暑假華藝文章9-水飛薊賓對T細胞免疫反應之調節作用
文章名稱:水飛薊賓對T細胞免疫反應之調節作用 The modulatory effect of silibinin on T cell immune responses
作者名稱:郭馥華 , 碩士 指導教授：詹東榮
資料來源:無
內容摘要: 水飛蓟賓 (silibinin) 和水飛蓟 (silymarin) 用於治療肝臟疾病已經有相當久的歷史 (Gazak
at al, 2007)，近年來，更廣泛作為保健食品或是醫療用途的藥品製劑，包含臺灣 。截至目前為止，
科學文獻的研究報告證實水飛蓟賓和水飛蓟具有許多有潛力的生物活性作用，其中包含對免疫的
調節作用，例如影響 T 細胞的功能及其細胞激素基因的表現。然而，有關水飛蓟賓和水飛蓟對
Th1/Th2免疫平衡的影響，現有的文獻報告之結果並不ㄧ致，仍有待進一步釐清。因此，本論文
的主旨在研究水飛蓟賓對Th1/Th2 免疫反應的作用，採用包含離體細胞培養和活體動物模式，探
討水飛蓟賓對 T 細胞參與的抗體生成、呼吸道過敏性免疫反應和細胞激素基因表現的影響。實
驗結果顯示，在卵白蛋白(ovalbumin；OVA)免疫的 BALB/c 小鼠，於免疫前連續三天口服投予
水飛蓟賓，具有促進脾臟細胞表現 IFN-γ和血清中OVA 專一性IgG2a 抗體生成的作用；而且，脾
臟細胞表現IL-4 和血清中OVA 專一性抗體IgE及total IgE 則受到水飛蓟賓的抑制。這些證據顯
示口服水飛蓟賓會使OVA 免疫小鼠的 T 細胞免疫反應，傾向Th1 的方向。本論文進一步採用以
OVA氣霧刺激OVA 免疫小鼠之呼吸道過敏的動物模式，結果發現在免疫前以及氣霧刺激前口服
投予水飛蓟賓，對呼吸道所引起的過敏性發炎反應沒有影響，但有促進肺臟組織中IFN-γ mRNA
表現的效果。在離體細胞培養的實驗模式，以水飛蓟賓處理由 OVA 免疫小鼠分離的脾臟細胞，
發現對 IFN-γ和 IL-4 皆有抑制作用，這些結果顯示在離體細胞直接暴露於水飛蓟賓的實驗條件
下，水飛蓟賓對於脾臟細胞表現細胞激素基因的作用和活體給藥的結果不同。 本論文採用BALB/c
鼠，嘗試了二種動物模式活體投予水飛蓟賓，和一種離體細胞模式處理水飛蓟賓，所得實驗結果
仍然欠缺一致的結論，分析水飛蓟賓在現有文獻報告中，對 Th1/Th2 的影響亦有許多分歧的實驗
證據，顯示水飛蓟賓對 T 細胞免疫反應作用之複雜，仍有待進一步加以釐清。值得一提的是，
在本論文的離體試驗模式下，水飛蓟賓在較低的濃度(5-10 μM)下，即對Th1 (IFN-γ)和Th2 (IL-4)
細胞激素有明顯的影響，合併活體給藥的實驗結果，明顯指出 T 細胞是水飛蓟賓的作用標的之
一，其影響細胞激素基因表現的機轉值得未來加以深入探討。
Silibinin and silymarin have been used as herbal medicines to treat liver disease for a long time.
Recent years, silibinin and silymarin has been commonly used as dietary supplements, as well as
medicinal products in many countries, including Taiwan. To date, scientific evidence indicates that
silibinin and silymarin possess potential biological activities, including immune modulation (i.e. effects
on T cell reactivity and cytokine expression). Although the immunomodulatory activity of silibinin on
T cell functionality has been documented, contrasting effects on the balance of T helper (Th)1/Th2
cell-mediated immunity were reported. Hence, the objective of the present study was to investigate the
effect of silibinin on Th1/Th2 immune balance. Both animal models and cell culture experiments were
employed to examine the influence of silibinin on T-dependent antibody production, T cell-mediated
allergic airway responses, and cytokine expression. The results demonstrated that daily oral
administration of silibinin for 3 days prior to ovalbumin (OVA) sensitization markedly enhanced the
production of IFN-γ
by splenocytes and the serum level of OVA-specific IgG2a in OVA-sensitized
BALB/c mice. In contrast, the production of IL-4 and OVA-specific IgE and total IgE was attenuated.
These finding indicates that silibinin administration polarizes the Th1/Th2 balance toward the Th1
direction. In the murine model of allergic airway responses induced by the challenge of OVA aerosol to
OVA-sensitized mice, no significant effect on the airway allergic immune response by silibinin
administration was observed; however, the steady state mRNA expression of IFN-γ in the lung tissues
of OVA-sensitized and challenged mice was markedly enhanced by silibinin administration.
Furthermore, the direct effect of silibinin on T cell-derived cytokine expression was also studied in
vitro. Splenocytes obtained from OVA-sensitized mice were exposed to silibinin in culture and
stimulated with OVA to induce cytokine production. The results showed that silibinin exposure
significantly attenuated the production of both IFN-γ and IL-4 by OVA-stimulated splenocytes. These
results demonstrated that the effects of silibinin on T cell cytokine expression between the employed in
vivo and in vitro experimental settings are inconsistent. The present study utilized 3 experimental
systems, including animal models and cell culture experiments, to examine the immunomodulatory
effect of silibinin on T cells; however, the results on T cell cytokine expression are contrasting. The
inconsistency of silibinin-mediated effects on the Th1/Th2 immune balance has been reported in the
literature, suggesting a very complicated profile of silibinin influence on the immune system. It is
noticed that, under the employed condition of cell culture studies, the effective concentration range of
IV
silibinin (5-10 μM) to affect Th1 (IFN-γ) and Th2 (IL-4) cytokine expression is lower than the
concentrations used by many reports in the literature. Together with the demonstrated effects of
silibinin on Th1/Th2 cytokine expression in murine models, it is apparent that T cells are a sensitive
target for silibinin. Further studies to elucidate the mechanism of silibinin-mediated effects on cytokine
expression are warranted.
參考文獻:
1.Agoston, M., Cabello, R.G., Blazovics, A., Feher, J. and Vereckei, A. (2001) The effect of amiodarone and/or antioxidant treatment on splenocyte blast transformation. Clinica chimica acta; international journal of clinical chemistry 303, 87-94.
連結：
2.Apasov, S., Redegeld, F. and Sitkovsky, M. (1993) Cell-mediated cytotoxicity: contact and secreted factors. Current opinion in immunology 5, 404-410.
連結：
3.Baer-Dubowska, W., Szaefer, H. and Krajka-Kuzniak, V. (1998) Inhibition of murine hepatic cytochrome P450 activities by natural and synthetic phenolic compounds. Xenobiotica; the fate of foreign compounds in biological systems 28, 735-743.
連結：
4.Breschi, M.C., Martinotti, E., Apostoliti, F. and Nieri, P. (2002) Protective effect of silymarin in antigen challenge- and histamine-induced bronchoconstriction in in vivo guinea-pigs. European journal of pharmacology 437, 91-95.
連結：
5.Chang, J.W., Kim, C.S., Kim, S.B., Park, S.K., Park, J.S. and Lee, S.K. (2006) Proinflammatory cytokine-induced NF-kappaB activation in human mesangial cells is mediated through intracellular calcium but not ROS: effects of silymarin. Nephron 103, e156-165.
連結：
6.Chen, P.N., Hsieh, Y.S., Chiang, C.L., Chiou, H.L., Yang, S.F. and Chu, S.C. (2006) Silibinin inhibits invasion of oral cancer cells by suppressing the MAPK pathway. Journal of dental research 85, 220-225.
連結：
7.Colombo, M.P. and Trinchieri, G. (2002) Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine & growth factor reviews 13, 155-168.
連結：
8.De La Puerta, R., Martinez, E., Bravo, L. and Ahumada, M.C. (1996) Effect of silymarin on different acute inflammation models and on leukocyte migration. The Journal of pharmacy and pharmacology 48, 968-970.
連結：
9.Dehmlow, C., Erhard, J. and de Groot, H. (1996) Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology (Baltimore, Md 23, 749-754.
連結：
10.Doherty, P.C. (1997) Cell mediated immunity in virus infections. Bioscience reports 17, 367-387.
連結：
11.Fiebrich, F. and Koch, H. (1979) Silymarin, an inhibitor of prostaglandin synthetase. Experientia 35, 1550-1552.
連結：
12.Flora, K., Hahn, M., Rosen, H. and Benner, K. (1998) Milk thistle (Silybum marianum) for the therapy of liver disease. The American journal of gastroenterology 93, 139-143.
連結：
13.Gazak, R., Walterova, D. and Kren, V. (2007) Silybin and silymarin--new and emerging applications in medicine. Current medicinal chemistry 14, 315-338.
連結：
14.Ikeda, H., Old, L.J. and Schreiber, R.D. (2002) The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine & growth factor reviews 13, 95-109.
連結：
15.Jan, T.R., Farraj, A.K., Harkema, J.R. and Kaminski, N.E. (2003) Attenuation of the ovalbumin-induced allergic airway response by cannabinoid treatment in A/J mice. Toxicology and applied pharmacology 188, 24-35.
連結：
16.Jan, T.R., Wey, S.P., Kuan, C.C., Liao, M.H. and Wu, H.Y. (2007) Diosgenin, a steroidal sapogenin, enhances antigen-specific IgG2a and interferon-gamma expression in ovalbumin-sensitized BALB/c mice. Planta medica 73, 421-426.
連結：
17.Johnson, V.J., He, Q., Osuchowski, M.F. and Sharma, R.P. (2003) Physiological responses of a natural antioxidant flavonoid mixture, silymarin, in BALB/c mice: III. Silymarin inhibits T-lymphocyte function at low doses but stimulates inflammatory processes at high doses. Planta medica 69, 44-49.
連結：
18.Johnson, V.J., Osuchowski, M.F., He, Q. and Sharma, R.P. (2002) Physiological responses to a natural antioxidant flavonoid mixture, silymarin, in BALB/c mice: II. alterations in thymic differentiation correlate with changes in c-myc gene expression. Planta medica 68, 961-965.
連結：
19.Krecman, V., Skottova, N., Walterova, D., Ulrichova, J. and Simanek, V. (1998) Silymarin inhibits the development of diet-induced hypercholesterolemia in rats. Planta medica 64, 138-142.
連結：
20.Lee, J.S., Kim, S.G., Kim, H.K., Lee, T.H., Jeong, Y.I., Lee, C.M., Yoon, M.S., Na, Y.J., Suh, D.S., Park, N.C., Choi, I.H., Kim, G.Y., Choi, Y.H., Chung, H.Y. and Park, Y.M. (2007) Silibinin polarizes Th1/Th2 immune responses through the inhibition of immunostimulatory function of dendritic cells. Journal of cellular physiology 210, 385-397.
連結：
21.Li, Y.Q., Kobayashi, M., Yuan, L., Wang, J., Matsushita, K., Hamada, J.I., Kimura, K., Yagita, H., Okumura, K. and Hosokawa, M. (1998) Protein kinase C mediates the signal for interferon-gamma mRNA expression in cytotoxic T cells after their adhesion to laminin. Immunology 93, 455-461.
連結：
22.Meeran, S.M., Katiyar, S., Elmets, C.A. and Katiyar, S.K. (2006) Silymarin inhibits UV radiation-induced immunosuppression through augmentation of interleukin-12 in mice. Molecular cancer therapeutics 5, 1660-1668.
連結：
23.Morokata, T., Ishikawa, J. and Yamada, T. (2000) Antigen dose defines T helper 1 and T helper 2 responses in the lungs of C57BL/6 and BALB/c mice independently of splenic responses. Immunology letters 72, 119-126.
連結：
24.Muriel, P. and Mourelle, M. (1990) Prevention by silymarin of membrane alterations in acute CCl4 liver damage. J Appl Toxicol 10, 275-279.
連結：
25.Ngoc, P.L., Gold, D.R., Tzianabos, A.O., Weiss, S.T. and Celedon, J.C. (2005) Cytokines, allergy, and asthma. Current opinion in allergy and clinical immunology 5, 161-166.
連結：
26.Price, D. (2008) The use of omalizumab in asthma. Prim Care Respir J 17, 62-72.
連結：
27.Sakai, S., Akiyama, H., Harikai, N., Toyoda, H., Toida, T., Maitani, T. and Imanari, T. (2002) Effect of chondroitin sulfate on murine splenocytes sensitized with ovalbumin. Immunology letters 84, 211-216.
連結：
28.Saller, R., Meier, R. and Brignoli, R. (2001) The use of silymarin in the treatment of liver diseases. Drugs 61, 2035-2063.
連結：
29.Santana, M.A. and Rosenstein, Y. (2003) What it takes to become an effector T cell: the process, the cells involved, and the mechanisms. Journal of cellular physiology 195, 392-401.
連結：
30.Schumann, J., Prockl, J., Kiemer, A.K., Vollmar, A.M., Bang, R. and Tiegs, G. (2003) Silibinin protects mice from T cell-dependent liver injury. Journal of hepatology 39, 333-340.
連結：
31.Shear, N.H., Malkiewicz, I.M., Klein, D., Koren, G., Randor, S. and Neuman, M.G. (1995) Acetaminophen-induced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin. Skin Pharmacol 8, 279-291.
連結：
32.Skottova, N., Z, S.V., Vecera, R., Urbanek, K., Jegorov, A. and Simanek, V. (2001) Pharmacokinetic study of iodine-labeled silibinins in rat. Pharmacol Res 44, 247-253.
連結：
33.Tyagi, A.K., Agarwal, C., Singh, R.P., Shroyer, K.R., Glode, L.M. and Agarwal, R. (2003) Silibinin down-regulates survivin protein and mRNA expression and causes caspases activation and apoptosis in human bladder transitional-cell papilloma RT4 cells. Biochemical and biophysical research communications 312, 1178-1184.
連結：
34.Zhao, J. and Agarwal, R. (1999) Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis 20, 2101-2108.
連結：
35.Agarwal, R., Agarwal, C., Ichikawa, H., Singh, R.P. and Aggarwal, B.B. (2006)
36.Anticancer potential of silymarin: from bench to bed side. Anticancer research 26, 4457-4498.
37.Desplaces, A., Choppin, J., Vogel, G. and Trost, W. (1975) The effects of silymarin on experimental phalloidine poisoning. Arzneimittel-Forschung 25, 89-96.
38.Fuchs, E.C., Weyhenmeyer, R. and Weiner, O.H. (1997) Effects of silibinin and of a synthetic analogue on isolated rat hepatic stellate cells and myofibroblasts. Arzneimittel-Forschung 47, 1383-1387.
39.Koch, H.P., Bachner, J. and Loffler, E. (1985) Silymarin: potent inhibitor of cyclic AMP phosphodiesterase. Methods and findings in experimental and clinical pharmacology 7, 409-413.
40.Luper, S. (1998) A review of plants used in the treatment of liver disease: part 1. Altern Med Rev 3, 410-421.
41.Maezawa, Y., Nakajima, H., Kumano, K., Kubo, S., Karasuyama, H. and Iwamoto, I. (2003) Role of IgE in Th2 cell-mediated allergic airway inflammation. International archives of allergy and immunology 131 Suppl 1, 2-6.
42.Manna, S.K., Mukhopadhyay, A., Van, N.T. and Aggarwal, B.B. (1999) Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J Immunol 163, 6800-6809.
43.Meroni, P.L., Barcellini, W., Borghi, M.O., Vismara, A., Ferraro, G., Ciani, D. and Zanussi, C. (1988) Silybin inhibition of human T-lymphocyte activation. International journal of tissue reactions 10, 177-181.
44.Rainone, F. (2005) Milk thistle. American family physician 72, 1285-1288.
45.Tumova, L., Gallova, K. and Rimakova, J. (2004) [Silybum marianum in vitro]. Ceska Slov Farm 53, 135-140.
46.Tyutyulkova, N., Gorantcheva, U., Tuneva, S., Chelibonova-Lorer, H., Gavasova, E. and Zhivkov, V. (1983) Effect of silymarin (Carsil) on the microsomal glycoprotein and protein biosynthesis in liver of rats with experimental galactosamine hepatitis. Methods and findings in experimental and clinical pharmacology 5, 181-184.
47.Wilasrusmee, C., Kittur, S., Shah, G., Siddiqui, J., Bruch, D., Wilasrusmee, S. and Kittur, D.S. (2002) Immunostimulatory effect of Silybum Marianum (milk thistle) extract. Med Sci Monit 8, BR439-443.
48.Young, H.A. and Hardy, K.J. (1995) Role of interferon-gamma in immune cell regulation. Journal of leukocyte biology 58, 373-381.
作者名稱:郭馥華 , 碩士 指導教授：詹東榮
資料來源:無
內容摘要: 水飛蓟賓 (silibinin) 和水飛蓟 (silymarin) 用於治療肝臟疾病已經有相當久的歷史 (Gazak
at al, 2007)，近年來，更廣泛作為保健食品或是醫療用途的藥品製劑，包含臺灣 。截至目前為止，
科學文獻的研究報告證實水飛蓟賓和水飛蓟具有許多有潛力的生物活性作用，其中包含對免疫的
調節作用，例如影響 T 細胞的功能及其細胞激素基因的表現。然而，有關水飛蓟賓和水飛蓟對
Th1/Th2免疫平衡的影響，現有的文獻報告之結果並不ㄧ致，仍有待進一步釐清。因此，本論文
的主旨在研究水飛蓟賓對Th1/Th2 免疫反應的作用，採用包含離體細胞培養和活體動物模式，探
討水飛蓟賓對 T 細胞參與的抗體生成、呼吸道過敏性免疫反應和細胞激素基因表現的影響。實
驗結果顯示，在卵白蛋白(ovalbumin；OVA)免疫的 BALB/c 小鼠，於免疫前連續三天口服投予
水飛蓟賓，具有促進脾臟細胞表現 IFN-γ和血清中OVA 專一性IgG2a 抗體生成的作用；而且，脾
臟細胞表現IL-4 和血清中OVA 專一性抗體IgE及total IgE 則受到水飛蓟賓的抑制。這些證據顯
示口服水飛蓟賓會使OVA 免疫小鼠的 T 細胞免疫反應，傾向Th1 的方向。本論文進一步採用以
OVA氣霧刺激OVA 免疫小鼠之呼吸道過敏的動物模式，結果發現在免疫前以及氣霧刺激前口服
投予水飛蓟賓，對呼吸道所引起的過敏性發炎反應沒有影響，但有促進肺臟組織中IFN-γ mRNA
表現的效果。在離體細胞培養的實驗模式，以水飛蓟賓處理由 OVA 免疫小鼠分離的脾臟細胞，
發現對 IFN-γ和 IL-4 皆有抑制作用，這些結果顯示在離體細胞直接暴露於水飛蓟賓的實驗條件
下，水飛蓟賓對於脾臟細胞表現細胞激素基因的作用和活體給藥的結果不同。 本論文採用BALB/c
鼠，嘗試了二種動物模式活體投予水飛蓟賓，和一種離體細胞模式處理水飛蓟賓，所得實驗結果
仍然欠缺一致的結論，分析水飛蓟賓在現有文獻報告中，對 Th1/Th2 的影響亦有許多分歧的實驗
證據，顯示水飛蓟賓對 T 細胞免疫反應作用之複雜，仍有待進一步加以釐清。值得一提的是，
在本論文的離體試驗模式下，水飛蓟賓在較低的濃度(5-10 μM)下，即對Th1 (IFN-γ)和Th2 (IL-4)
細胞激素有明顯的影響，合併活體給藥的實驗結果，明顯指出 T 細胞是水飛蓟賓的作用標的之
一，其影響細胞激素基因表現的機轉值得未來加以深入探討。
Silibinin and silymarin have been used as herbal medicines to treat liver disease for a long time.
Recent years, silibinin and silymarin has been commonly used as dietary supplements, as well as
medicinal products in many countries, including Taiwan. To date, scientific evidence indicates that
silibinin and silymarin possess potential biological activities, including immune modulation (i.e. effects
on T cell reactivity and cytokine expression). Although the immunomodulatory activity of silibinin on
T cell functionality has been documented, contrasting effects on the balance of T helper (Th)1/Th2
cell-mediated immunity were reported. Hence, the objective of the present study was to investigate the
effect of silibinin on Th1/Th2 immune balance. Both animal models and cell culture experiments were
employed to examine the influence of silibinin on T-dependent antibody production, T cell-mediated
allergic airway responses, and cytokine expression. The results demonstrated that daily oral
administration of silibinin for 3 days prior to ovalbumin (OVA) sensitization markedly enhanced the
production of IFN-γ
by splenocytes and the serum level of OVA-specific IgG2a in OVA-sensitized
BALB/c mice. In contrast, the production of IL-4 and OVA-specific IgE and total IgE was attenuated.
These finding indicates that silibinin administration polarizes the Th1/Th2 balance toward the Th1
direction. In the murine model of allergic airway responses induced by the challenge of OVA aerosol to
OVA-sensitized mice, no significant effect on the airway allergic immune response by silibinin
administration was observed; however, the steady state mRNA expression of IFN-γ in the lung tissues
of OVA-sensitized and challenged mice was markedly enhanced by silibinin administration.
Furthermore, the direct effect of silibinin on T cell-derived cytokine expression was also studied in
vitro. Splenocytes obtained from OVA-sensitized mice were exposed to silibinin in culture and
stimulated with OVA to induce cytokine production. The results showed that silibinin exposure
significantly attenuated the production of both IFN-γ and IL-4 by OVA-stimulated splenocytes. These
results demonstrated that the effects of silibinin on T cell cytokine expression between the employed in
vivo and in vitro experimental settings are inconsistent. The present study utilized 3 experimental
systems, including animal models and cell culture experiments, to examine the immunomodulatory
effect of silibinin on T cells; however, the results on T cell cytokine expression are contrasting. The
inconsistency of silibinin-mediated effects on the Th1/Th2 immune balance has been reported in the
literature, suggesting a very complicated profile of silibinin influence on the immune system. It is
noticed that, under the employed condition of cell culture studies, the effective concentration range of
IV
silibinin (5-10 μM) to affect Th1 (IFN-γ) and Th2 (IL-4) cytokine expression is lower than the
concentrations used by many reports in the literature. Together with the demonstrated effects of
silibinin on Th1/Th2 cytokine expression in murine models, it is apparent that T cells are a sensitive
target for silibinin. Further studies to elucidate the mechanism of silibinin-mediated effects on cytokine
expression are warranted.
參考文獻:
1.Agoston, M., Cabello, R.G., Blazovics, A., Feher, J. and Vereckei, A. (2001) The effect of amiodarone and/or antioxidant treatment on splenocyte blast transformation. Clinica chimica acta; international journal of clinical chemistry 303, 87-94.
連結：
2.Apasov, S., Redegeld, F. and Sitkovsky, M. (1993) Cell-mediated cytotoxicity: contact and secreted factors. Current opinion in immunology 5, 404-410.
連結：
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