臺灣博碩士論文加值系統

先前由松杉靈芝(Ganoderma tsugae)當中發現的真菌類免疫調節蛋白FIP-gts (Fungal Immunomodulatory Protein)，在此研究中我們利用重組蛋白工程在大腸桿菌中表現並純化得reFIP-gts。利用PI染色與流式細胞儀分析，發現FIP-gts可促使HPBMCs (Human peripheral blood mononuclear cells)的細胞週期由G0/G1期進入S期進而造成細胞增生，而預先處理PI 3-kinase (phosphatidylinositol 3-kinase)專一性抑制劑LY294002則可抑制由FIP-gts所誘導之S期的增加。另一方面分析FIP-gts誘導HPBMCs產生的細胞激素時，發現IFN-γ持續大量表現；而預先處理LY294002亦可抑制FIP-gts誘導之IFN-γ的表現；此外以Western blot方式證實，以FIP-gts處理HPBMCs後會磷酸化而活化PI 3-kinase的下游基因Akt，由此顯示PI 3-kinase在FIP-gts活化HPBMCs的過程中扮演一個相當重要的角色。另一方面，評估FIP-gts對於家塵蟎(Dermatophagoides pteronyssinus，Der p)致敏性氣喘(Allergic asthma)的減敏效果。初步發現餵食二週FIP-gts後Balb/c小鼠的脾臟細胞於體外若再以FIP-gts刺激後，反而不會誘發IFN-γ的表現；而利用白血球分類計數 (Differential Leucocyte Counting，DLC)，發現致敏後Balb/c小鼠血液中之嗜鹼性球比例增加，而在餵食FIP-gts後會逐漸降低至正常範圍。然而遺憾的是我們在致敏小鼠體內無法測得血液中嗜酸性球的增加或是血清中total IgE的增加。本研究證實了FIP-gts調控HPBMCs的增生與誘導HPBMCs產生IFN-γ的機制是透過PI 3-kinase的訊息途徑；雖然在Der p致敏之動物實驗一直無法觀察到明顯誘發小鼠氣喘的病徵，但發現餵食FIP-gts後會改變Balb/c小鼠體內的免疫反應，顯示其確實具有發展成調整免疫系統之健康食品的潛能。

In this study, we expressed and purified the fungal immunomodulatory protein (FIP-gts) in E.coli. Using PI staining and flow cytometry, we found that FIP-gts promoted cell cycle progression from G0/G1 phase to S phase in HPBMCs. Pre-treatment of LY294002, a specific inhibitor of PI 3-kinase, was abolished the increased S phase induced by FIP-gts. Analyzing the cytokines induced by FIP-gts, IFN-γ persistent expressed significantly. Pre-treatment of LY294002 was also inhibited the secretion of IFN-γ stimulated by FIP-gts in HPBMCs. Moreover our results demonstrated that Akt, a downstream effecter of phosphatidylinositol 3-kinase (PI 3-kinase), was phosphorylated and activated by FIP-gts. It indicated that PI 3-kinase play an important role in the process of HPBMCs activation induced by FIP-gts. On the other part, developing allergen of house dust mite Dermatophagoides pteronyssinus (Der p)-sensitized animal model, we evaluated whether FIP-gts could attenuate the symptoms of allergic asthma. The expression of IFN-γ in the splenocytes of Balb/c mice after feeding with FIP-gts for two weeks restimulated with FIP-gts was not increased but decreased instead. Using Differential Leucocyte Counting (DLC), we found that after sensitized with Der p increased the percentage of basophils in Balb/c mice blood, after fed with FIP-gts the basophils decreased to normal level. Unfortunately, we did not observe the percentage of eosinophils and total IgE were increased in asthma Balb/c mice. Our study demonstrated that FIP-gts regulated the proliferation of HPBMCs and induced the secretion of IFN-γ in HPBMCs via PI 3-kinase activation. Though we did not observed the symptoms of allergic asthma in Der p-sensitized mice, fed with FIP-gts could truly modify the immune response in Balb/c mice. It is suggested that FIP-gts may be as a health food with immunodulatory function.

壹、中文摘要----6
貳、英文摘要----7
叁、縮寫表----9
肆、前言
一、靈芝簡介----11
二、松杉靈芝免疫調節功能蛋白 (FIP-gts)----16
三、松杉靈芝免疫調節功能蛋白具有的生理活性----17
四、體內與細胞激素相關之免疫反應----18
五、IFN-γ的相關調控機制----20
六、過敏性氣喘與衛生假說----21
七、研究動機----24
伍、實驗材料與方法
一、儀器----26
二、藥品----27
三、質體----28
四、實驗動物來源----28
五、實驗方法
1.在大腸桿菌中表現融合蛋白重組FIP-gts與純化----29
2.SDS-聚丙烯醯銨板膠電泳法----30
3.流式細胞儀分析細胞週期----32
4.細胞激素之活性測定----36
5.Western blot (西方點墨法)----40
6.塵蟎蛋白Der p的粗萃取----43
7.重組塵蟎蛋白Der pⅡ的構築與製備----43
8.塵蟎致敏動物模式的建立----50
陸、結果
一、大腸桿菌中重組FIP-gts的表現與純化----53
二、reFIP-gts免疫調節功能活性之分析─促進細胞增生----53
三、reFIP-gts免疫調節功能活性之分析─釋出細胞激素----55
四、FIP-gts刺激HPBMCs產生IFN-γ的標的細胞----56
五、探討FIP-gts誘發細胞激素之訊息傳遞途徑----58
六、本研究中二種致敏用之Der p蛋白----61
七、致敏小鼠之動物實驗----63
柒、討論----69
捌、圖目錄
圖1.pGEX4T-1-FIP-gts之構築、表現與純化----83
圖2.處理不同濃度與不同時間FIP-gts對HPBMCs細胞週期的影響----84
圖3.不同抑制劑對於FIP-gts誘導HPBMCs增生的影響----85
圖4.處理不同濃度與不同時間FIP-gts對HPBMCs誘發產生IFN-γ的影響----86
圖5.處理不同濃度與不同時間FIP-gts對HPBMCs誘發產生IL-4的影響----87
圖6.處理不同濃度與不同時間FIP-gts對T細胞之細胞週期的影響----88
圖7.不同抑制劑對於FIP-gts誘導T細胞增生的影響----89
圖8.處理不同濃度與不同時間FIP-gts對T細胞誘發產生IFN-γ的影響----90
圖9.不同抑制劑對於FIP-gts誘導HPBMCs產生IFN-γ的影響----91
圖10.處理不同濃度LY294002對於FIP-gts誘導HPBMC產生IFN-γ的影響----92
圖11.不同抑制劑對於FIP-gts誘導HPBMCs產生IL-4的影響----93
圖12.不同抑制劑對於FIP-gts誘導T細胞產生IFN-γ的影響----94
圖13.FIP-gts活化HPBMCs中Akt的情形----95
圖14.FIP-gts活化HPBMCs中GSK-3β的情形----96
圖15.FIP-gts活化HPBMCs中p38 MAPK的情形----97
圖16.FIP-gts活化HPBMCs中ERK 1/2的情形----98
圖17.FIP-gts活化HPBMCs中COX-2的情形----99
圖18.Der p誘導HPBMCs中IL-4產生的情形----100
圖19.Der p粗蛋白萃取液之製備流程說明圖----101
圖20.pGEX4T-1-Der pⅡ1-129之構築、表現與純化----102
圖21.Der p噴霧致敏用之噴霧器----103
圖22.Balb/c小鼠血液中白血球之型態----104
圖23.Der p粗蛋白致敏之Balb/c小鼠血液中的白血球分類計數----105
圖24.Der p粗蛋白致敏之Balb/c小鼠脾臟細胞於體外再次以FIP-gts刺激對於產生IFN-γ的影響----106
圖25.Der p粗蛋白致敏之Balb/c小鼠脾臟細胞於體外再次以FIP-gts刺激對於產生IL-4的影響----107
圖26.重組Der pⅡ1-129致敏之Balb/c小鼠血液中的白血球分類計數----108
圖27.重組Der pⅡ1-129致敏之Balb/c小鼠BAL液中total IgE的含量----109
圖28.餵食reFIP-gts對於Balb/c小鼠體重的影響----110
玖、參考文獻----111

Ausiello, C.M., Spagnoli, G.C., Boccanera, M., Casalinuovo, I., Malavasi, F., Casciani, C.U. and Cassone, A. (1986) Proliferation of human peripheral blood mononuclear cells induced by Candida albicans and its cell wall fractions. J Med Microbiol, 22, 195-202.
Banchereau, J. and Steinman, R.M. (1998) Dendritic cells and the control of immunity. Nature, 392, 245-252.
Bochner, B.S., Undem, B.J. and Lichtenstein, L.M. (1994) Immunological aspects of allergic asthma. Annu Rev Immunol, 12, 295-335.
Cai, G., Radzanowski, T., Villegas, E.N., Kastelein, R. and Hunter, C.A. (2000) Identification of STAT4-dependent and independent mechanisms of resistance to Toxoplasma gondii. J Immunol, 165, 2619-2627.
Cao, L.Z. and Lin, Z.B. (2003) Regulatory effect of Ganoderma lucidum polysaccharides on cytotoxic T-lymphocytes induced by dendritic cells in vitro. Acta Pharmacol Sin, 24, 321-326.
Carter, A.B., Monick, M.M. and Hunninghake, G.W. (1999) Both Erk and p38 kinases are necessary for cytokine gene transcription. Am J Respir Cell Mol Biol, 20, 751-758.
Chen, H.L., Li, D.F., Chang, B.Y., Gong, L.M., Piao, X.S., Yi, G.F. and Zhang, J.X. (2003) Effects of lentinan on broiler splenocyte proliferation, interleukin-2 production, and signal transduction. Poult Sci, 82, 760-766.
Chen, H.Y., Chen, C.H., Yeh, M.Y., Wu, J.S., Yazama, K. and Mikami, Y. (1992) In vivo anti-candidal activity induced by tranditional Chinese herbal medicine, Ganoderma lucidium. Jpn. J. Med. Mycol., 33, 505-512.
Cheshire, J.L., Williams, B.R. and Baldwin, A.S., Jr. (1999) Involvement of double-stranded RNA-activated protein kinase in the synergistic activation of nuclear factor-kappaB by tumor necrosis factor-alpha and gamma-interferon in preneuronal cells. J Biol Chem, 274, 4801-4806.
Chhabra, S.K. and Pandey, K.K. (2002) Comparison of acute bronchodilator effects of inhaled ipratropium bromide and salbutamol in bronchial asthma. J Asthma, 39, 375-381.
Chua, K.Y., Doyle, C.R., Simpson, R.J., Turner, K.J., Stewart, G.A. and Thomas, W.R. (1990) Isolation of cDNA coding for the major mite allergen Der p II by IgE plaque immunoassay. Int Arch Allergy Appl Immunol, 91, 118-123.
Cippitelli, M., Sica, A., Viggiano, V., Ye, J., Ghosh, P., Birrer, M.J. and Young, H.A. (1995) Negative transcriptional regulation of the interferon-gamma promoter by glucocorticoids and dominant negative mutants of c-Jun. J Biol Chem, 270, 12548-12556.
Croll, A.D., Siggins, K.W., Morris, A.G. and Pither, J.M. (1987) The induction of IFN-gamma production and m-RNAs of interleukin 2 and IFN-gamma by phorbol esters and a calcium ionophore. Biochem Biophys Res Commun, 146, 927-933.
Del Prete, G.F., De Carli, M., D''Elios, M.M., Maestrelli, P., Ricci, M., Fabbri, L. and Romagnani, S. (1993) Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients with allergic respiratory disorders. Eur J Immunol, 23, 1445-1449.
Delgado, M. and Ganea, D. (2000) Inhibition of IFN-gamma-induced janus kinase-1-STAT1 activation in macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. J Immunol, 165, 3051-3057.
Deng, L., Zhou, Y., Peng, X., Deng, H., Deng, Y. and Yao, J. (2001) [Serum markers and pathological evaluation in hepatitis fibrosis of chronic hepatitis B treated with interferon alpha]. Zhonghua Gan Zang Bing Za Zhi, 9 Suppl, 66-67.
Diehl, J.A., Cheng, M., Roussel, M.F. and Sherr, C.J. (1998) Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev, 12, 3499-3511.
Dietrich, G., Viret, J.F. and Hess, J. (2003) Novel vaccination strategies based on recombinant Mycobacterium bovis BCG. Int J Med Microbiol, 292, 441-451.
Dijkers, P.F., Medema, R.H., Pals, C., Banerji, L., Thomas, N.S., Lam, E.W., Burgering, B.M., Raaijmakers, J.A., Lammers, J.W., Koenderman, L. and Coffer, P.J. (2000) Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol Cell Biol, 20, 9138-9148.
Doble, B.W. and Woodgett, J.R. (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci, 116, 1175-1186.
Elser, B., Lohoff, M., Kock, S., Giaisi, M., Kirchhoff, S., Krammer, P.H. and Li-Weber, M. (2002) IFN-gamma represses IL-4 expression via IRF-1 and IRF-2. Immunity, 17, 703-712.
Favata, M.F., Horiuchi, K.Y., Manos, E.J., Daulerio, A.J., Stradley, D.A., Feeser, W.S., Van Dyk, D.E., Pitts, W.J., Earl, R.A., Hobbs, F., Copeland, R.A., Magolda, R.L., Scherle, P.A. and Trzaskos, J.M. (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem, 273, 18623-18632.
Fuggetta, M.P., D''Onofrio, C. and Bonmassar, E. (1990) Role of biological response modifiers in immunochemotherapy of solid tumors and retroviral-induced leukemia. Ann Ist Super Sanita, 26, 385-395.
Fukao, T., Tanabe, M., Terauchi, Y., Ota, T., Matsuda, S., Asano, T., Kadowaki, T., Takeuchi, T. and Koyasu, S. (2002) PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat Immunol, 3, 875-881.
Gabius, H.J., Walzel, H., Joshi, S.S., Kruip, J., Kojima, S., Gerke, V., Kratzin, H. and Gabius, S. (1992) The immunomodulatory beta-galactoside-specific lectin from mistletoe: partial sequence analysis, cell and tissue binding, and impact on intracellular biosignalling of monocytic leukemia cells. Anticancer Res, 12, 669-675.
Galant, S.P. (1990) Treatment of asthma. New and time-tested strategies. Postgrad Med, 87, 229-236.
Girdlestone, J. and Wing, M. (1996) Autocrine activation by interferon-gamma of STAT factors following T cell activation. Eur J Immunol, 26, 704-709.
Graff, J.R., Konicek, B.W., McNulty, A.M., Wang, Z., Houck, K., Allen, S., Paul, J.D., Hbaiu, A., Goode, R.G., Sandusky, G.E., Vessella, R.L. and Neubauer, B.L. (2000) Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem, 275, 24500-24505.
Haak-Frendscho, M., Kino, K., Sone, T. and Jardieu, P. (1993) Ling Zhi-8: a novel T cell mitogen induces cytokine production and upregulation of ICAM-1 expression. Cell Immunol, 150, 101-113.
Hewitt, C.R., Brown, A.P., Hart, B.J. and Pritchard, D.I. (1995) A major house dust mite allergen disrupts the immunoglobulin E network by selectively cleaving CD23: innate protection by antiproteases. J Exp Med, 182, 1537-1544.
Hikino, H., Konno, C., Mirin, Y. and Hayashi, T. (1985) Isolation and hypoglycemic activity of ganoderans A and B, glycans of Ganoderma lucidum fruit bodies. Planta Med, 339-340.
Horner, W.E., Helbling, A. and Lehrer, S.B. (1993) Basidiomycete allergens: comparison of three Ganoderma species. Allergy, 48, 110-116.
Hseu, R.S. (1996) Prevention and Treatment of Allergic Diseases by Direct Allergen-gene Transfer. Department of Microbiology. Nationl Taiwan Uniservity, Taipei.
Hseu, R.S., Wang, H.H., Wang, H.F. and Moncalvo, J.M. (1996) Differentiation and grouping of isolates of the Ganoderma lucidum complex by random amplified polymorphic DNA-PCR compared with grouping on the basis of internal transcribed spacer sequences. Appl Environ Microbiol, 62, 1354-1363.
Hsu, C.-i. (1996) Study on the Fungal Immunomodulatory Proteins. Department of Medical Technology, college of medicine. National Taiwan University, Taipei.
Iniguez, M.A., Punzon, C. and Fresno, M. (1999) Induction of cyclooxygenase-2 on activated T lymphocytes: regulation of T cell activation by cyclooxygenase-2 inhibitors. J Immunol, 163, 111-119.
Ip, Y.T. and Davis, R.J. (1998) Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development. Curr Opin Cell Biol, 10, 205-219.
Irazoqui, F.J., Zalazar, F.E., Nores, G.A. and Vides, M.A. (1997) Agaricus bisporus lectin binds mainly O-glycans but also N-glycans of human IgA subclasses. Glycoconj J, 14, 313-319.
Irimura, T., McIsaac, A.M., Carlson, D.A., Yagita, M., Grimm, E.A., Menter, D.G., Ota, D.M. and Clary, K.R. (1990) Soluble factor in normal tissues that stimulates high-molecular-weight sialoglycoprotein production by human colon carcinoma cells. Cancer Res, 50, 3331-3338.
Jaffuel, D., Mathieu, M., Godard, P., Michel, F.B. and Demoly, P. (1999) [Mechanism of action of glucocorticoids in asthma]. Rev Mal Respir, 16, 431-442.
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. Toxicol Appl Pharmacol, 188, 24-35.
Kahn, D.A., Archer, D.C., Gold, D.P. and Kelly, C.J. (2001) Adjuvant immunotherapy is dependent on inducible nitric oxide synthase. J Exp Med, 193, 1261-1268.
Kawagishi, H., Fukuhara, F., Sazuka, M., Kawashima, A., Mitsubori, T. and Tomita, T. (1993) 5''-Deoxy-5''-methylsulphinyladenosine, a platelet aggregation inhibitor from Ganoderma lucidium. Phytochemistry, 32, 239-241.
Kawagishi, H., Mori, H., Uno, A., Kimura, A. and Chiba, S. (1994) A sialic acid-binding lectin from the mushroom Hericium erinaceum. FEBS Lett, 340, 56-58.
Kim, H.M., Yim, H.G., Yoon, H.S., Park, S.T., Jeung, J.Y., Lee, K.N., Baek, S.H., Song, Y.S., Oh, G.J., Kim, N.S. and An, N.H. (2001) Phosphatidylinositol 3-kinase regulates proliferation of RAW 264.7 macrophages. Immunopharmacol Immunotoxicol, 23, 355-365.
Kimura, Y., Taniguchi, M. and Baba, K. (2002) Antitumor and antimetastatic effects on liver of triterpenoid fractions of Ganoderma lucidum: mechanism of action and isolation of an active substance. Anticancer Res, 22, 3309-3318.
Kino, K., Mizumoto, K., Sone, T., Yamaji, T., Watanabe, J., Yamashita, A., Yamaoka, K., Shimizu, K., Ko, K. and Tsunoo, H. (1990) An immunomodulating protein, Ling Zhi-8 (LZ-8) prevents insulitis in non-obese diabetic mice. Diabetologia, 33, 713-718.
Kino, K., Sone, T., Watanabe, J., Yamashita, A., Tsuboi, H., Miyajima, H. and Tsunoo, H. (1991) Immunomodulator, LZ-8, prevents antibody production in mice. Int J Immunopharmacol, 13, 1109-1115.
Kino, K., Yamashita, A., Yamaoka, K., Watanabe, J., Tanaka, S., Ko, K., Shimizu, K. and Tsunoo, H. (1989) Isolation and characterization of a new immunomodulatory protein, ling zhi-8 (LZ-8), from Ganoderma lucidium. J Biol Chem, 264, 472-478.
Ko, J.L., Hsu, C.I., Lin, R.H., Kao, C.L. and Lin, J.Y. (1995) A new fungal immunomodulatory protein, FIP-fve isolated from the edible mushroom, Flammulina velutipes and its complete amino acid sequence. Eur J Biochem, 228, 244-249.
Konska, G., Guillot, J., Dusser, M., Damez, M. and Botton, B. (1994) Isolation and characterization of an N-acetyllactosamine-binding lectin from the mushroom Laetiporus sulfureus. J Biochem (Tokyo), 116, 519-523.
Krilis, S., Baldo, B.A., Sutton, R. and Basten, A. (1984) Antigens and allergens from the common house dust mite Dermatophagoides pteronyssinus. Part I. Demonstration of multiple allergens by immunochemical and biologic analyses. J Allergy Clin Immunol, 74, 132-141.
Kuehr, J., Frischer, T., Meinert, R., Barth, R., Schraub, S., Urbanek, R., Karmaus, W. and Forster, J. (1995) Sensitization to mite allergens is a risk factor for early and late onset of asthma and for persistence of asthmatic signs in children. J Allergy Clin Immunol, 95, 655-662.
Kung, T.T., Jones, H., Adams, G.K., 3rd, Umland, S.P., Kreutner, W., Egan, R.W., Chapman, R.W. and Watnick, A.S. (1994) Characterization of a murine model of allergic pulmonary inflammation. Int Arch Allergy Immunol, 105, 83-90.
Labuda, T., Sundstedt, A. and Dohlsten, M. (2000) Selective induction of p38 mitogen-activated protein kinase activity following A6H co-stimulation in primary human CD4(+) T cells. Int Immunol, 12, 253-261.
Laemmli, U.K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 680-685.
Lai, C.L., Shyur, S.D., Wu, C.Y., Chang, C.L. and Chu, S.H. (2002) Specific IgE to 5 different major house dust mites among asthmatic children. Acta Paediatr Taiwan, 43, 265-270.
Lee, C.S., Tang, R.B. and Chung, R.L. (2000) The evaluation of allergens and allergic diseases in children. J Microbiol Immunol Infect, 33, 227-232.
Lee, Y.L., Fu, C.L., Ye, Y.L. and Chiang, B.L. (1999) Administration of interleukin-12 prevents mite Der p 1 allergen-IgE antibody production and airway eosinophil infiltration in an animal model of airway inflammation. Scand J Immunol, 49, 229-236.
Lichtenstein, L.M. and Bochner, B.S. (1991) The role of basophils in asthma. Ann N Y Acad Sci, 629, 48-61.
Lin, J.M., Lin, C.C., Chiu, H.F., Yang, J.J. and Lee, S.G. (1993) Evaluation of the anti-inflammatory and liver-protective effects of anoectochilus formosanus, ganoderma lucidum and gynostemma pentaphyllum in rats. Am J Chin Med, 21, 59-69.
Lin, W.H. (1996) Molecular cloning, expression and site-directed mutagenesis of fungal immunomodulatory protein, FIP-gts, from ganoderma tsugae. Graduated Institute of Biochemistry and Molecularboilogy, college of medicine. National Taiwan University, Taipei.
Lin, W.H., Hung, C.H., Hsu, C.I. and Lin, J.Y. (1997) Dimerization of the N-terminal amphipathic alpha-helix domain of the fungal immunomodulatory protein from Ganoderma tsugae (Fip-gts) defined by a yeast two-hybrid system and site-directed mutagenesis. J Biol Chem, 272, 20044-20048.
Lin, Y.-C. (2001) The Influence of Der p 2-induced Th2 Response on Host Defense against Intracellular Pathogen. Graduate Institute of Immunology, College of Medicine. National Taiwan University, Taipei.
Min, B.S., Gao, J.J., Hattori, M., Lee, H.K. and Kim, Y.H. (2001) Anticomplement activity of terpenoids from the spores of Ganoderma lucidum. Planta Med, 67, 811-814.
Miyasaka, N., Inoue, H., Totsuka, T., Koike, R., Kino, K. and Tsunoo, H. (1992) An immunomodulatory protein, Ling Zhi-8, facilitates cellular interaction through modulation of adhesion molecules. Biochem Biophys Res Commun, 186, 385-390.
Mizuki, D., Miura, T., Sasaki, S., Mizuki, M., Madarame, H. and Nakane, A. (2001) Interference between host resistance to Listeria monocytogenes infection and ovalbumin-induced allergic responses in mice. Infect Immun, 69, 1883-1888.
Navarro, A., Anand-Apte, B., Tanabe, Y., Feldman, G. and Larner, A.C. (2003) A PI-3 kinase-dependent, Stat1-independent signaling pathway regulates interferon-stimulated monocyte adhesion. J Leukoc Biol, 73, 540-545.
Nguyen, H., Ramana, C.V., Bayes, J. and Stark, G.R. (2001) Roles of phosphatidylinositol 3-kinase in interferon-gamma-dependent phosphorylation of STAT1 on serine 727 and activation of gene expression. J Biol Chem, 276, 33361-33368.
Nick, J.A., Avdi, N.J., Gerwins, P., Johnson, G.L. and Worthen, G.S. (1996) Activation of a p38 mitogen-activated protein kinase in human neutrophils by lipopolysaccharide. J Immunol, 156, 4867-4875.
O''Donoghue, G.V., Okarma, T.B. and Lee, Y.M. (1993) An immune complex selective affinity column utilizing site-specific attachment of bovine conglutinin. Anal Biochem, 213, 310-317.
Ohteki, T., Parsons, M., Zakarian, A., Jones, R.G., Nguyen, L.T., Woodgett, J.R. and Ohashi, P.S. (2000) Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3. J Exp Med, 192, 99-104.
Ohtsuka, T., Kaziro, Y. and Satoh, T. (1996) Analysis of the T-cell activation signaling pathway mediated by tyrosine kinases, protein kinase C, and Ras protein, which is modulated by intracellular cyclic AMP. Biochim Biophys Acta, 1310, 223-232.
Patocka, J. (1999) Anti-inflammatory triterpenoids from mysterious mushroom Ganoderma lucidum and their potential possibility in modern medicine. Acta Medica (Hradec Kralove), 42, 123-125.
Peebles, R.S., Jr., Dworski, R., Collins, R.D., Jarzecka, K., Mitchell, D.B., Graham, B.S. and Sheller, J.R. (2000) Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice. Am J Respir Crit Care Med, 162, 676-681.
Puddu, P., Fantuzzi, L., Borghi, P., Varano, B., Rainaldi, G., Guillemard, E., Malorni, W., Nicaise, P., Wolf, S.F., Belardelli, F. and Gessani, S. (1997) IL-12 induces IFN-gamma expression and secretion in mouse peritoneal macrophages. J Immunol, 159, 3490-3497.
Rincon, M., Enslen, H., Raingeaud, J., Recht, M., Zapton, T., Su, M.S., Penix, L.A., Davis, R.J. and Flavell, R.A. (1998) Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. Embo J, 17, 2817-2829.
Rooney, J.W., Hodge, M.R., McCaffrey, P.G., Rao, A. and Glimcher, L.H. (1994) A common factor regulates both Th1- and Th2-specific cytokine gene expression. Embo J, 13, 625-633.
Rossig, L., Jadidi, A.S., Urbich, C., Badorff, C., Zeiher, A.M. and Dimmeler, S. (2001) Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells. Mol Cell Biol, 21, 5644-5657.
Sanceau, J., Hiscott, J., Delattre, O. and Wietzerbin, J. (2000) IFN-beta induces serine phosphorylation of Stat-1 in Ewing''s sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7. Oncogene, 19, 3372-3383.
Seger, R. and Krebs, E.G. (1995) The MAPK signaling cascade. Faseb J, 9, 726-735.
Shimizu, A., Yano, T., Saito, Y. and Inada, Y. (1985) Isolation of an inhibitor of platelet aggregation from a fungus, Ganoderma lucidum. Chem Pharm Bull (Tokyo), 33, 3012-3015.
Stark, G.R., Kerr, I.M., Williams, B.R., Silverman, R.H. and Schreiber, R.D. (1998) How cells respond to interferons. Annu Rev Biochem, 67, 227-264.
Stein, R.C. and Waterfield, M.D. (2000) PI3-kinase inhibition: a target for drug development? Mol Med Today, 6, 347-357.
Tandon, P. and Diamond, S.L. (1998) Kinetics of beta2-integrin and L-selectin bonding during neutrophil aggregation in shear flow. Biophys J, 75, 3163-3178.
Tang, S.-C. (2001) Regulation of Interferon-gamma by the Immunomodulatory protein from Flammulina velutipes. Institute of Toxicology. Chung Shan Medical University, Taichung.
Thiele, D.L., Kurosaka, M. and Lipsky, P.E. (1983) Phenotype of the accessory cell necessary for mitogen-stimulated T and B cell responses in human peripheral blood: delineation by its sensitivity to the lysosomotropic agent, L-leucine methyl ester. J Immunol, 131, 2282-2290.
Toker, A., Meyer, M., Reddy, K.K., Falck, J.R., Aneja, R., Aneja, S., Parra, A., Burns, D.J., Ballas, L.M. and Cantley, L.C. (1994) Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3. J Biol Chem, 269, 32358-32367.
Townley, R.G. and Suliaman, F. (1987) The mechanism of corticosteroids in treating asthma. Ann Allergy, 58, 1-6.
Ueno, Y., Kohgo, Y., Sakamaki, S., Itoh, Y., Takahashi, M., Hirayama, Y. and Niitsu, Y. (1994) Immunochemotherapy in B-16-melanoma-cell-transplanted mice with combinations of interleukin-2, cyclophosphamide, and PSK. Oncology, 51, 296-302.
van der Hem, L.G., van der Vliet, J.A., Bocken, C.F., Kino, K., Hoitsma, A.J. and Tax, W.J. (1995) Ling Zhi-8: studies of a new immunomodulating agent. Transplantation, 60, 438-443.
van der Zee, J.S., van Swieten, P., Jansen, H.M. and Aalberse, R.C. (1988) Skin tests and histamine release with P1-depleted Dermatophagoides pteronyssinus body extracts and purified P1. J Allergy Clin Immunol, 81, 884-896.
Vanhaesebroeck, B., Welham, M.J., Kotani, K., Stein, R., Warne, P.H., Zvelebil, M.J., Higashi, K., Volinia, S., Downward, J. and Waterfield, M.D. (1997) P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A, 94, 4330-4335.
Vivanco, I. and Sawyers, C.L. (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer, 2, 489-501.
Wang, S.Y., Hsu, M.L., Hsu, H.C., Tzeng, C.H., Lee, S.S., Shiao, M.S. and Ho, C.K. (1997) The anti-tumor effect of Ganoderma lucidum is mediated by cytokines released from activated macrophages and T lymphocytes. Int J Cancer, 70, 699-705.
Wang, Y.Y., Khoo, K.H., Chen, S.T., Lin, C.C., Wong, C.H. and Lin, C.H. (2002) Studies on the immuno-modulating and antitumor activities of Ganoderma lucidum (Reishi) polysaccharides: functional and proteomic analyses of a fucose-containing glycoprotein fraction responsible for the activities. Bioorg Med Chem, 10, 1057-1062.
Ward, S.G., June, C.H. and Olive, D. (1996) PI 3-kinase: a pivotal pathway in T-cell activation? Immunol Today, 17, 187-197.
Wedemeyer, J. and Galli, S.J. (2000) Mast cells and basophils in acquired immunity. Br Med Bull, 56, 936-955.
Yazdanbakhsh, M., Kremsner, P.G. and van Ree, R. (2002) Allergy, parasites, and the hygiene hypothesis. Science, 296, 490-494.
Ye, J., Ortaldo, J.R., Conlon, K., Winkler-Pickett, R. and Young, H.A. (1995) Cellular and molecular mechanisms of IFN-gamma production induced by IL-2 and IL-12 in a human NK cell line. J Leukoc Biol, 58, 225-233.
Yoneda, O., Imai, T., Nishimura, M., Miyaji, M., Mimori, T., Okazaki, T., Domae, N., Fujimoto, H., Minami, Y., Kono, T., Bloom, E.T. and Umehara, H. (2003) Membrane-bound form of fractalkine induces IFN-gamma production by NK cells. Eur J Immunol, 33, 53-58.
Young, P.R., McLaughlin, M.M., Kumar, S., Kassis, S., Doyle, M.L., McNulty, D., Gallagher, T.F., Fisher, S., McDonnell, P.C., Carr, S.A., Huddleston, M.J., Seibel, G., Porter, T.G., Livi, G.P., Adams, J.L. and Lee, J.C. (1997) Pyridinyl imidazole inhibitors of p38 mitogen-activated protein kinase bind in the ATP site. J Biol Chem, 272, 12116-12121.
Yssel, H., Johnson, K.E., Schneider, P.V., Wideman, J., Terr, A., Kastelein, R. and De Vries, J.E. (1992) T cell activation-inducing epitopes of the house dust mite allergen Der p I. Proliferation and lymphokine production patterns by Der p I-specific CD4+ T cell clones. J Immunol, 148, 738-745.
Yu, C.K., Lee, S.C., Wang, J.Y., Hsiue, T.R. and Lei, H.Y. (1996) Early-type hypersensitivity-associated airway inflammation and eosinophilia induced by Dermatophagoides farinae in sensitized mice. J Immunol, 156, 1923-1930.
Zhang, G.L., Wang, Y.H., Ni, W., Teng, H.L. and Lin, Z.B. (2002) Hepatoprotective role of Ganoderma lucidum polysaccharide against BCG-induced immune liver injury in mice. World J Gastroenterol, 8, 728-733.
Zuany-Amorim, C., Sawicka, E., Manlius, C., Le Moine, A., Brunet, L.R., Kemeny, D.M., Bowen, G., Rook, G. and Walker, C. (2002) Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med, 8, 625-629.