Share This Article:

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

Abstract Full-Text HTML Download Download as PDF (Size:998KB) PP. 1-10
DOI: 10.4236/ojcb.2011.11001    1,799 Downloads   3,834 Views   Citations

ABSTRACT

Excessive nitric oxide generation, caused by the disturbances in nitric oxide synthase (NOS) isozyme system, plays a key role in defining the extent of gastric mucosal inflammatory response to H. pylori infection. Here, we report that H. pylori LPS-induced enhancement in gastric mucosal inducible (i) iNOS expression and the impairment in constitutive (c) cNOS activity was associated with up-regulation in the inhibitory kB kinase-β (IKK?β) activation through phosphorylation, rise in IκB-α degradation, and the increase in the transcriptional factor, NF-κB, nuclear translocation. Further, we show that the countering effect of peptide hormone, ghrelin, on the LPS-induced disturbances in NOS isozyme system was reflected in the increase in Src/Akt-dependent cNOS activation through phosphorylation and the suppression of IKK-β activity through cNOSmediated IKK-β protein S-nitrosylation. As a consequence, ghrelin exerted the inhibitory effect on the LPS-induced rise in IκB-α degradation and NF-κB nuclear translocation, thus leading to iNOS gene suppression and the repression of iNOS induction. These results point to a central role of cNOS activation in controlling the signaling pathways of the LPS-triggered iNOS gene induction. Moreover, our findings suggest a molecular mechanism by which ghrelin suppresses the gastric mucosal proinflammatory consequences of H. pylori infection.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

B. Slomiany and A. Slomiany, "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," CellBio, Vol. 1 No. 1, 2011, pp. 1-10. doi: 10.4236/ojcb.2011.11001.

References

[1] M. Stolte and S. Edit, “Helicobacter Pylori and Evolution of Gastritis,” Scandinavian Journal of Gastro-enterology, Vol. 31, No. 214, 1996, pp. 13-16. doi:10.3109/00365529609094508
[2] J. Piotrowski, E. Piotrowski, D. Skrodzka, A. Slomiany and B. L. Slomiany, “Induction of Acute Gastritis and Epithelial Cell Apoptosis by Helicobacter pylori lipopolysaccharide,” Scandinavian Journal of Gastroenterology, Vol. 32, 1997, pp. 203-211. doi:10.3109/00365529709000195
[3] W. A. de Boer, “Helicobacter Pylori Infection: Focus on a ‘Search-And-Treat’ Strategy for Ulcer Disease,” Scandinavian Journal of Gastroenterology, Vol. 35, No. 232, 2000, pp. 4-9.
[4] F. Fu, K. S. Ramanujan, A. Wong, et al., “Increased Expression and Cellular Localization of Inducible Nitric Oxide Synthase and Cyclooxygenase-2 in Helicobacter pylori Gastritis,” Gastroenterology, Vol. 116, No. 6, 1999 pp. 1319-1329. doi:10.1016/S0016-5085(99)70496-8
[5] B. L. Slomiany, J. Piotrowski and A. Slomiany, “Gastric Mucosal Inflammatory Responses to Helicobacter pylori lipopolysaccharide: Down-Regulation of Nitric Oxide Synthase-2 and Caspase-3 by Sulglycotide,” Biochemicaland Biophysical Research Communications, Vol. 261, No. 1, 1999, pp. 15-20. doi:10.1006/bbrc.1999.1003
[6] R. A. Gupta, D. B. Polk, U. Krishna, et al., “Activation of Peroxisome Proliferator-Activated Receptor g Suppresses Nuclear Factor kB-Mediated Apoptosis Induced by Helicobacter pylori in Gastric Epithelial Cells,” Journal of Biological Chemistry, Vol. 276, No. 33, 2001, pp. 31059-31066. doi:10.1074/jbc.M104141200
[7] G. Reider, J. A. Hofmann, R. A. Hatz, M. Stolte and G. A. Enders, “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,” International Journal of Medical Microbiology, Vol. 293, No. 6, 2003, pp. 403-412. doi:10.1078/1438-4221-00280
[8] S. Cuzzocrea and D. Salvemini, “Molecular Mechanisms Involved in the Reciprocal Regulation of Cyclooxy-Genase and Nitric Oxide Synthase Enzymes,” Kidney International, Vol. 71, No. 4, 2007, pp. 290-297. doi:10.1038/sj.ki.5002058
[9] B. L. Slomiany and A. Slomiany, “Helicobacter pylori Induces Disturbances in Gastric Mucosal Akt Activation through Inducible Nitric Oxide Syn-Thase-Dependent S-Nitrosylation: Effect of Ghrelin,” ISRN Gastroenterology, Article No. 308727, 2010. doi:10.5402/2011
[10] S. Brandt, T. Kwok, R. Harting, W. Konig and S. Backert, “NF-κB Activation and Potentiation of Proinflammatory Responses by the Helicobacter pylori CagA Protein,” Proceedings of the National Academy of Sciences of the USA, Vol. 102, No. 26, 2005, pp. 9300-9305. doi:10.1073/pnas.0409873102
[11] R. L. Ferrero, P. Ave, D. Nadiaye, et al., “NF-kB Activation During Acute Helicobacter pylori Infection in Mice,” Infection and Immunity, Vol. 76, No. 2, 2008, pp. 551-561. doi:10.1128/IAI.01107-07
[12] S. Backert and M. Neumann, “What a Disorder: ProinFlammatory Signaling Pathways Induced by Helicobacter pylori,” Trends in Microbiology, Vol. 18, No. 11, 2010, pp. 479-486. doi:10.1016/j.tim.2010.08.003
[13] K. W. Kang, S. Y. Choi, M. K. Cho, C. C. Lee and S. G. Kim, “Thrombin Induces Nitric-Oxide Synthase via Ga12/13-Coupled Protein Kinase C-Dependent I-kBa Phos-phorylation and JNK-Mediated I-kBa Degradation,” Journal of Biological Chemistry, Vol. 278, 2003, pp. 17368-17378. doi:10.1074/jbc.M300471200
[14] K. Singh, R. Chaturvedi, M. Asim, D. P. Barry, N. D. Lewis, M. P. Vitek and K. T. Wilson, “The Apolipoprotein E-Mimetic Peptide COG112 Inhibits the Inflammatory Response to Citrobacter rodentium in Colonic Epithelial Cells by Preventing NF-kB Activation,” Journal of Biological Chemistry, Vol. 283, No. 24, 2008, pp. 16752-16761. doi:10.1074/jbc.M710530200
[15] H. Tanaka, N. Fujita and T. Tsuruo, “3-Phospho-Inositide-Dependent Protein Kinase-1-Mediated IκB Kinase β (IKKB) Phosphorylation Activates NF-κB Signaling,” Journal of Biological Chemistry, Vol. 280, No. 49, 2005, pp. 40965-40973. doi:10.1074/jbc.M506235200
[16] J. L. Kang, H. W. Lee, H. J. Kim, H. S. Lee, V. Castranova, C. M. Lim and Y. Koh, “Inhibition of Src Tyrosine Kinase β Suppresses Activation of Nuclear Factor-kB, and Serine and Tyrosine Phosphorylation of IκB-a in Lipopolysaccharide-Stimulated Raw 264.7 Macrophages,” Journal of Toxicology and Environmental Health, Part A, Vol. 68, 2005, pp. 1643-1662. doi:10.1080/15287390500192114
[17] S. C. Gupta, S. Prasad, S. Reuter, et al., “Modification of Cysteine 179 of IkBa Kinase by Nimbolide Leads to Down-Regulation of NF-kB-Regulated Cell Survival and Proliferative Proteins and Sensitization of Tumor Cells to Chemotherapeutic Agents, Journal of Biological Chemistry, Vol. 285, No. 46, 2010, pp. 35406-35417. doi:10.1074/jbc.M110.161984
[18] H. Nakano, M. Shinodo, S. Sakon, S. Nishinaka, M. Mihara, H. Yagita and K. Okumura, “Differential Regulation of IκB Kinase a and b by Two Upstreamkinases, NF-κB-Inducing Kinase and Mitogen-Activated Protein Kinase/ERK Kinase-1,” Proceedings of the National Academy of Sciences of the USA, Vol. 95, 1998, pp. 3537-3542. doi:10.1073/pnas.95.7.3537
[19] S. Gosh and M. Karin, “Missing Pieces in the NF-κB Puzzle,” Cell, Vol. 109, 2002, pp. S81-S96. doi:10.1016/S0092-8674(02)00703-1
[20] C. Rieke, A. Papendieck, O. Sokolova and M. Naumann, “Helicobacter pylori-Induced Tyrosine Phosphorylation of IKKβ Contributes to NF-κB Activation,” Biological Chemistry, Vol. 392, 2011, pp. 387-393. doi:10.1515/BC.2011.029
[21] N. L. Reynaert, K. Ckless, S. H. Korn, et al., “Nitric Oxide Represses Inhibitory κB Kinase through S-Nitrosylation,” Proceedings National Academy of Sciences of the USA, Vol. 101, No. 24, 2004, pp. 8945-8950. doi:10.1073/pnas.0400588101
[22] N. D. Perkins, “Integrating Cell-Signalling Path Ways with NF- and IKK Function,” Nature Reviews Molecular Cell Biology, Vol. 8, No. 1, 2007, pp. 49-62. doi:10.1038/nrm2083
[23] M. Kojima, H. Hosoda, Y. Date, M. Nakazato and K. Kangawa, “Ghrelin is a Growth-Hormone-Releasing Acylated Peptide from Stomach,” Nature, Vol. 402, No. 6762, 1999, pp. 656-660. doi:10.1038/45230
[24] X. Xu, B. S. Jhun, C. H. Ha and Z. G. Jin, “Molecular Mechanisms of Ghrelin-Mediated Endothelial Nitric-Oxide Synthase Activation. Endocrinology, Vol. 149, No. 8, 2008, pp. 4183-4192. doi:10.1210/en.2008-0255
[25] B. L. Slomiany and A. Slomiany, “Ghrelin Protection against Lipopolysaccharide-Induced Gastric Mucosal Cell Apoptosis Involves Constitutive Nitric Oxide Synthase-Mediated Caspase-3 S-Nitrosylation,” Mediators of Inflammation, 2010. doi:1155/2010/280464
[26] B. L. Slomiany and A. Slomiany, “Role of Ghrelin-Induced cSrc Activation in Modulation of Gastric Mucosal Inflammatory Responses to Helicobacter pylori,” Inflammopharmacology, Vol. 19, No. 4, 2011, pp. 197-204.
[27] A. Slomiany and B. L. Slomiany, “Transformations of Phosphatidyl-Inositol Phosphates in the Outer and Inner Nuclear Membrane are Linked to Synthesis and Restitution of Cellular Membranes,” Health, Vol. 3, No. 4, 2011, pp. 187-199. doi:10.4236/health.2011.34035
[28] S. M. Noha, A. G. Atanasov, D. Schuster, et al., “Discovery of a Novel IKK-b Inhibitor by Ligand-Based Virtual Screening Techniques,” Bioorganic and Medicinal Chemistry Letters, Vol. 21, 2011, pp. 577-583. doi:10.1016/j.bmcl.2010.10.051
[29] S. R. Jaffrey, H. Erdjument-Bromage, D. Ferris, P. Tempst and S. H. Snyder, “Protein S-Nitrosylation: A Physiological Signal for Neuronal Nitric Acid,” Nature Cell Biology, Vol. 3, No. 2, 2001, pp. 193-197. doi:10.1038/35055104
[30] M. T. Forrester, M. W. Foster and J. S. Stamler, “Assessment and Application of the Biotin Switch Technique for Examining Protein S-Nitrosylation under Conditions of Pharmacologically Induced Oxidative Stress,” Journal of Biological Chemistry, Vol. 282, No. 19, 2007, pp. 13977-13983. doi:10.1074/jbc.M609684200
[31] H. E. Marshall, D. T. Hess and J. S. Stamler, “S-Nitrosylation: Physiological Regulation of NF-κB,” Proceedings of the National Academy of Sciences of the USA, Vol. 101, 2004, pp. 8841-8842. doi:10.1073/pnas.0403034101
[32] R. Korhonen, A. Lahti, H. Kankaanranta and E. Moilanen, “Nitric Oxide Production and Signaling in Inflammation,” Current Drug Targets: Inflammation and Allergy, Vol. 4, No. 4, 2005, pp. 471-479. doi:10.2174/1568010054526359
[33] B. L. Slomiany and A. Slomiany, “Ghrelin Suppression of Helicobacter pylori-Induced S-Nitrosylation-Dependent Gastric Mucosal Akt Inactivation Exerts Modulatory Influence on Gastric Mucin Synthesis,” Inflammopharmacology, Vol. 19, 2011, pp. 89-97. doi:10.1007/s10787-011-0078-4
[34] P. Lodeiro, M. Theodoropoulou, M. Pardo, F. F. Casa-nueva and J. P. Camina, “C-Src Regulates Akt Signaling in Response to Ghrelin via β-Arrestin Signaling-Independent and -Dependent Mechanism,” PLoS ONE, Vol. 4, No. 3, 2009, p.e4686.

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.