significance to the processes of gastric mucosal defense and repair. Here, using primary culture of rat gastric mucosal cells, we report on the mechanism of ghrelin protection against ethanol cytotoxicity. We show that the protective effect of ghrelin was associated with the increase in NO and PGE2 production, and characterized by a marked up-regulation in cytosolic phospholipase A(2) (cPLA(2)) activity and arachidonic acid (AA) release.