Planta Med 2001; 67(5): 406-410
DOI: 10.1055/s-2001-15808
Original Paper
Pharmacology
© Georg Thieme Verlag Stuttgart · New York

Kaurane Diterpenes from Isodon japonicus Inhibit Nitric Oxide and Prostaglandin E2 Production and NF-κB Activation in LPS-Stimulated Macrophage RAW264.7 Cells

Bang Yeon Hwang1, 2 , Jeong-Hyung Lee1 , Tae Hyeon Koo1 , Hang Sub Kim1 , Young Soo Hong1 , Jai Seup Ro2 , Kyong Soon Lee2 , Jung Joon Lee1,*
  • 1 Anticancer Agents Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Taejon, Korea
  • 2 College of Pharmacy, Chungbuk National University, Cheongju, Korea
Further Information

Publication History

July 6, 2000

October 22, 2000

Publication Date:
31 December 2001 (online)

Abstract

A methanolic extract of the whole plant of Isodon japonicus (Labiatae) showed potent inhibition on the LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW264.7 cells. Four known kaurane diterpenes were isolated by activity-guided fractionation and their structures were identified as kamebanin (1), kamebacetal A (2), kamebakaurin (3), excisanin A (4). All compounds also inhibited the LPS-induced NF-κB activation as assessed by NF-κB reporter assay and electrophoretic mobility shift assay (EMSA). Compounds 2 - 4 showed comparable inhibitory effects on the LPS-induced production of NO and PGE2, and activation of NF-κB without affecting cell viability. These results suggest that kaurane diterpenes could exert their inhibitory effects on the production of NO and PGE2 through the suppression of NF-κB activation, and be partially responsible for the anti-inflammatory activities of the genus Isodon.

References

  • 1 Appleton I, Tomlinson A, Willoughby D A. Induction of cyclo-oxygenase and nitric oxide synthase in inflammation. In: August JT, Anders MW, Murad F, Coyle JT, editors Advances in pharmacology. Vol. 35 New York; Academic Press 1996: 26-78
  • 2 Anggard E. Nitric oxide: mediator, murderer, and medicine.  Lancet. 1994;  343 1199-206
  • 3 Lee S H, Soyoola E, Chanmugam P, Hart S, Sun W, Zhong H, Liou S, Simmons D, Hwang D. Selective expression of mitogen-inducible cyclooxygenase in macrophage stimulated with lipopolysaccharide.  Journal of Biological Chemistry. 1992;  191 1294-300
  • 4 Baeuerle P A, Baltimore D. NF-kappa B: ten years after.  Cell. 1996;  87 13-20
  • 5 Baeuerle P A, Henkel T. Function and activation of NF-kappa B in the immune system.  Annual Review of Immunology. 1994;  12 141-79
  • 6 Jung B S, Shin M K. Encyclopedia of illustrated Korean natural drugs. Seoul; Young Lim Sa 1989: 845-6
  • 7 Takeda Y, Ichihara T, Takaishi Y, Fujita T, Shingu T, Kusano G. Structural elucidation of new diterpenoids isolated from Rabdosia umbrosa var. leucantha f. kameba .  Journal of the Chemical Society, Perkin Transactions I. 1987;  2403-9
  • 8 Sun H D, Sun X C, Lin Z W, Xu Y L, Minami Y, Marunaka T, Fujita T. Excisanin A and B, new diterpenoids from Rhabdosia excisa .  Chemistry Letters. 1981;  753-6
  • 9 Schmidt H HHW, Kelm M. Determination of nitrite and nitrate by the Griess reaction.  In: Methods in Nitric Oxide Research. London; John Wiley & Sons Ltd. 1996: 491-7
  • 10 Scudiero D A, Shoemaker R H, Paull K D, Monks A, Tierney S, Nofziger T H, Currens M J, Seniff D, Boyd M R. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines.  Cancer Research. 1988;  48 4827-33
  • 11 Pradelles P, Grassi J, Maclouf J. Enzyme immunoassays of eicosanoids using acetylcholine esterase as label: an alternative to radioimmunoassay.  Analytical Chemistry. 1985;  57 1170-3
  • 12 Erkel G, Anke T, Sterner O. Inhibition of NF-kappa B activation by panepoxydone.  Biochemical and Biophysical Research Communications. 1996;  226 214-21
  • 13 Gilad E, Wong H R, Zingarelli B, Virag L, O'Connor M, Salzman A L, Szabo C. Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: role of inhibition of NF kappaB activation.  FASEB Journal. 1998;  12 685-93
  • 14 Salvemini D, Manning P T, Zweifel B S, Seibert K, Connor J, Currie M G, Needleman P, Masferrer J L. Dual inhibition of nitric oxide and prostaglandin production contributes to the anti-inflammatory properties of nitric oxide synthase inhibitors.  Journal of Clinical Investigation. 1995;  96 301-8
  • 15 Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin.  Science. 1994;  265 956-9
  • 16 Auphan N, DiDonato J A, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis.  Science. 1995;  270 286-90
  • 17 Rungeler P, Lyss G, Castro V, Mora G, Pahl H L, Merfort I. Study of three sesquiterpene lactones from Tithonia diversifolia on their anti-inflammatory activity using the transcription factor NF-kappa B and enzymes of the arachidonic acid pathway as targets.  Planta Medica. 1998;  64 588-93
  • 18 Zidorn C, Dirsch V M, Rungeler P, Sosa S, Della Loggia R, Merfort I, Pahl H L, Vollmar A M, Stuppner H. Anti-inflammatory activities of hypocretenolides from Leontodon hispidus .  Planta Medica. 1999;  65 704-8
  • 19 Hehner S P, Heinrich M, Bork P M, Vogt M, Ratter F, Lehmann V, Schulze-Osthoff K, Dröge W, Schmitz M L. Sesquiterpene lactones specifically inhibit activation of NF-kappa B by preventing the degradation of I kappa B-alpha and I kappa B-beta.  Journal of Biological Chemistry. 1998;  273 1288-97
  • 20 Lyss G, Knorre A, Schmidt T J, Pahl H L, Merfort I. The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65.  Journal of Biological Chemistry. 1998;  273 33508-16
  • 21 Rungeler P, Castro V, Mora G, Goren N, Vichnewski W, Pahl H L, Merfort I, Schmidt T J. Inhibition of transcription factor NF-kappaB by sesquiterpene lactones: a proposed molecular mechanism of action.  Bioogranic & Medicinal Chemistry. 1999;  7 2343-52
  • 22 Schmidt T J. Helenanolide-type sesquiterpene lactones-III. Rates and stereochemistry in the reaction of helenalin and related helenanolides with sulfhydryl containing biomolecules.  Bioorganic & Medicinal Chemistry. 1997;  5 645-53

Dr. Jung Joon Lee

Anticancer Agents Research Laboratory

Korea Research Institute of Bioscience and Biotechnology

P. O. Box 115

Yusong

Taejon 305-600

Korea

Email: jjlee@mail.kribb.re.kr

Fax: +82-42-860-4595