, Volume 27, Issue 2, pp 203–211 | Cite as

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

  • Bronislaw L. SlomianyEmail author
  • Amalia Slomiany


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. The LPS-induced TLR4 activation and the ensuing phosphorylation of its intracellular tyrosine domain by Src-family kinases not only leads to recruitment to the cytoplasmic domain of TLR4 of adaptor molecules directly involved in propagation of the signaling cascades converging on MAPK and IKK, but also provides a propitious docking site for a non-receptor tyrosine kinase, spleen tyrosine kinase (Syk), the activation of which apparently leads to upregulation in the expression of proinflammatory genes. Here, we review the pathways engaged by H. pylori in the recruitment and interaction of Syk with TLR4 in gastric mucosa, and discuss the cascades involved in Syk-mediated amplification in proinflammatory signaling. We focus, moreover, on the potential role of drugs targeting Syk and TLR4 in the treatment of H. pylori-related gastric disease.


Gastric mucosa H. pylori TLR4 Syk Proinflammatory signal amplification Therapeutic agents 


Compliance with ethical standards

Ethical standards

The authors declare that they have no conflict of interest.


  1. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801CrossRefGoogle Scholar
  2. Amith SR, Abdulkhalek S, Szewczuk MR (2016) Role of glycosylation in toll-like receptor activation and pro-inflammatory responses. In: Weiderschain G (ed) Glycobiology and human diseases. CRC, Boca Raton, pp 165–184CrossRefGoogle Scholar
  3. Ayala G, Escobedo-Hinojosa WI, Cruz-Herrera CF, Romero I (2014) Exploring alternative treatments for Helicobacter pylori infection. World J Gastroenterol 20:1450–1469CrossRefGoogle Scholar
  4. Backert S, Neumann M (2010) What a disorder: proinflammatory signaling pathways induced by Helicobacter pylori. Trends Microbiol 18:479–486CrossRefGoogle Scholar
  5. Barochia A, Slomon S, Cui X, Natanson C, Eichacker PQ (2011) Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Expert Opin Drug Metab Toxicol 7:479–494CrossRefGoogle Scholar
  6. Barukcic I (2017) Helicobacter pylori—the cause of human cancer. J Biosci Med 5:1–9Google Scholar
  7. Bauer B, Meyer TF (2011) The human gastric pathogen Helicobacter pylori and its association with gastric cancer and ulcer disease. Ulcers 2011 (Article ID 340157).
  8. Beutler B, Jiang Z, Georgel P et al (2006) Gen etic analysis of host resistance: toll-like receptor signaling and immunity at large. Ann Rev Immunol 24:353–389CrossRefGoogle Scholar
  9. Bhat NR, Feinstein DL, Shen O, Bhat AN (2002) p38 MAPK-mediated transcriptional activation of inducible nitric oxide synthase in glial cells. Roles of nuclear factors, nuclear factor κB, cAMP response element-binding protein, CCAAT/enhancer-binding protein-β, and activating transcription factor-2. J Biol Chem 277:29584–29592CrossRefGoogle Scholar
  10. Bijli KM, Fazal F, Minhajuddin M, Rahman A (2008) Activation of Syk by protein kinase C-d regulates thrombin-induced intracellular adhesion molecule-1 expression in endothelial cells via tyrosine phosphorylation on RelA/p65. J Biol Chem 283:14674–14684CrossRefGoogle Scholar
  11. Bohnenberger H, Oellerich T, Engelke M et al (2011) Complex phosphorylation dynamics control the composition of the Syk interactome in B cells. Eur J Immunol 41:1550–1562CrossRefGoogle Scholar
  12. Bryant CE, Quellette A, Lohmann K et al (2007) The cellular Toll-like receptor 4 antagonist E5531 can act as an agonist in horse whole blood. Vet Immunol Immunopathol 116:182–189CrossRefGoogle Scholar
  13. Bunnell E, Lynn M, Habet K et al (2000) A lipid A analog, E5531, block the endotoxin response in human volunteers with experimental endotoxemia. Crit Care Med 28:2713–2720CrossRefGoogle Scholar
  14. Caivano M, Gorgoni B, Cohen P, Poli V (2001) The induction of cyclooxygenase-2 mRNA in macrophages is biphasic and requires both CCAAT enhancer-binding protein β(C/EBPβ) and C/EBPδ transcription factors. J Biol Chem 276:48693–48701CrossRefGoogle Scholar
  15. 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 422:1–10CrossRefGoogle Scholar
  16. Chen XZ, Schottker B, Castro FA (2016) Association of Helicobacter pylori infection and chronic atrophic gastritis with risk of colonic, pancreatic and gastric cancer: a ten-year follow-up of the ESTHER cohort study. Oncotarget 7:17182–17193Google Scholar
  17. Chey WD, Leontiadis GI, Howden CW, Moss SF (2017) ACG clinical guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol 112:212–239CrossRefGoogle Scholar
  18. Cho I, Kim SG (2009) A novel mitogen-activated protein kinase phosphatase-1 and glucocorticoid receptor (GR) interacting protein-1-dependnt combinatorial mechanism of gene transrepression by GR. Mol Endocrinol 23:86–99CrossRefGoogle Scholar
  19. Choi SH, Wiesner P, Almazan F, Kim J, Miller YI (2012) Spleen tyrosine kinase regulates AP-1 dependent transcriptional response to minimally oxidized LDL. PLoS One 7:e32378CrossRefGoogle Scholar
  20. Dhar SK, Soni RK, Das BK, Mukhopadhyay G (2003) Molecular mechanism of action of major Helicobacter pylori virulence factors. Mol Cell Biochem 253:207–215CrossRefGoogle Scholar
  21. Echizen K, Hirose O, Maeda Y, Ochima M (2016) Inflammation in gastric cancer: interplay of the COX-2/prostaglandin E2 and Toll-like receptor/MyD88 pathways. Cancer Sci 107:391–397CrossRefGoogle Scholar
  22. Elsori DH, Yakubenko VP, Roome T et al (2011) Protein kinase Cd is acritical component of Dectin-1 signaling in primary human monocytes. J Leukoc Biol 90:599–611CrossRefGoogle Scholar
  23. Endale M, Park SC, Kim S et al (2013) Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-κB-induced inflammatory mediators production in RAW 264.7 cells. Immunobiology 218:1452–1467CrossRefGoogle Scholar
  24. Fallone CA, Chiba N, van Zanten SV et al (2016) The Toronto Consensus for the treatment of Helicobacter pylori infection in adults. Gastroenterology 151:51–69CrossRefGoogle Scholar
  25. Furlong MT, Mahrenholtz AM, Kim KH, Ashendel CL, Harrison ML, Geahlen RL (1997) Identification of the major site of autophosphorylation of the murine protein-tyrosine kinase Syk. Biochim Biophys Acta Mol Cell Res 1355:177–190CrossRefGoogle Scholar
  26. Garate JA, Stockl J, Fernandez-Alonso MC et al (2015) Anti-endotoxic and structural basis for human MD-2.TLR4 antagonism of tetraacylated lipid A mimetics based on βGlcN(1↔1)αGlcN scaffold. Innate Immun 21:490–503CrossRefGoogle Scholar
  27. Grishin AV, Wang J, Potoka DA et al (2006) Lipopolysaccharide induces cyclooxygenase-2 in intestinal epithelium via a noncanonical p38 MAPK pathway. J Immunol 176:580–588CrossRefGoogle Scholar
  28. Hirota M, Miyazaki S, Minnakuchi T, Takagi T, Shibata H (2002) Myrsinoic Acids B, C and F, anti-inflammatory compounds from Myrsine seguinii. Biosci Biotechnol Biochem 66:655–659CrossRefGoogle Scholar
  29. Hossen MJ, Kim SC, Son YJ et al (2015) AP-1 targeting anti-inflammatory activity of the methanolic extract of Persicaria chinensis. Evid Based Complement Altern Med 2015 (Article ID 608126) Google Scholar
  30. Ii M, Matsunaga N, Ket Hazeki et al (2006) A novel cyclohexene derivative, ethyl (6R0-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits Toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol 69:1288–1295CrossRefGoogle Scholar
  31. Inoue I, Mukoubayashi C, Yoshimura N et al (2011) Elevated risk of colorectal adenoma with Helicobacter pylori-related chronic gastritis: a population-based case-control study. Int J Cancer 129:2704–2711CrossRefGoogle Scholar
  32. Jeong D, Yang WS, Yang Y et al (2013) In vitro anti-inflammatory effect of Rhodomyrtus tomentosa methanol extract. J Ethnopharmacol 146:205–213CrossRefGoogle Scholar
  33. Jeong D, Yi YS, Sung GH et al (2014) Anti-inflammatory activities and mechanism of Artemisia asiatica. J Ethnopharmacol 152:487–496CrossRefGoogle Scholar
  34. Jones KR, Whitmire JM, Merrell S (2010) A tale of two toxins: Helicobacter pylori CagA and VacA modulate host pathways that impact disease. Front Microbiol 1:1–17 (Article 115) CrossRefGoogle Scholar
  35. Karin M (1995) The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270:16483–16486CrossRefGoogle Scholar
  36. Kaur M, Singh M, Silakari O (2013) Inhibitors of switch kinase ‘spleen tyrosine kinase’ in inflammation and immune-mediated disorders: a review. Eur J Med Chem 67:434–446CrossRefGoogle Scholar
  37. Kawahara T, Teshima S, Oka A, Sugiyama T, Kishi K, Rokutan K (2001) Type I Helicobacter pylori lipopolysaccharide stimulates Toll-like receptor 4 and activates mitogen oxidase 1 in gastric pit cells. Infect Immun 69:4382–4389CrossRefGoogle Scholar
  38. Kawamoto K, Ii M, Kitazaki T, Iizawa Y, Kimura H (2008) TAk-242 selectively suppresses Toll-like receptor 4-signaling mediated by internal domain. Eur J Pharmacol 584:40–48CrossRefGoogle Scholar
  39. Kazi JU (2011) The mechanism of protein kinase C regulation. Front Biol 6:328–336Google Scholar
  40. Kim HM, Park BS, Jl Kim et al (2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin eritoran. Cell 130:906–917CrossRefGoogle Scholar
  41. Kulathu Y, Grothe G, Reth M (2009) Autoinhibition and adapter function of Syk. Immunol Rev 232:286–299CrossRefGoogle Scholar
  42. Kusters JG, van Vliet AHM, Kupiers EJ (2006) Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev 19:449–490CrossRefGoogle Scholar
  43. Liao JC, Deng JS, Chiu CS et al (2012) Anti-inflammatory activities of Cinnamomum cassia constituents in vitro and in vivo. Evid Based Complement Altern Med 201 (Article ID 429320) Google Scholar
  44. Lin YC, Huang DY, Chu CL, Lin WW (2010) Anti-inflammatory actions of Syk inhibitors in macrophages involve non-specific inhibition of toll-like receptors-mediated JNK signaling pathway. Mol Immunol 47:1569–1578CrossRefGoogle Scholar
  45. Lopez-Bergami P, Lau E, Ronai Z (2010) Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat Rev Cancer 10:65–76CrossRefGoogle Scholar
  46. Miller YI, Choi SH, Weisner P, Bae YS (2012) The SYK side of TLR4: signaling mechanism in response to LPS and minimally oxidized LDL. Br J Pharmacol 167:990–999CrossRefGoogle Scholar
  47. Mullarkey M, Rose JR, Bristol J et al (2003) Inhibition of endotoxin response by E5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Therapeutics 304:1093–1102CrossRefGoogle Scholar
  48. Pannee C, Chandhanee I, Wacharee L (2014) Antiinflammatory effects of essential oil from the leaves of Cinnamomum cassia and cinnamaldehyde on lipopolysaccharide-stimulated J774A.1 cells. J Adv Pharm Technol Res 5:164–170CrossRefGoogle Scholar
  49. Paris L, Hu J, Galan J et al (2010) Regulation of Syk by phosphorylation on serine in the linker insert. J Biol Chem 285:3984–39854Google Scholar
  50. Park BS, Lee JO (2013) Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp Mol Med 45:66. CrossRefGoogle Scholar
  51. Piotrowska H, Kucinska M, Murias M (2012) Biological activity of piceatannol: leaving the shadow of resveratrol. Mutat Res 750:60–82CrossRefGoogle Scholar
  52. Piotrowski J (1998) Lipopolysaccharide a virulence factor of Helicobacter pylori: effect of antiulcer agents. J Physiol Pharmacol 49:3–24Google Scholar
  53. Quing Y, Wang M, Lin YM et al (2016) Correlation between Helicobacter pylori-associated gastric disease and colorectal neoplasia. World J Gastroenterol 22:4576–4584CrossRefGoogle Scholar
  54. Ruggiero P, Rossi G, Tombola F et al (2007) Red wine and green tea reduce H. pylori-or VacA-induced gastritis in a mouse model. World J Gastroenterol 13:349–354CrossRefGoogle Scholar
  55. Shirey KA, Lai W, Scott AJ et al (2013) The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature 497:498–502CrossRefGoogle Scholar
  56. Slomiany BL, Slomiany A (2006) Cytosolic phospholipase A2 activation in Helicobacter pylori lipopolysaccharide-induced interference with gastric mucin synthesis. IUBMB Life 58:217–223CrossRefGoogle Scholar
  57. Slomiany BL, Slomiany A (2011) Role of ghrelin-induced cSrc activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori. Inflammopharmacology 19:197–204CrossRefGoogle Scholar
  58. Slomiany BL, Slomiany A (2013a) 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 21:241–251CrossRefGoogle Scholar
  59. Slomiany BL, Slomiany A (2013b) Involvement of p38 MAPK-dependent activator protein (AP-1) activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori to ghrelin. Inflammopharmacology 21:67–78CrossRefGoogle Scholar
  60. Slomiany BL, Slomiany A (2014a) Modulation of gastric mucosal inflammatory responses to Helicobacter pylori via ghrelin-induced protein kinase Cδ tyrosine phosphorylation. Inflammopharmacology 22:251–262CrossRefGoogle Scholar
  61. Slomiany BL, Slomiany A (2014b) 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 2:20–33Google Scholar
  62. Slomiany BL, Slomiany A (2016) Helicobacter pylori-induced changes in microtubule dynamics conferred by a-tubulin phosphorylation on Ser/Tyr mediate gastric mucosal secretion of matrix metalloproteinase-9 (MMP-9) and its modulation by ghrelin. Inflammopharmacology 24:197–205CrossRefGoogle Scholar
  63. Slomiany BL, Slomiany A (2017) Role of LPS-elicited signaling in triggering gastric mucosal inflammatory responses to H. pylori: modulatory effect of ghrelin. Inflammopharmacology 25:415–429CrossRefGoogle Scholar
  64. Slomiany BL, Slomiany A (2018a) Role of protein kinase Cδ-mediated spleen tyrosine kinase (Syk) phosphorylation on Ser in the amplification of oral mucosal inflammatory responses to Porphyromonas gingivalis. J Biosci Med 6(3):70–85Google Scholar
  65. Slomiany BL, Slomiany A (2018b) Helicobacter pylori LPS-induced gastric mucosal spleen tyrosine kinase (Syk) recruitment to TLR4 and activation occurs with the involvement of protein kinase Cδ. Inflammopharmacology 26:805–815CrossRefGoogle Scholar
  66. Slomiany BL, Slomiany A (2018c) Proinflammatory signaling cascades of periodontopathic oral pathogen Porphyromonas gingivalis. J Biosci Med 6(5):63–88Google Scholar
  67. Slomiany BL, Piotrowski J, Slomiany A (1997) Anti-Helicobacter pylori activities of ebrotidine. Arzneim Forsch Drug Res. 47:475–482Google Scholar
  68. Smith SM (2014) Role of Toll-like receptors in Helicobacter pylori infection and immunity. World J Gastrointest Pathophysiol 5:133–146CrossRefGoogle Scholar
  69. Steimle A, Autenrieth JB, Frick JS (2016) Structure and function: lipid A modifications in commensals and pathogens. Int J Med Microbiol 306:290–301CrossRefGoogle Scholar
  70. Surh YJ, Na HK (2016) Therapeutic potential and molecular targets of piceatannol in chronic diseases. Adv Exp Med Biol 928:185–211CrossRefGoogle Scholar
  71. Takashima K, Matsunaga N, Yoshimatsu M et al (2009) Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on muse sepsis model. Br J Pharmacol 157:1250–1262CrossRefGoogle Scholar
  72. Tombola F, Campello S, De Luca L et al (2003) Plant polyphenols inhibit VacA, a toxin secreted by the gastric pathogen Helicobacter pylori. FEBS Lett 543:184–189CrossRefGoogle Scholar
  73. Trent MS, Stead CM, Tran AX, Hankins JV (2006) Diversity of endotoxin and its impact on pathogenesis. J Endotox Res 12:205–223Google Scholar
  74. Venerito M, Krieger T, Ecker T, Leandro G, Malfertheiner P (2013) Meta-analysis of bismuth quadruple therapy versus clarithromycin triple therapy for empiric primary treatment of Helicobacter pylori infection. Digestion 88:33–45CrossRefGoogle Scholar
  75. Wang JG, Aikawa M (2015) Toll-like receptors and Src-family kinases in atherosclerosis—focus on macrophages. Circulation J 79:2332–2334CrossRefGoogle Scholar
  76. Wittebole X, Castanares-Zapatero D, Laterre PF (2010) Toll-like receptor-4 modulation as a strategy to treat sepsis. Mediat Inflamm 2010 (Article ID 568396) Google Scholar
  77. Yang WS, Lee J, Kim TW et al (2012) Src/NF-kB-targeted inhibition of LPS-induced macrophage activation and dextran sodium sulphate-induced colitis by Archidendron clypearia. J Ethnopharmacol 142:287–293CrossRefGoogle Scholar
  78. Yang WS, Jeong D, Nam G et al (2013a) AP-1 pathway-targeted inhibition of inflammatory responses in LPS-treated macrophages and EtOH/HCl-treated stomach by Archidendron clyperaria methanol extract. J Ethnopharmacol 146:637–644CrossRefGoogle Scholar
  79. Yang WS, Jeong D, Yi YS et al. (2013b) IRAK1/4-targeted anti-inflammatory action of caffeic acid. Mediat Inflamm 2013 (Article ID 518183) Google Scholar
  80. Yang Y, Yu T, Lee YG et al (2013c) Methanol extract of Hopea odorata suppresses inflammatory responses via the direct inhibition of multiple kinases. J Ethnopharmacol 145:598–607CrossRefGoogle Scholar
  81. Ye Y, Martinez JD, Perez-Polo RJ, Lin Y, Uretsky BF, Birnbaum Y (2008) The role of eNOS, iNOS, and NF-κB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastin. Am J Physil Heart Circ Physiol 295:H343–H351CrossRefGoogle Scholar
  82. Yi YS, Son YJ, Ryou C et al (2014) Functional roles of Syk in macrophage-mediated inflammatory responses. Mediat Inflamm 2014 (Article ID 270302) Google Scholar
  83. Yi YS, Cho JY, Kim D (2016) Cerbera manghas methanol extract exerts anti-inflammatory activity by targeting c-Jun N-terminal kinase in the AP-1 pathway. J Ethnopharmacol 193:387–396CrossRefGoogle Scholar
  84. Yoon JY, Jeong HY, Kim SH et al (2013) Methanol extract of Evodia lepta displays Syk/Src-targeted anti-inflammatory activity. J Ethnopharmacol 148:999–1007CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Research Center, C855, Rutgers School of Dental MedicineRutgers, The State University of New JerseyNewarkUSA

Personalised recommendations