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

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Abstract

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. Moreover, we demonstrate that PLCγ2 phosphorylation on Tyr remains under the control of the Src family protein tyrosine kinases (SFK-PTKs), and is intimately linked to PLCγ2 membrane localization, while the LPS-induced phosphorylation of membrane-recruited PLCγ2 on Ser displays dependence on protein kinase Cδ (PKCδ) and leads to the amplification in PLCγ2 activation. Thus, our findings link the extent of H. pylori-elicited gastric mucosal inflammatory involvement to the PKCδ-mediated amplification in PLCγ2 activation through phosphorylation on Ser.

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References

  • Aki D, Minoda Y, Yoshida H et al (2008) Peptidoglycan and lipopolysaccharide activate PLCγ2, leading to enhanced cytokine production in macrophages and dendritic cells. Gens Cells 13:199–208

    Article  CAS  Google Scholar 

  • Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

    Article  CAS  PubMed  Google Scholar 

  • 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

  • Carpenter S, O’Neill LAJ (2009) Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signaling proteins. Biochem J 422:1–10

    Article  CAS  PubMed  Google Scholar 

  • Chen P, Xie H, Sekar MC, Gupta K, Wells A (1994) Epidermal growth factor receptor-mediated cell motility: phospholipase C activity is required, but mitogen-activated protein kinase activity is not sufficient for induced cell movement. J Cell Biol 127:847–857

    Article  CAS  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 

  • Deason-Towne F, Perraud AL, Schmitz C (2012) Identification of Ser/Thr phosphorylation sites in the C2-domain of phospholipase Cγ2 (PLCγ2) using TRPM7-kinase. Cell Signal 24:2070–2075

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Everett KL, Bunney TD, Yoon Y et al (2009) Characterization of phospholipase Cγ enzymes with gain-of-function mutations. J Biol Chem 284:23083–23093

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Everett KL, Buehler A, Bunney T et al (2011) Membrane environment exerts an important influence on Rac-mediated activation of phospholipase Cγ2. Mol Cell Biol 31:1240–1251

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gong P, Angelini DJ, Yang S et al (2008) TLR4 signaling is coupled to SRC family kinase activation, tyrosine phosphorylation of zonula adherens proteins, and opening of the paracellular pathway in human lung microvascular endothelia. J Biol Chem 283:13437–13449

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gresset A, Hicks SN, Harden TK, Sondek J (2010) Mechanism of phosphorylation-induced activation of phospholipase Cγ isozymes. J Biol Chem 285:35836–35847

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Harden TK, Hicks SN, Sondek J (2009) Phospholipase C isozymes as effectors of Ras superfamily GTPases. J Lipid Res 50:S243–S248

    Article  PubMed Central  PubMed  Google Scholar 

  • Kadamur G, Ross EM (2013) Mammalian phospholipase C. Annu Rev Physiol 75:127–154

    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 

  • Kubo-Murai M, Hazeki K, Sukenobu N et al (2007) Protein kinase Cδ binds TIRAP/Mal to participate in TLR signaling. Mol Immunol 44:2257–2264

    Article  CAS  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 

  • Lodeiro M, Alen BO, Mosteiro CS et al (2011) The SHP-1 protein tyrosine phosphatase negatively modulates Akt signaling in the ghrelin/GHSR1a system. Mol Biol Cell 22:4182–4191

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nishida M, Sugimoto K, Hara T et al (2003) Amplification of receptor signaling by Ca2+ entry-mediated translocation and activation of PLCg2 in B lymphocytes. EMBO J 22:4677–4688

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signaling. Nat Rev Immunol 7:353–364

    Article  PubMed  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 

  • Oude Weernink PA, Han L, Jakobs KH, Schmidt M (2007) Dynamic phospholipid signaling by G protein-coupled receptors. Biochim Biophys Acta 1768:888–900

    Article  CAS  PubMed  Google Scholar 

  • Piechulek T, Rehlen T, Walliser C, Vatter P, Moepps B, Gierschik P (2005) Isozyme-specific stimulation of phospholipase C-γ2 by Rac GTPases. J Biol Chem 280:38923–38931

    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 (2000) Blockade of p38 mitogen-activated protein kinase pathway inhibits inducible nitric oxide synthase and gastric mucosal inflammatory reaction to Helicobacter pylori lipopolysaccharide. Inflammopharmacology 8:371–382

    Article  CAS  Google Scholar 

  • Slomiany BL, Slomiany A (2011) 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

    Article  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 (2013) 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. Inflammopharmacology 21:241–251

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2014a) Role of ghrelin-induced phosphatidylinositol 3-kinase activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori. Inflammopharmacology 22:169–177

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2014b) Modulation of gastric mucosal inflammatory responses to Helicobacter pylori via ghrelin-induced protein kinase Cδ tyrosine phosphorylation. Inflammopharmacology 22:251–262

    Article  CAS  PubMed  Google Scholar 

  • Slomiany BL, Slomiany A (2014c) Protein kinase Cδ-mediated posttranslational phosphorylation of constitutive nitric oxide synthase regulates gastric mucosal inflammatory responses to Helicobacter pylori: effect of ghrelin. J Biosci Med 2:20–33

    CAS  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 

  • 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 

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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 amplification in phospholipase Cγ2 activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori: effect of ghrelin. Inflammopharmacol 23, 37–45 (2015). https://doi.org/10.1007/s10787-014-0220-1

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  • DOI: https://doi.org/10.1007/s10787-014-0220-1

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