Anti-inflammatory Effect of Citrus Unshiu

진피(陳皮)의 염증 억제 효과

  • Park, Seong-Heak (Dept. of Oriental Rehabilitation Medicine, College of Oriental Medicine, Won-Kwang University) ;
  • Yun, Sang-Hak (Dept. of Oriental Rehabilitation Medicine, College of Oriental Medicine, Won-Kwang University) ;
  • Kwon, Young-Mi (Radiology, College of Oriental Medicine, Won-Kwang University) ;
  • Yeom, Seung-Ryong (Dept. of Oriental Rehabilitation Medicine, College of Oriental Medicine, Won-Kwang University) ;
  • Kwon, Young-Dal (Dept. of Oriental Rehabilitation Medicine, College of Oriental Medicine, Won-Kwang University) ;
  • Shin, Byung-Cheul (Dept. of Oriental Rehabilitation Medicine, College of Oriental Medicine, Won-Kwang University)
  • 박성혁 (원광대학교 한의과대학 한방재활의학과교실) ;
  • 윤상학 (원광대학교 한의과대학 한방재활의학과교실) ;
  • 권영미 (원광대학교 한의과대학 방사선과) ;
  • 염승룡 (원광대학교 한의과대학 한방재활의학과교실) ;
  • 권영달 (원광대학교 한의과대학 한방재활의학과교실) ;
  • 신병철 (원광대학교 한의과대학 한방재활의학과교실)
  • Received : 2004.12.23
  • Accepted : 2005.01.17
  • Published : 2005.01.30

Abstract

목적 : 진피(Citus Unshiu, CU)는 실험적으로 항산화, 항알러지, 항종양 효과 등이 있다고 보고되고 있다. 본 연구에서는 비만세포에서 PMA와 A23187에 의하여 유도된 싸이토카인의 증가에 대한 진피 추출물의 억제 효과와 그 기전을 알아보고자 한다. 방법 : PMA+A23187에 의한 싸이토카인 생성에 대한 진피 추출물의 억제효과 기전을 조사하기 위하여 진피를 처리한 후 $IL-1{\beta}$, IL-8, $TNF-{\alpha}$의 생산 및 혈관내피성장인자 (VEGF), 과립구 대식구 군집 자극 인자 (GM-CSF), 저산소 유도 인자(HIF-1)의 발현을 조사하였다. 결과 : 실험에서 PMA와 A23187을 처리한 경우 대조군에 비하여 $IL-1{\beta}$, IL-8, $TNF-{\alpha}$의 생산을 유의하게 증가시켰으나 진피 추출물을 처리한 군에서는 유의하게 억제되었다. 특히 $IL-1{\beta}$의 생성은 $103.7{\pm}5%$, IL-8 생성은 $34.6{\pm}7%$, $TNF-{\alpha}$의 생성은 $85.9{\pm}4.5%$ 억제되었다. (P<0.05). 또한 진피 추출물은 PMA와 A23187에 의하여 증가한 VEGF, GM-CSF, $HIF-1{\alpha}$의 발현 증가를 억제하였다 (약 90.9%의 VEGF, 61.6%의 GM-CSF). 결론 : 이러한 결과는 진피가 염증반응에 대한 HIF-1의 억제자로 작용할 수 있으면, 진피가 비만세포 매개성 염증 질환 치료제의 후보 물질이 될 것으로 사료된다.

Keywords

References

  1. J Agric Food Chem. v.52 no.11 Effect of heat treatment on the antioxidant activity of extracts from citrus peels Jeong, S.M.;Kim, D.R.;Jo, S.C.;Nam, K.C.;Ahn, D.U.;Lee, S.C.
  2. Ady Immunol. v.55 The kit ligand, stem cell factor Galli, S.J.;Zsebo, K.M.;Geissler, E.N.
  3. Curr Pharm Des. v.10 no.15 Modulation of the Fcepsilon receptor I signaling by tyrosine kinase inhibitors: search for therapeutic targets of inflammatory and allergy diseases Luskova, P.;Draber, P.
  4. Arch Immunol Ther Exp(Warsz). v.50 no.3 Mast cells and inflammation Stassen, M.;Hultner, L.;Muller, C.;Schmitt, E.
  5. J Im-munol. v.151 Immunolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, IL-6 in human allergic mucosal inflammation Bradding, P.;Feather, I.H.;Wilson, S.;Bardin, P.G.;Heusser, C.H.;Holgate, S.T.;Howarth, P.H.J.
  6. Nature. v.339 Mast cell lines produce lymphokines in response to cross-linkage of Fc epsilon RI or to calcium ionophores Plaut, M.;Pierce, J.H.;Watson, C.J.;Hanley-Hyde, J.;Nordan, R.P.;Paul, W.E.
  7. Nature. v.339 Production of the haemopoietic growth factors GM-CSF and interleukin-3 by mast cell in re-sponse to IgE receptor-mediated activation Wodnar-Filipowicz, A.;Heusser, C.H.;Moroni, C.
  8. J Immunol. v.172 no.2 Prostaglandin E2 induces degranulation-independent production of vascular endothelial growth factor by human mast cells Abdel-Majid, R.M.;Marshall, J.S.
  9. APMIS. v.110 no.5 Mast cells and angiogenesis Norrby, K.
  10. Int Immunopharmacol. v.4 no.12 Angiogenesis as an immunopharma-cologic target in inflammation and cancer Bian, X.W.;Chen, J.H.;Jiang, X.F.;Bai, J.S.;Wang, Q.L.;Zhang, X.
  11. J Biol Chem. v.268 Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia Wang, G.L.;Semenza, G.L.
  12. Blood. v.82 Desferrioxamine induces erythropoietin gene expression and hypoxiainducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction Wang, G.L.;Semenza, G.L.
  13. J Biol Chem. v.276 Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP Yamashita, K.;Discher, D.J.;Hu, J.;Bishopric, N.H.;Webster, K.A.
  14. J Biol Chem. v.270 Purification and characterization of hypoxia-inducible factor 1 Wang, G.L.;Semenza, G.L.
  15. J Biol Chem. v.269 Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1 Semenza, G.L.;Roth, P.H.;Fng, H.M.;Wang, G.L.
  16. Agric Biol Chem. v.54 no.11 Toxicity of dimethyl sulfoxide as a solvent in bioassay system with HeLa cells evaluatedcolormetrically with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-te-trazolium bromide Ben Trivedi, A.;Kitabatake, N.;Doi, E.
  17. Endocrinology. v.144 no.9 Inhibition of the stem cell factor-induced migration of mast cells by dexamethasone Jeong, H.J.;Na, H.J.;Hong, S.H.;Kim, H.M.
  18. Curr Drug Targets Infglamm Allergy. v.2 no.4 GM-CSF and dendritic cells in allergic airway inflamma-tion: basic mechanisms and prospects for thera-peutic intervention Gajewska, B.U.;Wiley, R.E.;Jordana, M.
  19. Cancer Res. v.60 no.18 Inhigbitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice Murakami, A.;Nakamura, Y.;Torikai, K.;Tanaka, T.;Koshiba, T.;Koshimizu, K.;Kuwahara, S.;Takahashi, Y.;Ogawa, K.;Yano, M.;Tokuda, H.;Nishino, H.;Mimaki, Y.;Sashida, Y.;Kitanaka, S.;Ohigashi, H.
  20. Yakugaku Zasshi. v.109 no.11 Pharmacological study on citrus fruits. I. Anti-allergic effect of fruit of Citrus unshiu Markovich Kubo, M.;Yano, M.;Matsuda, H.
  21. Clin Exp Allergy. v.27 no.9 Seasonal allergic conjunctivitis is accompanied by in-creased mast cell numbers in the absence of leucocyte infiltration Anderson, D.F.;MacLeod, J.D.;Baddeley, S.M.;Bacon, A.S.;McGill, J.I.;Holgate, S.T.;Roche, W.R.
  22. Proc Natl Acad Sci U S A. v.94 no.17 Chymase cleavage of stem cell factor yields a bioactive, soluble product Longley, B.J.;Tyrrell, L.;Ma, Y.;Williams, D.A.;Halaban, R.;Langley, K.;Lu, H.S.;Schechter, N.M.
  23. Inflammation. v.25 Transient exposure of human bronchial epithelial cells to cytokines leads to persistent increased expression of ICAM-1 Subauste, M.C.;Choi, D.C.;Pround, D.
  24. Curr Drug Targets. v.5 Cytokines in neuroinflammation and Alzhei-mer's disease Cacquevel, M.;Lebeurrier, N.;Cheenne, S.;Vivien, D.
  25. Mol Biotechnol. v.19 no.2 Anti-TNF therapy for rheumatoid arthritis and other inflammatory diseases Taylor, P.C.
  26. Rheum Dis Clin North Am. v.27 no.2 Tumor necrosis factor-alpha blockade in the treatment of rheumatoid arthritis Keystone, E.C.
  27. Mol Endocrinol. v.10 Involvment of CCAAT/enhancer-binding protein and nuclear factor-kappa B binding site in interleukin-6 pro-moter inhibition by estrogens Galien, R.;Evans, H.F.;Garcia, T.
  28. Dev Immunol. v.7 Adhesion of immature and mature T cells induces in human thymic epithelial cells (TEC) activation of IL-6 gene trascription factors (NF-kappaB AND NF-IL6) and IL-6 gene expression: role of alpha3betal and alpha6beta4 integrins Fiorini, E.;Marchisio, P.C.;Scupoli, M.T.;Poffe, O.;Tagliabue, E.;Brentegani, M.;Colombatti, M.;Santini, F.;Tridente, G.;Ramarli, D.
  29. Immunol Today. v.15 NF-ATp: a transcription factor required for the co-ordinate induction of several cytokine genes Rao, A.
  30. Biochem Biophys Res Commun. v.306 Expression of proinflammatory cytokines via HIF-1alpha and NF-kappaB activation on desferrioxamine-stimulated HMC-1 cells Jeong, H.J.;Chung, H.S.;Lee, B.R.;Kim, S.J.;Yoo, S.J.;Hong, S.H.;Kim, H.M.
  31. J Allergy Clin Immunol. v.89 Cytokines in symptomatic asthma airways Broide, D.H.;Lotz, M.;Cuomo, A.J.;Coburm, D.A.;Federman, E.C.;Wasserman, S.I.
  32. Ann Allergy Asthma Immunol. v.82 Analysis of induced sputum to examine the effects of inhaled corti-costeroid on airway inflammation in children with asthma Oh, J.W.;Lee, H.B.;Kim, C.R.;Yum, M.K.;Koh, Y.J.;Moon, S.J.;Kang, J.O.;Park, I.L.
  33. J Physiol. v.260 A bronchial epithelial cell-derived factor in asthma that promotes eosinophil activation and survival as GW-CSF Soloperto, M.;Mattoso, V.L.;Fasoli, A.;Mattoli, S.
  34. Am J Respir Cell Mol Biol. v.4 Promotion of eosinophil survival by human bronchial epithelial cells and its modulation by steroids Cox, G.;Ohtoshi, T.;Vancheri, C.;Denburg, J.A.;Dolovich, J.Gauldie, J.;Jordana, M.
  35. Respiration. v.59 no.4 Airway epithelial cells enhance eosinophil survival Masuda, T.;Suda, Y.;Shimura, S.;Maruyama, N.;Aizawa, T.;Tamura, G.;Sasaki, H.;Takishima, T.
  36. J Allergy Clin Immunol. v.103 Evaluation of apoptosis of eosinophils, macrophages, and T lymphocytes in mucosal biopsy specimens of patients with asthma and chronic bronchitis Vignola, A.M.;Chanez, P.;Chiappara, G.;Siena, L.;Merendino, A.;Reina, C.;Gagliardo, R.;Profita, M.;Bousquet, J.;Bonsignore, G.
  37. Am J Respir Cell Mol Biol. v.21 Mechanisms and regulation of polymorphonuclear leukocyte and eosinophil adherence to human airway epithelial cells Jagels, M.A.;Daffern, P.J.;Zuraw, B.L.;Hugli, T.E.
  38. Blood. v.77 Molecular physiology of granulocytemacrophage colony-stimulating factor Gasson, J.C.
  39. J Clin Invest. v.78 Recombinant human granulocyte-macrophage olony-stimulating factor stimulates in vitro mature human neutrophil and eosinophil function, surface receptor expression, and survival Lopez, A.F.;Williamson, J.;Gamble, J.R.;Begley, C.G.;Harlan, J.M.;Klebanoff, S.J.;Waltersdorph, A.;Wong, G.;Clark, S.C.;Vadas, M.A.
  40. Int Arch Allergy Immunol. v.112 Activation of signaling pathways and prevention of apoptosis by cytokines in eosinophils Yousefi, S.K.;Blaser, H.;Simon, U.
  41. Cell Immunol. v.219 Attenuation of airway hyperresponsiveness in a murine asthma model by neutralization of granulocyte-macrophage colony-stimulating factor(GM-CSF) Yamashita, N.;Tashimo, H.;Ishida, H.;Kaneko, F.;Nakano, J.;Kato,H.;Hirai, K.;Horiuchi, T.;Ohta, K.
  42. Clin Exp Immunol. v.113 Compartmentalized transgene expreeion of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mouse lung enhances allergic airways inflammation Lei, X.F.;Ohkawara, Y.;Stampfli, M.R.;Gauldie, J.;Croitoru, K.;Jordana, M.;Xing, Z.
  43. Reproduction. v.127 no.3 Mast cells degranulation affects angiogenesis in the rat uterine cervix during pregnancy Varayoud, J.;Romos, J.G.;Bosquiazzo, V.L.;Munozde-Toro, M.;Luque, E.H.
  44. J Clin Pathol. v.57 no.6 Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma Eaposito, I.;Menicagli, M.;Funel, N.;Bergmann, F.;Boggi, U.;Mosca, F.;Bevilacqua, G.;Campani, D.
  45. J Pathol. v.180 no.1 The role of vascular endothelial growth factor in a murine chronic granulomatous tissue air pouch model of angiogenesis Appleton, I.;Brown, N.J.;Willis, D.;Colville-Nash, P.R.;Alam, C.;Brown, J.R.;Willoughby, D.A.
  46. Cancer Res. v.55 no.18 Peripheral blood T lymphocytes and lym-phocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis Freeman, M.R.;Schneck, F.X.;Gagnon, M.L.;Corless, C.;Soker, S.;Niknejad, K.;Peoples, G.E.;Klagsbrun, M.;
  47. J Biol Chem. v.276 Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide Sandau, K.B.;Zhou, J.;Kietzmann, T.;Brune, B.
  48. FEBS Lett. v.512 Normoxic induction of the hypoxia-inducible factor 1alpha by insulin and inter-leukin-1beta involves the phosphatidylinositol 3-kinase pathway Stiehl, D.P.;Jelkmann, W.;Wenger, R.H.;Hellwig-Burgel, T.
  49. Biochem J. v.350 Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts Thornton, R.D.;Lane, P.;Borghaei, R.C.;Pease, E.A.;Caro, J.;Mochan, E.
  50. Proc Natl Acad Sci U S A. v.95 no.14 Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway Huang, L.E.;Gu, J.;Schau, M.;Bunn, H.F.
  51. Kidney Int. v.51 Complex role of protein phosphorylation in gene activation by hypoxia Salceda, S.;Beck, I.;Srinivas, V.;Caro, J.
  52. Arthritis Rheum. v.44 no.7 Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: implications for trgeting of therapeutic genes to the inflamed joint Hollander, A.P.;Corke, K.P.;Freemont, A.J.;Lewis, C.E.