Journal of Molecular Medicine

, Volume 85, Issue 6, pp 635–645 | Cite as

Local administration of WIN 55,212-2 reduces chronic granuloma-associated angiogenesis in rat by inhibiting NF-κB activation

  • Daniele De Filippis
  • Annapina Russo
  • Daniela De Stefano
  • Maria Chiara Maiuri
  • Giuseppe Esposito
  • Maria Pia Cinelli
  • Concetta Pietropaolo
  • Rosa Carnuccio
  • Giulia Russo
  • Teresa Iuvone
Original Article

Abstract

Chronic inflammation is often associated with granuloma formation that is a hallmark of many human diseases. The transcription factor nuclear factor-kappa B (NF-κB) plays a central role in this process by regulating the expression of several pro-inflammatory genes. Cannabinoids (CBs) from Cannabis sativa L. exert a large number of biological effects including anti-inflammatory and anti-angiogenic effects. In this study, we investigated the role of CBs on granuloma formation induced by λ-carrageenin-soaked sponge implant in rat. Our results show that local administration of WIN 55,212-2, a CB1/CB2 agonist, given daily or at time of implantation significantly decreased weight and neo-angiogenesis in granuloma tissue and inhibited nuclear factor-kappa B (NF-κB)/DNA binding that was associated with a reduced inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-α), and vascular endothelial growth factor (VEGF) messenger RNA (mRNA) and protein expression. Also, arachidonyl-2-chloroethylamide (ACEA), a CB1 selective agonist, and JWH-015, a CB2 selective agonist, exhibited the same effects that were reversed by SR141716-A and SR144528, respectively, CB1 and CB2 selective antagonists. These results indicate that CBs given locally may represent a potential therapeutic tool in controlling chronic inflammation avoiding psychotropic effects.

Keywords

Cannabinoids Chronic inflammation Angiogenesis Nuclear factor-kappa B 

References

  1. 1.
    Drapier JC, Petit JF (1986) Development of antitumor activity in LPS-stimulated mouse granuloma macrophage regulation by eicosanoids. Inflammation 10:195–204PubMedCrossRefGoogle Scholar
  2. 2.
    Colville-Nash PR, Alam CA, Appleton I, Brown JR, Seed MP, Willoughby DA (1995) The pharmacological modulation of angiogenesis in chronic granulomatous inflammation. J Pharmacol Exp Ther 274:1463–1472PubMedGoogle Scholar
  3. 3.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674PubMedCrossRefGoogle Scholar
  4. 4.
    Jackson JR, Bolognese B, Kircher CH, Marshall LA, Winkler JD (1997) Modulation of angiogenesis in a model of chronic inflammation. Inflamm Res 46:129–130CrossRefGoogle Scholar
  5. 5.
    Kobayashi SD, Voyich JM, Braughton KR, Whitney AR, Nauseef WM, Malech HL, DeLeo FR (2004) Gene expression profiling provides insight into the pathophysiology of chronic granulomatous disease. J Immunol 172:636–643PubMedGoogle Scholar
  6. 6.
    Tripp CS, Needleman P, Kassab JT, Weinstock JV (1988) Macrophages isolated from liver granulomas of murine Schistosoma mansoni synthesize predominantly TxA2 during the acute and chronic phases of infection. J Immunol 140:3140–3143PubMedGoogle Scholar
  7. 7.
    Martin-Padura I, De Castellarnau C, Uccini S, Pilozzi E, Natali PG, Nicotra MR, Ughi F, Azzolini C, Dejana E, Ruco L (1995) Expression of VE (vascular endothelial)-cadherin and other endothelial-specific markers in haemangiomas. J Pathol 175:51–57PubMedCrossRefGoogle Scholar
  8. 8.
    Russo A, Russo G, Peticca M, Pietropaolo C, Di Rosa M, Iuvone T (2004) Inhibition of granuloma-associated angiogenesis by controlling mast cell mediator release: role of mast cell protease-5. Br J Pharmacol 145:24–33CrossRefGoogle Scholar
  9. 9.
    Brown JF, Chafee KA, Tepperman BL (1998) Role of mast cells, neutrophils and nitric oxide in endotoxin-induced damage to the neonatal rat colon. Br J Pharmacol 123:31–38PubMedCrossRefGoogle Scholar
  10. 10.
    Maiuri MC, Tajana G, Iuvone T, De Stefano D, Mele G, Ribecco MT, Cinelli MP, Romano MF, Turco MC, Carnuccio R (2004) Nuclear factor-kappaB regulates inflammatory cell apoptosis and phagocytosis in rat carrageenin–sponge implant model. Am J Pathol 165:115–126PubMedGoogle Scholar
  11. 11.
    Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18:621–663PubMedCrossRefGoogle Scholar
  12. 12.
    Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop-Bailey D, Croxtall J, Willoughby DA (1994) Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci USA 91:2046–2050PubMedCrossRefGoogle Scholar
  13. 13.
    Kawachi S, Cockrell A, Laroux FS, Gray L, Granger DN, van der Heyde HC, Grisham MB, van der Heyde HC (1999) Role of inducible nitric oxide synthase in the regulation of VCAM-1 expression in gut inflammation. Am J Physiol 277:572–576Google Scholar
  14. 14.
    Campbell KJ, Perkins ND (2006) Regulation of NF-kappaB function. Biochem Soc Symp 73:165–180PubMedGoogle Scholar
  15. 15.
    Nocerino E, Amato M, Izzo AA (2002) Cannabis and cannabinoid receptors. Fitoterapia 71:6–12CrossRefGoogle Scholar
  16. 16.
    Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462PubMedCrossRefGoogle Scholar
  17. 17.
    Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 129–180Google Scholar
  18. 18.
    Matias I, Pochard P, Orlando P, Salzet M, Pestel J, Di Marzo V (2002) Presence and regulation of the endocannabinoid system in human dendritic cells. Eur J Biochem 269:3771–3778PubMedCrossRefGoogle Scholar
  19. 19.
    Do Y, McKallip RJ, Nagarkatti M, Nagarkatti PS (2004) Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation. J Immunol 173:2373–2382PubMedGoogle Scholar
  20. 20.
    Sacerdote P, Massi P, Panerai AE, Parolaro DJ (2000) In vivo and in vitro treatment with the synthetic cannabinoid CP55, 940 decreases the in vitro migration of macrophages in the rat: involvement of both CB1 and CB2 receptors. Neuroimmunology 109:155–163CrossRefGoogle Scholar
  21. 21.
    Klein TW (2005) Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 5:400–411PubMedCrossRefGoogle Scholar
  22. 22.
    Klein TW, Newton C, Larsen K, Chou J, Perkins I, Lu L, Nong L, Friedman H (2004) Cannabinoid receptors and T helper cells. J Neuroimmunol 147:91–94PubMedCrossRefGoogle Scholar
  23. 23.
    Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I (2006) Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci USA 103:696–701PubMedCrossRefGoogle Scholar
  24. 24.
    Ross RA, Brockie HC, Pertwee RG (2000) Inhibition of nitric oxide production in RAW 264.7 macrophages by cannabinoids and palmitoylethanolamide. Eur J Pharmacol 401:121–130PubMedCrossRefGoogle Scholar
  25. 25.
    Costa B, Colleoni M, Conti S, Parolaro D, Franke C, Trovato AE, Giagnoni G (2004) Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol 369:294–299PubMedCrossRefGoogle Scholar
  26. 26.
    Mbvundula EC, Bunning RA, Rainsford KD (2006) Arthritis and cannabinoids: HU-210 and Win-55,212-2 prevent IL-1alpha-induced matrix degradation in bovine articular chondrocytes in-vitro. J Pharm Pharmacol 58:351–358PubMedCrossRefGoogle Scholar
  27. 27.
    Blazquez C, Casanova ML, Planas A, Del Pulgar TG, Villanueva C, Fernandez-Acenero MJ, Aragones J, Huffman JW, Jorcano JL, Guzman M (2003) Inhibition of tumor angiogenesis by cannabinoids. FASEB J 7:529–531Google Scholar
  28. 28.
    Muramtsu M, Katada J, Hayashi I, Majama M (2000) Chymase as a proangiogenic factor. A possible involvement of chymase angiotensin dependent pathway in the hamster sponge angiogenesis model. J Biol Chem 275:5545–5552CrossRefGoogle Scholar
  29. 29.
    Mullane KM, Kraemer R, Smith B (1985) Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium. J Pharmacol Methods 14:157–167PubMedCrossRefGoogle Scholar
  30. 30.
    Gramolini AO, Belanger G, Thompson JM, Chakkalakal JV, Jasmin BJ (2001) Increased expression of utrophin in a slow vs a fast muscle involves posttranscriptional events. Am J Physiol Cell Physiol 281:1300–1309Google Scholar
  31. 31.
    Sancho R, Calzado MA, Di Marzo V, Appendino G, Munoz E (2003) Anandamide inhibits nuclear factor-kappaB activation through a cannabinoid receptor-independent pathway. Mol Pharmacol 63:429–438PubMedCrossRefGoogle Scholar
  32. 32.
    Juttler E, Potrovita I, Tarabin V, Prinz S, Dong-Si T, Fink G, dSchwaninger M (2004) The cannabinoid dexanabinol is an inhibitor of the nuclear factor-kappa B (NF-kappa B). Neuropharmacology 47:580–592PubMedCrossRefGoogle Scholar
  33. 33.
    Esposito G, De Filippis D, Maiuri MC, De Stefano D, Carnuccio R, Iuvone T (2006) Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci Lett 399:91–95PubMedCrossRefGoogle Scholar
  34. 34.
    Samson MT, Small-Howard A, Shimoda LM, Koblan-Huberson M, Stokes AJ, Turner HJ (2003) Differential roles of CB1 and CB2 cannabinoid receptors in mast cells. J Immunol 170:4953–4962PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Daniele De Filippis
    • 1
  • Annapina Russo
    • 2
  • Daniela De Stefano
    • 1
  • Maria Chiara Maiuri
    • 1
  • Giuseppe Esposito
    • 1
  • Maria Pia Cinelli
    • 3
  • Concetta Pietropaolo
    • 2
  • Rosa Carnuccio
    • 1
  • Giulia Russo
    • 2
  • Teresa Iuvone
    • 1
  1. 1.Dipartimento di Farmacologia SperimentaleUniversità degli Studi di Napoli “Federico II”NapoliItaly
  2. 2.Dipartimento di Biochimica e Biotecnologie MedicheUniversità degli Studi di Napoli “Federico II”NapoliItaly
  3. 3.Dipartimento di Scienze BiomorfologicheUniversità degli Studi di Napoli “Federico II”NapoliItaly

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