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

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Abstract

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. We demonstrate that cNOS activation through phosphorylation induced by ghrelin is associated with PI3K activation which occurs upstream of cSrc, and that PI3K is required for cSrc activation of Akt. We show further that ghrelin-induced activation of PI3K, as well as that of Src and Akt, was susceptible to suppression by the inhibitors of phospholipase C (U73122) and protein kinase C (BIM). Both these inhibitors also blocked the ghrelin-induced membrane translocation of PI3K and cSrc, whereas the inhibitor of PI3K (LY294002) blocked only the membrane translocation of cSrc. Collectively, our findings suggest that the modulatory influence of ghrelin in countering gastric mucosal responses to H. pylori LPS relies on PI3K activation that depends on PLC/PKC signaling pathway, and that PI3K activity is required for the induction of cSrc/Akt activation.

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References

  • Backert S, Neumann M (2010) What a disorder: proinflammatory signaling pathways induced by Helicobacter pylori. Trends Microbiol 18:479–486

    Article  CAS  PubMed  Google Scholar 

  • Bauer B, Meyer TF (2011) The human gastric pathogen Helicobacter pylori and its association with gastric cancer and ulcer disease. Ulcers, Article ID 340157. doi:10.1155/2011/340157

  • Brandt DT, Goerke A, Heuer M et al (2003) Protein kinase C delta induces Src kinase activity via activation of protein tyrosine phosphatase PTP alpha. J Biol Chem 278:34073–34078

    Article  CAS  PubMed  Google Scholar 

  • Cahill CM, Rogers JT, Walker WA (2012) The role of phosphoinositide 3-kinase signaling in intestinal inflammation. J Signal Transduct 2012, Article ID 358476. doi:10.1155/2012/358476

  • Cao X, Kambe F, Moeller LC, Refetoff S, Seo H (2005) Thyroid hormone induces rapid activation of Akt/protein kinase B-mammalian target of rapamycin-p70S6K cascade through phosphatidylinositol 3-kinase in human fibroblasts. Mol Endocrinol 19:102–112

    Article  CAS  PubMed  Google Scholar 

  • Cao X, Kambe F, Yamauchi M, Seo H (2009) Thyroid-hormone-dependent activation of the phosphoinositide 3-kinase/Akt cascade requires Src and enhances neuronal survival. Biochem J 424:201–209

    Article  CAS  PubMed  Google Scholar 

  • Chaurasia B, Mauer J, Koch I, Goldau J, Kock AS, Bruning JC (2010) Phosphoinositide-dependent kinase 1 provides negative feedback inhibition to toll-like receptor-mediated NF-κB activation in macrophages. Mol Cell Biol 30:4354–4366

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chiang CY, Veckman V, Limmer K, David M (2012) Phospholipase Cγ-2 and intracellular calcium are required for lipopolysaccharide-induced toll-like receptor-4 (TLR4) endocytosis and interferon regulatory factor 3 (IRF3) activation. J Biol Chem 287:3704–3709

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • de Boer WA (2000) Helicobacter pylori infection: focus on a ‘search-and-treat’ strategy for ulcer disease. Scand J Gastroenterol 35(Suppl 32):4–9

    Google Scholar 

  • Fleming I (2010) Molecular mechanisms underlying the activation of eNOS. Pflugers Arch Eur J Physiol 459:793–806

    Article  CAS  Google Scholar 

  • Fukao T, Koyasu S (2003) PI3K and negative regulation of TLR signaling. Trends Immunol 24:358–363

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez E, Kou R, Lin AJ, Golan DE, Michel T (2002) Subcellular targeting and agonist-induced site-specific phosphorylation of endothelial nitric oxide synthase. J Biol Chem 277:39554–39560

    Article  CAS  PubMed  Google Scholar 

  • Guha M, Mackman N (2002) The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem 277:32124–32132

    Article  CAS  PubMed  Google Scholar 

  • Huang C, Ma WY, Dong Z (1998) Potentiation of insulin-induced phosphatidylinositol-3 kinase activity by phorbol ester is mediated by protein kinase C epsilon. Cell Signal 10:185–190

    Article  CAS  PubMed  Google Scholar 

  • Jiang T, Qiu Y (2003) Interaction between Src and a C-terminal proline-rich motif of Akt is required for Akt activation. J Biol Chem 278:15789–15793

    Article  CAS  PubMed  Google Scholar 

  • Jin W, Jeong C, Park Y, Lee HD, Kim SJ (2008) c-Src is required for tropomyosin receptor kinase C (TrkC)-induced activation of phosphatidylinositol 3-kinase (PI3K)-Akt pathway. J Biol Chem 283:1391–1400

    Article  CAS  PubMed  Google Scholar 

  • Kojima M, Hosoda H, Date Y et al (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660

    Article  CAS  PubMed  Google Scholar 

  • Korhonen R, Lahti A, Kankaanrata H, Moilanen E (2005) Nitric oxide production and signaling in inflammation. Curr Drug Targets Inflamm Allergy 4:471–479

    Article  CAS  PubMed  Google Scholar 

  • Lee S, Lin X, Nam NH et al (2003) Determination of the substrate-docking site of protein tyrosine kinase c-terminal Src kinase. Proc Natl Acad Sci USA 100:14707–14712

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee JY, Chiu YH, Asara J, Cantley LC (2011) Inhibition of PI3K binding to activators by serine phosphorylation of PI3K regulatory subunit p85α Src homology-2 domains. Proc Natl Acad Sci USA 108:14157–14162

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu AMF, Wong YH (2004) G16-mediated activation of nuclear factor κB by the adenosine A1 receptor involves c-Src, protein kinase C, and ERK signaling. J Biol Chem 279:53196–53204

    Article  CAS  PubMed  Google Scholar 

  • Lodeiro M, Theodoropoulou M, Pardo FF, Camina JP (2009) c-Src regulates Akt signaling in response to ghrelin via β-arrestin signaling-independent and -dependent mechanisms. Plos One 4(3):e4686. doi:http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004686

    Article  PubMed Central  PubMed  Google Scholar 

  • Matsuda N, Hayashi Y, Takahashi Y, Hattori Y (2006) Phosphorylation of endothelial nitric-oxide synthase is diminished in mesenteric arteries from septic rabbits depending on the altered phosphatidylinositol 3-kinase/Akt pathway: reversal effect of fluvastatin therapy. J Pharmacol Exp Ther (JPET) 319:1348–1354

    Article  CAS  Google Scholar 

  • Osawa H, Nakazato M, Date Y et al (2005) Impaired production of gastric ghrelin in chronic gastritis associated with Helicobacter pylori. J Clin Endocrinol Metab 90:10–16

    Article  CAS  PubMed  Google Scholar 

  • Piotrowski J, Piotrowski E, Skrodzka D, Slomiany A, Slomiany BL (1997) Induction of acute gastritis and epithelial cell apoptosis by Helicobacter pylori lipopolysaccharide. Scand J Gastroenterol 32:203–211

    Article  CAS  PubMed  Google Scholar 

  • Reider G, Hoffman JA, Hatz RA, Stolte M, Enders GA (2003) Up-regulation of inducible nitric oxide synthase in Helicobacter pylori-associated gastritis may represent an increased risk factor to develop gastric carcinoma of the intestinal type. Int J Med Microbiol 293:403–412

    Article  Google Scholar 

  • Slomiany BL, Slomiany A (2010a) Ghrelin protection against lipopolysaccharide- induced gastric mucosal cell apoptosis involves constitutive nitric oxide synthase-mediated caspase-3 S-nitrosylation. Mediat Inflamm. doi:http://www.readcube.com/articles/10.1155/2010/280464?locale=en

    Google Scholar 

  • Slomiany BL, Slomiany A (2010b) Helicobacter pylori induces disturbances in gastric mucosal Akt activation through inducible nitric oxide synthase- dependent S-nitrosylation: effect of ghrelin. ISRN Gastroenterol. doi:10.5402/2011/308727

    PubMed Central  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2011a) Ghrelin suppression of Helicobacter pylori- induced gastric mucosal expression of iNOS is mediated through the inhibition of IKK-β activation by cNOS-dependent S-nitrosylation. Open J Cell Biol 1:1–10. doi:10.4236/ojcb

    Article  Google Scholar 

  • Slomiany BL, Slomiany A (2011b) Role of ghrelin-induced cSrc activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori. Inflammopharmacol 19:197–204

    Article  CAS  Google Scholar 

  • Slomiany A, Slomiany BL (2012) Phosphatidylglycerol-containing ER-transport vesicles built and restore outer mitochondrial membrane and deliver nuclear DNA translation products to generate cardiolipin in the inner mitochondrial membrane. Adv Biol Chem 2:132–145

    Article  CAS  Google Scholar 

  • Slomiany BL, Slomiany A (2013a) Involvement of p38 MAPK-dependent activator protein (AP-1) activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori by ghrelin. Inflammopharmacol 21:67–78

    Article  CAS  Google Scholar 

  • Slomiany BL, Slomiany A (2013b) 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. Inflammopharmacol 21:241–251

    Article  CAS  Google Scholar 

  • Slomiany BL, Piotrowski J, Slomiany A (1999) Effect of ebrotidine on Helicobacter pylori lipopolysaccharide-induced up-regulation of endothelin-1 in gastric mucosa. J Endotoxin Res 5:279–285

    Article  CAS  Google Scholar 

  • Tamiya S, Delamere NA (2005) Studies of tyrosine phosphorylation and Src family tyrosine kinases in the lens epithelium. Invest Ophthalmol Vis Sci 46:2076–2081

    Article  PubMed  Google Scholar 

  • Walker VG, Ammer A, Cao Z et al (2007) PI3K activation is required for PMA-directed activation of cSrc by AFAP-110. Am J Physiol Cell Physiol 293:C119–C132

    Article  CAS  PubMed  Google Scholar 

  • Waseem TM, Duxbury M, Ito H et al (2008) Exogenous ghrelin modulates release of proinflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways. Surgery 143:334–342

    Article  PubMed Central  PubMed  Google Scholar 

  • Wroblewski LA, Peek RM, Wilson KT (2010) Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev 23:713–739

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wu R, Dong W, Cui X (2007) Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve. Ann Surg 245:480–486

    Article  PubMed Central  PubMed  Google Scholar 

  • Xu X, Bong SJ, Chang HH, Jin ZG (2008) Molecular mechanism of ghrelin-mediated endothelial nitric oxide synthase activation. Endocrinology 149:4183–4192

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yao L, Suzuki H, Ozawa K et al (1997) Interaction between protein kinase C and pleckstrin homology domains. J Biol Chem 272:13033–13039

    Article  CAS  PubMed  Google Scholar 

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Research Center, C875, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA

    B. L. Slomiany & A. Slomiany

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  1. B. L. Slomiany
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  2. A. Slomiany
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Correspondence to B. L. Slomiany.

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Slomiany, B.L., Slomiany, A. Role of ghrelin-induced phosphatidylinositol 3-kinase activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori . Inflammopharmacol 22, 169–177 (2014). https://doi.org/10.1007/s10787-013-0190-8

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  • DOI: https://doi.org/10.1007/s10787-013-0190-8

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