臺灣博碩士論文加值系統

臨床上嚴重敗血症或敗血性休克病人多肇因於內毒素引起之免疫失衡，此類免疫失衡起因於早期感染時，釋出大量細胞激素，造成體內多器官受損、衰竭而死亡。其中，巨噬細胞移行抑制因子(macrophage migration inhibitory factor, MIF)於感染早期扮演調控細胞激素的重要角色而受重視。目前對於MIF在細胞感染模式下的表現調控，以及相關轉錄因子之功能與其重要性，並無太多探討。因此，本文探討在感染模式下，MIF基因啟動子上不同的轉錄因子結合部位所扮演的角色。我們建構不同長度的啟動子報導基因表現載體來探討MIF基因啟動子活性，並利用冷光酵素啟動子分析與電泳遷移分析(electrophoretic mobility shift assay, EMSA)技術，探討轉錄因子對MIF基因表現之影響。經由啟動子分析發現，脂多醣(lipopolysaccharide)可誘導MIF起動子活性，而同時給予地塞米松(dexamethasone)則可以抑制脂多醣的誘導效應。我們接下來定點突變MIF啟動子上，經由網路資源預測到的轉錄因子結合位點，發現一些點突變後，啟動子活性顯著降低，但脂多醣與地塞米松仍有作用。而突變缺氧誘導因子1 (hypoxia‐inducible factor 1 alpha, HIF-1α)位點時，啟動子活性顯著被抑制，脂多醣也無法誘導啟動子活性增加。突變cAMP-response element (CRE)和specific protein 1 (Sp1)位點亦會抑制啟動子活性，但不影響脂多醣與地塞米松的作用。類似HIF-1α位點，突變轉譯作用起點前-540的可能的醣皮質醇受體結合位點(GR540)，也發現啟動子活性顯著被抑制，且脂多醣也無法誘導啟動子活性。所以醣皮質醇受體調控MIF基因，可能不是直接經由醣皮質醇受體結合部位，可能是經由其他間接路徑，例如GILZ (glucocorticoid-induced leucine zipper)，去抑制脂多醣所誘導之啟動子活性。以上這些發現指出HIF-1α、GR540轉錄因子結合位點可能在MIF基因基礎表現調控上扮演重要角色，同時亦會影響脂多醣和地塞米松對MIF基因表現的作用。此結果有助於我們更瞭解醣皮質醇透過醣皮質醇受體調控MIF基因表現的轉錄機轉。

Clinically, the severe sepsis or septic shock in patients was caused by the immune imbalance by endotoxin, which induces a large number of cytokine release in the early infection, resulting in the subsequent multiple organ damage, failure and death. The macrophage migration inhibitory factor (MIF) gene plays an important role in regulating the cytokine release in the early stage of infection. The regulation of MIF gene expression and the importance of transcription factors on its promoter in the bacterial infection model is not clear. Therefore, we focused on the promoter activity of MIF gene and the role of different transcription factors in the cellular infection model in this study. We first constructed different lengths of MIF gene’s promoter fragments into PGL4.10 vectors to investigate the MIF gene promoter activities. Then, we used daul-luciferase assaies and electrophoretic mobility shift assaies (EMSA) to investigate the effects of the putative transcription factor binding sites on MIF gene expression. Treatment of lipopolysaccharide (LPS) induced the promoter activity and dexamethasone (Dex) reversed this effect. We also performed the site-directed mutagenesis of the predicted binding sites for the transcription factors on the MIF promoter and promoter studies to investigate the importance of these sites. Mutating the binding site of hypoxia‐inducible factor 1 alpha (HIF-1α) on MIF promoter, the promoter activities were significantly decreased and LPS-induced effects were also inhibited. Mutations of the cAMP-response element (CRE) and specific protein 1 (Sp1) binding sites deacreased the MIF promoter activities, whereas, the effects of LPS and Dex were not altered. Mutating the predicted GR binding site at -540 (GR540) also significantly inhibited the promoter activities of MIF gene and LPS effects. However, it did not showed any shifted bands in the EMSA, suggesting that glucocorticoid receptor regulates the MIF promoter activity induced by LPS may be through an indirect pathway, such as the glucocorticoid-induced leucine zipper (GILZ) pathway, rather than bind to the promoter region directly. These findings indicate that the transcription factor binding sites of GR540 and HIF-1α may play important roles in the basal MIF gene promoter activity, as well as the effects of LPS and Dex treatments. The results of the study help us further understand the transcriptional mechanisms of MIF by GRs.

論文口試委員審定書 i
誌謝 ii
中文摘要 iv
Abstract vi
縮寫表 viii
目錄 x
圖表目錄 xiii
附錄 x
第一章 前言 1
第一節 免疫系統的分類 1
第二節 MIF的發現與分子結構 2
第三節 MIF在腫瘤中表現與扮演之角色 3
第四節 MIF在免疫反應中扮演之角色 5
第五節 醣皮質醇對MIF與轉錄因子之功能影響 8
第二章 研究動機與目標 10
第三章 實驗材料與方法 12
第一節 建構質體和定點突變 12
第二節 Raw 264.7與HEK293細胞培養 13
第三節 純化質體DNA和去除內毒素 14
第四節 短暫性轉染 16
第五節 冷光酵素啟動子分析 17
第六節 核蛋白萃取 18
第七節 蛋白質定量 19
第八節 電泳遷移分析 20
第九節 統計方法 22
第四章 實驗結果 23
第一節 MIF基因結構與啟動子序列 23
第二節 藥物調控MIF基因啟動子活性 24
第三節 轉錄因子在MIF基因表現所扮演的角色 25
第四節 轉錄因子與MIF啟動子之交互作用 27
第五章 討論 30
第一節 HIF-1α結合位點在MIF啟動子調控是重要的 30
第二節 醣皮質醇受體可能不直接結合在MIF啟動子上 31
第三節 未來展望 31
第四節 結論 34
參考文獻 35
作者簡歷 75

Alberts B, Alexander J, Julian L, Martin R, Keith R, Peter W. Molecular Biology of the Cell. Fourth Edition.New York and London: Garland Science. 2002.
Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaud P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002, 288(7):862-871.
Ayroldi E, Migliorati G, Bruscoli S, Marchetti C, Zollo O, Cannarile L, D'Adamio F, Riccardi C. Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB. Blood. 2001, 98(3):743-753.
Ayroldi E, Riccardi C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J. 2009, 23(11):3649-3658.
Bach JP, Rinn B, Meyer B, Dodel R, Bacher M. Role of MIF in inflammation and tumorigenesis. Oncology. 2008, 75: 127–133.
Bacher M, Meinhardt A, Lan HY, Dhabhar FS, Mu W, Metz CN, Chesney JA, Gemsa D, Donnelly T, Atkins RC, Bucala R. MIF expression in the rat brain: implications for neuronal function. Mol Med. 1998, 4(4):217-230.
Bacher M, Metz CN, Calandra T, Mayer K, Chesney J, Lohoff M, Gemsa D, Donnelly T, Bucala R. An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci U S A. 1996, 93(15):7849-7854.
Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. 2006, 148(3):245-254.
Bloom BR, Bennett B. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science. 1966, 153(3731):80-82.
Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004, 25(6):280-288.
Bowers W. Immunology -Chapter Thirteen: Immunoregulation. Microbiology and Immunology On-Line Textbook. USC School of Medicine. 2006.
Bozza M, Satoskar AR, Lin G, Lu B, Humbles AA, Gerard C, David JR. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J Exp Med. 1999, 189(2):341-346.
Bucala R, Donnelly SC. Macrophage migration inhibitory factor: a probable link between inflammation and cancer. Immunity. Immunity. 2007, 26(3):281-285.
Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, Cerami A, Bucala R. MIF as a glucocorticoid-induced modulator of cytokine production. Nature. 1995, 377(6544):68-71.
Calandra T, Bernhagen J, Mitchell RA, Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med. 1994, 179(6):1895-1902.
Calandra T, Roger T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003, 3(10):791-800.
Calandra T, Spiegel LA, Metz CN, Bucala R. Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria. Proc Natl Acad Sci U S A. 1998, 95(19):11383-11388.
Chen ST. Effects of glucocorticoid on interleukin 6 gene expression. 2016. Master thesis.
Cheng Q, Morand E, Yang YH. Development of novel treatment strategies for inflammatory diseases-similarities and divergence between glucocorticoids and GILZ. Front Pharmacol. 2014, 5:169.
Chesney J, Metz C, Bacher M, Peng T, Meinhardt A, et al. An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma. Mol Med. 1999, 5(3):181-191.
Chrousos GP. The Hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.N Engl J 1995, 332(20):1351-1363.
Chuang CC, Chuang YC, Chang WT, Chen CC, Hor LI, Huang AM, Choi PC, Wang CY, Tseng PC, Lin CF. Macrophage migration inhibitory factor regulates interleukin-6 production by facilitating nuclear factor-kappa B activation during Vibrio vulnificus infection. BMC Immunol. 2010, 11:50.
Conroy H, Mawhinney L, Donnelly SC. Inflammation and cancer: Macrophage migration inhibitory factor (MIF) - the potential missing link. QJM. 2010, 103(11):831-836.
D'Adamio F, Zollo O, Moraca R, Ayroldi E, Bruscoli S, Bartoli A, Cannarile L, Migliorati G, Riccardi C. A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death. Immunity. 1997, 7(6):803-812.
David JR. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci U S A. 1966, 56(1):72-77.
Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM; Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004, 32(3):858-873.
Donn RP, Ray DW. Macrophage migration inhibitory factor: Molecular, cellular and genetic aspects of a key neuroendocrine molecule. J Endocrinol. 2004, 182(1):1-9.
Eddy JL, Krukowski K, Janusek L, Mathews HL. Glucocorticoids regulate natural killer cell function epigenetically. Cell Immunol. 2014, 290(1):120-130.
Fan H, Morand EF. Targeting the side effects of steroid therapy in autoimmune diseases: the role of GILZ.Discov Med. Discov Med. 2012, 13(69):123-133.
Fingerle-Rowson G, Petrenko O, Metz CN, Forsthuber TG, Mitchell R, Huss R, Moll U, Müller W, Bucala R. The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc Natl Acad Sci U S A. 2003, 100(16):9354-9359.
Frede S, Stockmann C, Freitag P, Fandrey J. Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB. Biochem J. 2006, 396(3):517-527.
Gelber JD. CORR Insights®: Corticosteroid injections give small and transient pain relief in rotator cuff tendinosis: A meta-analysis. Clin Orthop Relat Res. 2017, 475(1):244-246.
Gennari C. Differential effect of glucocorticoids on calcium absorption and bone mass. Br J Rheumatol. 1993, 32 Suppl 2:11-4.
Giaccia AJ, Simon MC, Johnson R. The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease. Genes Dev. 2004, 18(18):2183-2194.
Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009, 458(7242):1127-1130.
Hardman MJ, Waite A, Zeef L, Burow M, Nakayama T, Ashcroft GS. Macrophage migration inhibitory factor: a central regulator of wound healing. Am J Pathol. 2005, 167(6):1561-1574.
Harms K, Nozell S, Chen X. The common and distinct target genes of thep53 family transcription factors. Cell Mol Life Sci. 2004, 61(7-8):822-842.
Hoi AY, Hickey MJ, Hall P, Yamana J, O'Sullivan KM, Santos LL, James WG, Kitching AR, Morand EF. Macrophage migration inhibitory factor deficiency attenuates macrophage recruitment, glomerulonephritis, and lethality in MRL/lpr mice. J Immunol. 2006, 177(8):5687-5696.
Keenan PA, Jacobson MW, Soleymani RM, Mayes MD, Stress ME, Yaldoo DT. The effect on memory of chronic prednisone treatment in patients with systemic disease. Neurology. 1996, 47(6):1396-1402.
Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S, Bogatsch H, Briegel J, Engel C, Gerlach H, Goldmann A, Kuhn SO, Hüter L, Meier-Hellmann A, Nierhaus A, Kluge S, Lehmke J, Loeffler M, Oppert M, Resener K, Schädler D, Schuerholz T, Simon P, Weiler N, Weyland A, Reinhart K, Brunkhorst FM; SepNet-Critical Care Trials Group. Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial. JAMA. 2016, 316(17):1775-1785.
Kindt N, Preillon J, Kaltner H, Gabius HJ, Chevalier D, Rodriguez A, Johnson BD, Megalizzi V, Decaestecker C, Laurent G, Saussez S. Macrophage migration inhibitory factor in head and neck squamous cell carcinoma: Clinical and experimental studies. J Cancer Res Clin Oncol. 2013, 139(5):727-737.
Klein NC, Go CH, Cunha BA. Infections associated with steroid use. Infectious Disease Clinics of North America. 2001, 15 (2): 423-432.
Koch CA, Doppman JL, Patronas NJ, Nieman LK, Chrousos GP. Do glucocorticoids cause spinal epidural lipomatosis? When endocrinology and spinal surgery meet. Trends Endocrinol Metab. 2000, 11(3):86-90.
Krockenberger M, Kranke P, Häusler S, Engel JB, Horn E, Nürnberger K, Wischhusen J, Dietl J, Hönig A. Macrophage migration-inhibitory factor levels in serum of patients with ovarian cancer correlates with poor prognosis. Anticancer Res. 2012, 32(12):5233-5238.
Lannan EA, Galliher-Beckley AJ, Scoltock AB, Cidlowski JA. Proinflammatory actions of glucocorticoids: glucocorticoids and TNFα coregulate gene expression in vitro and in vivo. Endocrinology. 2012, 153(8):3701-3712.
Lee CY, Su MJ, Huang CY, Chen MY, Hsu HC, Lin CY, Tang CH. Macrophage migration inhibitory factor increases cell motility and up-regulates αvβ3 integrin in human chondrosar-coma cells. J Cell Biochem. 2012, 113(5):1590-1598.
Leng L, Bucala R. Macrophage migration inhibitory factor. Crit Care Med. 2005, 33:S475–477.
Leonard MO, Cottell DC, Godson C, Brady HR, Taylor CT. The role of HIF-1 alpha in transcriptional regulation of the proximal tubular epithelial cell response to hypoxia. J Biol Chem. 2003, 278(41):40296-40304.
Lim W, Park C, Shim MK, Lee YH, Lee YM, Lee Y. Glucocorticoids suppress hypoxia-induced COX-2 and hypoxia inducible factor-1α expression through the induction of glucocorticoid-induced leucine zipper. Br J Pharmacol. 2014, 171(3):735-745.
Litman GW, Cannon JP, Dishaw LJ. Reconstructing immune phylogeny: new perspectives. Nat Rev Immunol. 2005, 5(11):866-879.
Lubetsky JB, Dios A, Han J, Aljabari B, Ruzsicska B, Mitchell R, Lolis E, Al-Abed Y. The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents. J Biol Chem. 2002, 277(28):24976-24982.
Lue H, Kleemann R, Calandra T, Roger T, Bernhagen J. Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microbes Infect. 2002, 4(4):449-460.
Mayer G. Immunology - Chapter One: Innate (non-specific) Immunity. Microbiology and Immunology On-Line Textbook. USC School of Medicine. 2006.
Meyer-Siegler K. COX-2 specific inhibitor, NS-398, increases macrophage migration inhibitory factor expression and induces neuroendocrine differentiation in C4-2b prostate cancer cells. Mol Med. 2001, 7(12):850-860.
Mitchell RA, Liao H, Chesney J, Fingerle-Rowson G, Baugh J, David J, Bucala R. Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proc Natl Acad Sci U S A. 2002, 99(1):345-350.
Mitchell RA. Mechanisms and effectors of MIF-dependent promotion of tumourigenesis. Cell Signal. 2004, 16(1):13-19.
Mohamadi A, Chan JJ, Claessen FM, Ring D, Chen NC. Corticosteroid injections give small and transient pain relief in rotator cuff tendinosis: A meta-analysis. Clin Orthop Relat Res. 2017, 475(1):232-243.
Moll UM, Wolff S, Speidel D, Deppert W. Transcription-independent proapoptotic functions of p53. Curr Opin Cell Biol 2005, 17:631–636.
Morand EF, Leech M, Bernhagen J. MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis. Nat Rev Drug Discov. 2006, 5(5):399-410.
Newton R, Holden NS. Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? Mol Pharmacol. 2007, 72(4):799-809.
Nishihira J, Koyama Y, Mizue Y. Identification of macrophage migration inhibitory factor (MIF) in human vascular endothelial cells and its induction by lipopolysaccharide. Cytokine. 1998 Mar;10(3):199-205.
Nishihira J. Macrophage migration inhibitory factor (MIF): its essential role in the immune system and cell growth. J Interferon Cytokine Res. 2000, 20(9):751-762.
Pancer Z, Cooper MD. The evolution of adaptive immunity. Annual Review of Immunology. 2006, 24: 497–518.
Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V. Cutting edge: Essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J Immunol. 2007, 178(12):7516-7519.
Revollo JR, Cidlowski JA. Mechanisms generating diversity in glucocorticoid receptor signaling. Ann N Y Acad Sci. 2009, 1179:167-178.
Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med. 2005, 353(16):1711-1723.
Riedemann NC, Guo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med. 2003, 9(5):517-524.
Roger T, David J, Glauser MP, Calandra T. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature. 2001, 414(6866):920-924.
Roger T, Ding X, Chanson AL, Renner P, Calandra T. Regulation of constitutive and microbial pathogen-induced human macrophage migration inhibitory factor (MIF) gene expression. Eur J Immunol. 2007, 37(12):3509-3521.
Ronchetti S, Migliorati G, Riccardi C. GILZ as a Mediator of the Anti-Inflammatory Effects of Glucocorticoids. Front Endocrinol (Lausanne). 2015, 6:170.
Rossi AG, Haslett C, Hirani N, Greening AP, Rahman I, Metz CN, Bucala R, Donnelly SC. Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma. J Clin Invest. 1998, 101(12):2869-2874.
Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002, 96(1):23-43.
Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. Hypoxiainducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci U S A. 1991, 88(13):5680-5684.
Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R. CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity. 2006, 25(4):595-606.
Shibanuma M, Kuroki T, Nose K. Isolation of a gene encoding a putative leucine zipper structure that is induced by transforming growth factor beta 1 and other growth factors. J Biol Chem. 1992 ,267(15):10219-10224.
Simko V, Takacova M, Debreova M, Laposova K, Ondriskova-Panisova E, Pastorekova S, Csaderova L, Pastorek J. Dexamethasone downregulates expression of carbonic anhydrase IX via HIF-1α and NF-κB-dependent mechanisms. Int J Oncol. 2016, 49(4):1277-1288.
Speidel D. Transcription-independent p53 apoptosis: an alternative route to death. Trends Cell Biol. 2010, 20(1):14-24.
Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008, 358(2):111-124.
Stvrtinová V, Jakubovský J, Hulín I. Inflammation and Fever from Pathophysiology: Principles of Disease. Computing Centre, Slovak Academy of Sciences: Academic Electronic Press. 1995.
Wang 1, Ma YY, Song XL, Cai HY, Chen JC, Song LN, Yang R, Lu J. Upregulations of glucocorticoid-induced leucine zipper by hypoxia and glucocorticoid inhibit proinflammatory cytokines under hypoxic conditions in macrophages. J Immunol. 2012, 188(1):222-229.
Wang D, Luo L, Chen W, Chen LZ, Zeng WT, Li W, Huang XH. Significance of the vascular endothelial growth factor and the macrophage migration inhibitory factor in the progression of hepatocellular carcinoma. Oncol Rep. 2014, 31(3):1199-1204.
Weiser WY, Temple PA,Witek-Giannotti JS, Remold HG, Clark SC, David JR. Molecular cloning of a cDNA encoding a human macrophagemigration inhibitory factor. Proc Natl Acad Sci U S A. 1989, 86(19):7522-7526.
Welford SM, Bedogni B, Gradin K, Poellinger L, Broome Powell M, Giaccia AJ. HIF1alpha delays premature senescence through the activation of MIF.Genes Dev. 2006, 20(24):3366-3371.
Wu CC. Regulation of Macrophage Migration Inhibitory Factor Gene Expression in an Infection Model. 2017. Master thesis.
Xin D, Rendon BE, Zhao M, Winner M, McGhee Coleman A, Mitchell RA. The MIF homologue D-dopachrome tautomerase promotes COX-2 expression through β-catenin-dependent and -independent mechanisms. Mol Cancer Res. 2010, 8(12):1601-1609.
Xu J, Chen S, Chen H, Xiao Q, Hsu CY, Michael D, Bao J. STAT5 mediates antiapoptotic effects of methylprednisolone on oligodendrocytes. J Neurosci. 2009 , 29(7):2022-2026.
Yoshida T, Sonozaki H, Cohen S. The production of migration inhibition factor by B and T cells of the guinea pig. J Exp Med. 1973, 138(4):784-797.
Zis O, Zhang S, Dorovini-Zis K, Wang L, Song W. Hypoxia signaling regulates macrophage migration inhibitory factor (MIF) expression in stroke. Mol Neurobiol. 2015, 51(1):155-167.
汪福洲、景亮。巨噬細胞移動抑制因子活性機制與炎症性疾病。南京東南大學附屬中大醫院麻醉科(Zhongda Hospitoal Southeast University)。2010。