Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2000 Mar 15;346(Pt 3):793–798.

Cyclolinteinone, a sesterterpene from sponge Cacospongia linteiformis, prevents inducible nitric oxide synthase and inducible cyclo-oxygenase protein expression by blocking nuclear factor-kappaB activation in J774 macrophages.

F D'acquisto 1, V Lanzotti 1, R Carnuccio 1
PMCID: PMC1220914  PMID: 10698708

Abstract

We investigated the effect of cyclolinteinone, a sesterterpene from Caribbean sponge Cacospongia linteiformis, on inducible NO synthase (iNOS) and cyclo-oxygenase-2 (COX-2) protein expression in lipopolysaccharide (LPS)-stimulated J774 macrophages. Incubation of J774 cells with LPS (1 microgram/ml) caused an increase of both iNOS and COX-2 protein expression, which was prevented in a concentration-dependent fashion by cyclolinteinone (12.5, 25 and 50 microM). Electrophoretic mobility-shift assay indicated that cyclolinteinone blocked the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor necessary for either iNOS or COX-2 induction. Cyclolinteinone also blocked disappearance of I(kappa)B-alpha from cytosolic fraction and nuclear translocation of NF-kappaB subunits p50 and p65. These results show that cyclolinteinone down-regulates iNOS and COX-2 protein expression by inhibiting NF-kappaB activation and suggest that it may represent a novel anti-inflammatory compound capable of controlling the excessive production of prostaglandins and nitric oxide occurring in several inflammatory diseases.

Full Text

The Full Text of this article is available as a PDF (241.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. 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 Oct 13;270(5234):286–290. doi: 10.1126/science.270.5234.286. [DOI] [PubMed] [Google Scholar]
  2. Baeuerle P. A., Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. doi: 10.1146/annurev.iy.12.040194.001041. [DOI] [PubMed] [Google Scholar]
  3. D'Acquisto F., Iuvone T., Rombolà L., Sautebin L., Di Rosa M., Carnuccio R. Involvement of NF-kappaB in the regulation of cyclooxygenase-2 protein expression in LPS-stimulated J774 macrophages. FEBS Lett. 1997 Nov 24;418(1-2):175–178. doi: 10.1016/s0014-5793(97)01377-x. [DOI] [PubMed] [Google Scholar]
  4. D'Acquisto F., Sautebin L., Iuvone T., Di Rosa M., Carnuccio R. Prostaglandins prevent inducible nitric oxide synthase protein expression by inhibiting nuclear factor-kappaB activation in J774 macrophages. FEBS Lett. 1998 Nov 27;440(1-2):76–80. doi: 10.1016/s0014-5793(98)01407-0. [DOI] [PubMed] [Google Scholar]
  5. Faulkner D. J. Marine natural products. Nat Prod Rep. 1996 Apr;13(2):75–125. doi: 10.1039/np9961300075. [DOI] [PubMed] [Google Scholar]
  6. Fletcher B. S., Kujubu D. A., Perrin D. M., Herschman H. R. Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10-encoded protein is a functional prostaglandin G/H synthase. J Biol Chem. 1992 Mar 5;267(7):4338–4344. [PubMed] [Google Scholar]
  7. García Pastor P., De Rosa S., De Giulio A., Payá M., Alcaraz M. J. Modulation of acute and chronic inflammatory processes by cacospongionolide B, a novel inhibitor of human synovial phospholipase A2. Br J Pharmacol. 1999 Jan;126(1):301–311. doi: 10.1038/sj.bjp.0702302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ialenti A., Ianaro A., Moncada S., Di Rosa M. Modulation of acute inflammation by endogenous nitric oxide. Eur J Pharmacol. 1992 Feb 11;211(2):177–182. doi: 10.1016/0014-2999(92)90526-a. [DOI] [PubMed] [Google Scholar]
  9. Ialenti A., Moncada S., Di Rosa M. Modulation of adjuvant arthritis by endogenous nitric oxide. Br J Pharmacol. 1993 Oct;110(2):701–706. doi: 10.1111/j.1476-5381.1993.tb13868.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Iuvone T., Carnuccio R., Di Rosa M. Modulation of granuloma formation by endogenous nitric oxide. Eur J Pharmacol. 1994 Nov 14;265(1-2):89–92. doi: 10.1016/0014-2999(94)90227-5. [DOI] [PubMed] [Google Scholar]
  11. Kopp E., Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science. 1994 Aug 12;265(5174):956–959. doi: 10.1126/science.8052854. [DOI] [PubMed] [Google Scholar]
  12. Kosaka T., Miyata A., Ihara H., Hara S., Sugimoto T., Takeda O., Takahashi E., Tanabe T. Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem. 1994 May 1;221(3):889–897. doi: 10.1111/j.1432-1033.1994.tb18804.x. [DOI] [PubMed] [Google Scholar]
  13. 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 macrophages stimulated with lipopolysaccharide. J Biol Chem. 1992 Dec 25;267(36):25934–25938. [PubMed] [Google Scholar]
  14. Maier J. A., Hla T., Maciag T. Cyclooxygenase is an immediate-early gene induced by interleukin-1 in human endothelial cells. J Biol Chem. 1990 Jul 5;265(19):10805–10808. [PubMed] [Google Scholar]
  15. Mitchell J. A., Akarasereenont P., Thiemermann C., Flower R. J., Vane J. R. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11693–11697. doi: 10.1073/pnas.90.24.11693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  17. Riehemann K., Behnke B., Schulze-Osthoff K. Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB. FEBS Lett. 1999 Jan 8;442(1):89–94. doi: 10.1016/s0014-5793(98)01622-6. [DOI] [PubMed] [Google Scholar]
  18. Rüngeler 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 Med. 1998 Oct;64(7):588–593. doi: 10.1055/s-2006-957527. [DOI] [PubMed] [Google Scholar]
  19. 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 antiinflammatory properties of nitric oxide synthase inhibitors. J Clin Invest. 1995 Jul;96(1):301–308. doi: 10.1172/JCI118035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Schmidt H. H., Walter U. NO at work. Cell. 1994 Sep 23;78(6):919–925. doi: 10.1016/0092-8674(94)90267-4. [DOI] [PubMed] [Google Scholar]
  21. Schreck R., Meier B., Männel D. N., Dröge W., Baeuerle P. A. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med. 1992 May 1;175(5):1181–1194. doi: 10.1084/jem.175.5.1181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Sirois J., Levy L. O., Simmons D. L., Richards J. S. 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. 1993 Jun 5;268(16):12199–12206. [PubMed] [Google Scholar]
  23. Thanos D., Maniatis T. NF-kappa B: a lesson in family values. Cell. 1995 Feb 24;80(4):529–532. doi: 10.1016/0092-8674(95)90506-5. [DOI] [PubMed] [Google Scholar]
  24. Tomlinson A., Appleton I., Moore A. R., Gilroy D. W., Willis D., Mitchell J. A., Willoughby D. A. Cyclo-oxygenase and nitric oxide synthase isoforms in rat carrageenin-induced pleurisy. Br J Pharmacol. 1994 Nov;113(3):693–698. doi: 10.1111/j.1476-5381.1994.tb17048.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Vane J. Towards a better aspirin. Nature. 1994 Jan 20;367(6460):215–216. doi: 10.1038/367215a0. [DOI] [PubMed] [Google Scholar]
  26. Walker G., Kunz D., Pignat W., van den Bosch H., Pfeilschifter J. Pyrrolidine dithiocarbamate differentially affects cytokine- and cAMP-induced expression of group II phospholipase A2 in rat renal mesangial cells. FEBS Lett. 1995 May 8;364(2):218–222. doi: 10.1016/0014-5793(95)00402-u. [DOI] [PubMed] [Google Scholar]
  27. Weisz A., Oguchi S., Cicatiello L., Esumi H. Dual mechanism for the control of inducible-type NO synthase gene expression in macrophages during activation by interferon-gamma and bacterial lipopolysaccharide. Transcriptional and post-transcriptional regulation. J Biol Chem. 1994 Mar 18;269(11):8324–8333. [PubMed] [Google Scholar]
  28. Xie Q. W., Kashiwabara Y., Nathan C. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem. 1994 Feb 18;269(7):4705–4708. [PubMed] [Google Scholar]
  29. Yamamoto K., Arakawa T., Ueda N., Yamamoto S. Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells. J Biol Chem. 1995 Dec 29;270(52):31315–31320. doi: 10.1074/jbc.270.52.31315. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES