Skip to main content

Advertisement

SpringerLink
Log in

Geranylgeranylacetone Induces Cyclooxygenase-2 Expression in Cultured Rat Gastric Epithelial Cells Through NF-κB

  • Original Paper
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Geranylgeranylacetone (GGA) effectively protects the gastric mucosa against noxious agents. The precise mechanisms underlying the gastroprotective actions of GGA are not known. To elucidate the precise mechanism of GGA, the effect of GGA treatment on COX-2 expression in rat gastric epithelial (RGM1) cells was investigated. We used a prostaglandin E2 (PGE2) enzyme-linked immunoassay kit and Western blot analysis to measure PGE2 production and COX-2 induction by GGA treatment in serum-starved RGM1 cells. Gel-shift assay, Western blot analysis, and a reporter assay were performed to determine which COX-2 promoter was involved in GGA-induced COX-2 expression. GGA treatment dose dependently increased COX-2 expression and PGE2 production. The nuclear factor (NF)-κB sites of the COX-2 gene promoter were critical for GGA-mediated COX-2 expression. GGA induces COX-2 expression and increases PGE2 production in serum-starved RGM1 cells via activation of the NF-κB sites of COX-2 gene promoters.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Murakami M, Oketani K, Fujisaki H, Wakabayashi T, Ohgo T (1981) Antiulcer effect of geranylgeranylacetone, a new acyclic polyisoprenoid on experimentally induced gastric and duodenal ulcers in rats. Arzneimittelforschung 31:799–804

    PubMed  CAS  Google Scholar 

  2. Murakami M, Oketani K, Fujisaki H, Wakabayashi T (1982) Effect of geranylgeranylacetone (GGA) on gastric lesions induced by topical aspirin plus HCl. Jpn J Pharmacol 32:921–924

    PubMed  CAS  Google Scholar 

  3. Terano A, Shiga J, Mutoh H, Hiraishi H, Shiina S, Kurita M, Ota S, Itoh Y, Sugimoto T (1991) Tetraprenylacetone promotes healing process of ethanol-induced gastric damage in the rat. Jpn J Pharmacol 55:115–120

    PubMed  CAS  Google Scholar 

  4. Bilski J, Sarosiek J, Murty VL, Aono M, Moriga M, Slomiany A, Slomiany BL (1987) Enhancement of the lipid content and physical properties of gastric mucus by geranylgeranylacetone. Biochem Pharmacol 36:4059–4065

    Article  PubMed  CAS  Google Scholar 

  5. Ito M, Tanaka T, Suzuki Y (1986) Increasing action of teprenone, a new antiulcer agent, on high-molecular-weight glycoprotein in gastric mucus during the healing process of acetic acid-induced ulcer in rats. Jpn J Pharmacol 41:117–125

    PubMed  CAS  Google Scholar 

  6. Aono M, Moriga M, Mizuta K, Uchino H (1986) Effect of teprenone on the content of phospholipids in gastric secretion in man. Gastroenterol Jpn 21:454–458

    PubMed  CAS  Google Scholar 

  7. Nishisaki H, Sakamoto C, Konda Y, Nakano O, Matozaki T, Nagao M, Matsuda K, Wada K, Kasuga M (1992) Effects of antiulcer drugs on phosphatidylcholine synthesis in isolated guinea pig gastric glands. Dig Dis Sci 37:1593–1599

    Article  PubMed  CAS  Google Scholar 

  8. Hirakawa T, Rokutan K, Nikawa T, Kishi K (1996) Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. Gastroenterology 111:345–357

    Article  PubMed  CAS  Google Scholar 

  9. Yamagami K, Yamamoto Y, Ishikawa Y, Yonezawa K, Toyokuni S, Yamaoka Y (2000) Effects of geranyl-geranyl-acetone administration before heat shock preconditioning for conferring tolerance against ischemia-reperfusion injury in rat livers. J Lab Clin Med 135:465–475

    Article  PubMed  CAS  Google Scholar 

  10. Terano A, Hiraishi H, Ota S, Sugimoto T (1986) Geranylgeranylacetone, a novel anti-ulcer drug, stimulates mucus synthesis and secretion in rat gastric cultured cells. Digestion 33:206–210

    PubMed  CAS  Google Scholar 

  11. Nam SY, Kim N, Lee CS, Choi KD, Lee HS, Jung HC, Song IS (2005) Gastric mucosal protection via enhancement of MUC5AC and MUC6 by geranylgeranylacetone. Dig Dis Sci 50:2110–2120

    Article  PubMed  CAS  Google Scholar 

  12. Robert A, Nezamis JE, Lancaster C, Davis JP, Field SO, Hanchar AJ (1983) Mild irritants prevent gastric necrosis through “adaptive cytoprotection” mediated by prostaglandins. Am J Physiol 245:G113–G121

    PubMed  CAS  Google Scholar 

  13. Arakawa T, Nakamura A, Fukuda T, Higuchi K, Nakamura H, Kobayashi K (1990) In vitro adaptive cytoprotection in gastric cells isolated from rat stomach. J Clin Gastroenterol 12(Suppl 1):S32–S38

    Article  PubMed  Google Scholar 

  14. Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, Lee L, Isakson P (1994) Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA 91:12013–12017

    Article  PubMed  CAS  Google Scholar 

  15. Kargman S, Charleson S, Cartwright M, Frank J, Riendeau D, Mancini J, Evans J, O’Neill G (1996) Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts. Gastroenterology 111:445–454

    Article  PubMed  CAS  Google Scholar 

  16. Tsuji S, Kawano S, Sawaoka H, Takei Y, Kobayashi I, Nagano K, Fusamoto H, Kamada T (1996) Evidences for involvement of cyclooxygenase-2 in proliferation of two gastrointestinal cancer cell lines. Prostaglandins Leukot Essent Fatty Acids 55:179–183

    Article  PubMed  CAS  Google Scholar 

  17. Sawaoka H, Tsuji S, Tsujii M, Gunawan ES, Kawai N, Sasaki Y, Hori M, Kawano S (1999) Involvement of cyclooxygenase-2 in proliferation and morphogenesis induced by transforming growth factor alpha in gastric epithelial cells. Prostaglandins Leukot Essent Fatty Acids 61:315–322

    Article  PubMed  CAS  Google Scholar 

  18. Sun WH, Tsuji S, Tsujii M, Gunawan ES, Sawaoka H, Kawai N, Iijima H, Kimura A, Kakiuchi Y, Yasumaru M, Sasaki Y, Kawano S, Hori M (2000) Cyclo-oxygenase-2 inhibitors suppress epithelial cell kinetics and delay gastric wound healing in rats. J Gastroenterol Hepatol 15:752–761

    Article  PubMed  CAS  Google Scholar 

  19. Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T (1994) Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem 221:889–897

    Article  PubMed  CAS  Google Scholar 

  20. Appleby SB, Ristimaki A, Neilson K, Narko K, Hla T (1994) Structure of the human cyclo-oxygenase-2 gene. Biochem J 302(Pt 3):723–727

    PubMed  CAS  Google Scholar 

  21. Kobayashi I, Kawano S, Tsuji S, Matsui H, Nakama A, Sawaoka H, Masuda E, Takei Y, Nagano K, Fusamoto H, Ohno T, Fukutomi H, Kamada T (1996) RGM1, a cell line derived from normal gastric mucosa of rat. In Vitro Cell Dev Biol Anim 32:259–261

    PubMed  CAS  Google Scholar 

  22. Fu H, Yabe Y, Asahi K, Hayashi Y, Murata H, Eguchi H, Tsujii M, Tsuji S, Kawano S (2005) (2E,6Z,10E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol (Plaunotol) increases cyclooxygenase-2 expression via nuclear factor kappaB and cyclic AMP response element in rat gastric epithelial cells. Eur J Pharmacol 524:38–43

    Article  PubMed  CAS  Google Scholar 

  23. Murata H, Yabe Y, Tsuji S, Tsujii M, Fu HY, Asahi K, Eguchi H, Kawano S, Hayashi N (2005) Gastro-protective agent rebamipide induces cyclooxygenease-2 (COX-2) in gastric epithelial cells. Dig Dis Sci 50(Suppl 1):S70–S75

    Article  PubMed  CAS  Google Scholar 

  24. Inoue H, Tanabe T (1998) Transcriptional role of the nuclear factor kappa B site in the induction by lipopolysaccharide and suppression by dexamethasone of cyclooxygenase-2 in U937 cells. Biochem Biophys Res Commun 244:143–148

    Article  PubMed  CAS  Google Scholar 

  25. Fujiki M, Furukawa Y, Kobayashi H, Abe T, Ishii K, Uchida S, Kamida T (2005) Geranylgeranylacetone limits secondary injury, neuronal death, and progressive necrosis and cavitation after spinal cord injury. Brain Res 1053:175–184

    Article  PubMed  CAS  Google Scholar 

  26. Nakada J, Matsura T, Okazaki N, Nishida T, Togawa A, Minami Y, Inagaki Y, Ito H, Yamada K, Ishibe Y (2005) Oral administration of geranylgeranylacetone improves survival rate in a rat endotoxin shock model: administration timing and heat shock protein 70 induction. Shock 24:482–487

    Article  PubMed  CAS  Google Scholar 

  27. Zhu Z, Takahashi N, Ooie T, Shinohara T, Yamanaka K, Saikawa T (2005) Oral administration of geranylgeranylacetone blunts the endothelial dysfunction induced by ischemia and reperfusion in the rat heart. J Cardiovasc Pharmacol 45:555–562

    Article  PubMed  CAS  Google Scholar 

  28. Fujimoto M, Yamanaka T, Bessho M, Igarashi T (1982) Effects of geranylgeranylacetone on gastrointestinal secretion in rats. Eur J Pharmacol 77:113–118

    Article  PubMed  CAS  Google Scholar 

  29. Terano A, Shiga J, Hiraishi H, Ota S, Sugimoto T (1986) Protective action of tetraprenylacetone against ethanol-induced damage in rat gastric mucosa. Digestion 35:182–188

    PubMed  CAS  Google Scholar 

  30. Pappas TN, Mulvihill SJ, Goto Y, Debas HT (1987) Advances in drug therapy for peptic ulcer disease. Arch Surg 122:447–450

    PubMed  CAS  Google Scholar 

  31. Bilski J, Murty VL, Nadziejko C, Sarosiek J, Aono M, Moriga M, Slomiany A, Slomiany BL (1988) Protection against alcohol-induced gastric mucosal injury by geranylgeranylacetone: effect of indomethacin. Digestion 41:22–33

    Article  PubMed  CAS  Google Scholar 

  32. Sawaoka H, Tsuji S, Tsujii M, Gunawan ES, Nakama A, Takei Y, Nagano K, Matsui H, Kawano S, Hori M (1997) Expression of the cyclooxygenase-2 gene in gastric epithelium. J Clin Gastroenterol 25(Suppl 1):S105–S110

    Article  PubMed  Google Scholar 

  33. Fletcher BS, Kujubu DA, Perrin DM, Herschman HR (1992) Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10-encoded protein is a functional prostaglandin G/H synthase. J Biol Chem 267:4338–4344

    PubMed  CAS  Google Scholar 

  34. Sirois J, Levy LO, Simmons DL, Richards JS (1993) Characterization and hormonal regulation of the promoter of the rat prostaglandin endoperoxide synthase 2 gene in granulosa cells. Identification of functional and protein-binding regions. J Biol Chem 268:12199–12206

    PubMed  CAS  Google Scholar 

  35. Baldwin AS Jr (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683

    Article  CAS  Google Scholar 

  36. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716

    Article  PubMed  CAS  Google Scholar 

  37. Pai R, Szabo IL, Soreghan BA, Atay S, Kawanaka H, Tarnawski AS (2001) PGE(2) stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways. Biochem Biophys Res Commun 286:923–928

    Article  PubMed  CAS  Google Scholar 

  38. Jones MK, Kawanaka H, Baatar D, Szabo IL, Tsugawa K, Pai R, Koh GY, Kim I, Sarfeh IJ, Tarnawski AS (2001) Gene therapy for gastric ulcers with single local injection of naked DNA encoding VEGF and angiopoietin-1. Gastroenterology 121:1040–1047

    Article  PubMed  CAS  Google Scholar 

  39. Tarnawski A, Brzozowski T, Sarfeh IJ, Krause WJ, Ulich TR, Gergely H, Hollander D (1988) Prostaglandin protection of human isolated gastric glands against indomethacin and ethanol injury. Evidence for direct cellular action of prostaglandin. J Clin Invest 81:1081–1089

    Article  PubMed  CAS  Google Scholar 

  40. Ohkawara T, Takeda H, Nishiwaki M, Nishihira J, Asaka M (2006) Protective effects of heat shock protein 70 induced by geranylgeranylacetone on oxidative injury in rat intestinal epithelial cells. Scand J Gastroenterol 41:312–317

    Article  PubMed  CAS  Google Scholar 

  41. Ohkawara T, Nishihira J, Takeda H, Katsurada T, Kato K, Yoshiki T, Sugiyama T, Asaka M (2006) Protective effect of geranylgeranylacetone on trinitrobenzene sulfonic acid-induced colitis in mice. Int J Mol Med 17:229–234

    PubMed  CAS  Google Scholar 

  42. Zhang F, Hackett NR, Lam G, Cheng J, Pergolizzi R, Luo L, Shmelkov SV, Edelberg J, Crystal RG, Rafii S (2003) Green fluorescent protein selectively induces HSP70-mediated up-regulation of COX-2 expression in endothelial cells. Blood 102:2115–2121

    Article  PubMed  CAS  Google Scholar 

  43. Saika M, Ueyama T, Senba E (2000) Expression of immediate early genes, HSP70, and COX–2 mRNAs in rat stomach following ethanol ingestion. Dig Dis Sci 45:2455–2462

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory Science, School of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka, Japan

    Tsutomu Nishida, Yuki Yabe, Hai Ying Fu, Yujiro Hayashi, Kayoko Asahi, Hiroshi Eguchi & Sunao Kawano

  2. Department of Gastroenterology and Hepatology, Clinical Research Building (A8), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Tsutomu Nishida, Shingo Tsuji, Masahiko Tsujii & Norio Hayashi

Authors
  1. Tsutomu Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuki Yabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hai Ying Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yujiro Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kayoko Asahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroshi Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shingo Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masahiko Tsujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Norio Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sunao Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsutomu Nishida.

Additional information

The first two authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nishida, T., Yabe, Y., Fu, H.Y. et al. Geranylgeranylacetone Induces Cyclooxygenase-2 Expression in Cultured Rat Gastric Epithelial Cells Through NF-κB. Dig Dis Sci 52, 1890–1896 (2007). https://doi.org/10.1007/s10620-006-9661-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-006-9661-8

Keywords

Search

Navigation