巨噬细胞移动抑制因子在鱼类细菌性败血症中的生物学作用
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摘要
1966年发现了一种可抑制巨噬单核细胞移动的细胞因子,正式命名为巨噬细胞移动抑制因子(macrophage migration inhibitory factor,MIF),它是最早被鉴定的细胞因子之一。经过近几十年的研究发现,MIF是对发育、先天性免疫等发挥重要作用的多功能细胞因子,MIF被认为是调节其他炎症因子释放的炎症反应调控点。本文通过建立Aeromonas hydrophila引起的斑马鱼败血症模型,研究了MIF在细菌性败血症中的生物学功能。结果显示细菌感染后MIF含量迅速上升,而额外注射重组MIF会加剧败血症,当用抗MIF抗体处理后则能够明显缓解败血症,表明过量的MIF是有害的。我们的研究发现细菌感染诱导MIF,TLR5a,TLR5b,TLR9,TLR20a,IL-1β和TNF-α的产生,这些因子的相互关系研究证明细菌感染后MIF被释放出来,诱导TLR5a,TLR5b,TLR9,TLR20a的表达,大量的TLR受体使鱼体保持一种对细菌高敏感的状态,TLR受体识别并结合病原体相关分子模式(PAMPs),激活炎症信号通路,诱导大量炎症因子,而过量的炎症因子引起剧烈炎症反应,甚至导致鱼体休克。同时,我们用Tetraodon的MIF在斑马鱼上的功能研究与斑马鱼MIF的结果相似,显示出鱼类中MIF功能的保守性。对鱼类MIF的功能研究不仅丰富了鱼类免疫学知识,而且有助于深入了解MIF的分子进化及其在炎症反应中的作用。该研究还能为基于MIF治疗的临床研究和药物筛选提供一种新的鱼类模型。
Over the last decades, MIF has emerged to be a multi-functional cytokine that played pivotal roles in variety of biological activities, especially in innate immunity, MIF was believed to be critical in the control of inflammatory responses 'set point' by regulating the release of other pro-inflammatory cytokines. In the present study, by establishment of A.hydrophila mediated zebrafish sepsis model, we investigated the functions of MIF in the bacterial sepsis. The result showed that MIF was up-regulated after bacterial infection, and a bolus of recombinant MIF could exacerbate sepsis induced by this infection, neutralization of the MIF activity with anti-MIF antibody could protect fish from septic shock, confirming the harmful effect of an excessive amount of MIF. Our study showed that MIF, TLR5a, TLR5b, TLR9, TLR20a, IL-1βand TNF-αwas induced after infection with A.hydrophila, the research of the relationship between those during sepsis demonstrated that MIF was released after bacterial infection, which induced the expressions of TLR5a, TLR5b, TLR9, TLR20a, these abundant of TLRs made the body in the state of highly sensitive to the bacterial, TLRs recognized the molecules called pathogen-associated molecular patterns(PAMPs) of the bacteria, activating the cascade of the inflammatory pathway, resulting in releasing of inflammatory factors such as IL-1βand TNF-α, and if overdose of which will causing septic shock. The results using Tetraodon MIF in zebrafish were nearly the same of that using zebrafish MIF in zebrafish, confirming the conservatism of MIF between fishes. We hope that our functional characterization of MIF in fish will not only enrich the knowledge of fish immunology, but will also contribute to a better cross-species understanding of the evolutionary history of the MIF family and MIF-mediated regulatory roles in inflammatory immunity. We also hope that it will provide an opportunity to develop a novel fish model for clinical investigations and medical applications of MIF based therapies
Over the last decades, MIF has emerged to be a multi-functional cytokine that played pivotal roles in variety of biological activities, especially in innate immunity, MIF was believed to be critical in the control of inflammatory responses 'set point' by regulating the release of other pro-inflammatory cytokines. In the present study, by establishment of A.hydrophila mediated zebrafish sepsis model, we investigated the functions of MIF in the bacterial sepsis. The result showed that MIF was up-regulated after bacterial infection, and a bolus of recombinant MIF could exacerbate sepsis induced by this infection, neutralization of the MIF activity with anti-MIF antibody could protect fish from septic shock, confirming the harmful effect of an excessive amount of MIF. Our study showed that MIF, TLR5a, TLR5b, TLR9, TLR20a, IL-1βand TNF-αwas induced after infection with A.hydrophila, the research of the relationship between those during sepsis demonstrated that MIF was released after bacterial infection, which induced the expressions of TLR5a, TLR5b, TLR9, TLR20a, these abundant of TLRs made the body in the state of highly sensitive to the bacterial, TLRs recognized the molecules called pathogen-associated molecular patterns(PAMPs) of the bacteria, activating the cascade of the inflammatory pathway, resulting in releasing of inflammatory factors such as IL-1βand TNF-α, and if overdose of which will causing septic shock. The results using Tetraodon MIF in zebrafish were nearly the same of that using zebrafish MIF in zebrafish, confirming the conservatism of MIF between fishes. We hope that our functional characterization of MIF in fish will not only enrich the knowledge of fish immunology, but will also contribute to a better cross-species understanding of the evolutionary history of the MIF family and MIF-mediated regulatory roles in inflammatory immunity. We also hope that it will provide an opportunity to develop a novel fish model for clinical investigations and medical applications of MIF based therapies
引文
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32. Holmquist L, Lofstedt T, Pahlman S. Effect of hypoxia on the tumor phenotype: the neuroblastoma and breast cancer models. Adv Exp Med Biol 2006; 587: 179-193.
33. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006; 441: 437-443.
34. Koong AC, Denko NC, Hudson KM et al. Candidate genes for the hypoxic tumor phenotype. Cancer Res 2000; 60: 883-887.
35. Bando M, Hasegawa M, Tsuboi Y et al. The mycotoxin penicillic acid inhibits Fas ligand-induced apoptosis by blocking self-processing of caspase-8 in death-inducing signaling complex. J Biol Chem 2003; 278: 5786-5793.
36. Yao K, Shida S, Selvakumaran M et al. Macrophage migration inhibitory factor is a determinant of hypoxia-induced apoptosis in colon cancer cell lines. Clin Cancer Res 2005; 11: 7264-7272.
37. Winner M, Koong AC, Rendon BE et al. Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization. Cancer Res 2007; 67: 186-193.
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3.Bozza M,Satoskar AR,Lin G et al.Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J Exp Med 1999; 189: 341-346.
4. Bozza M, Kolakowski LF, Jr., Jenkins NA et al. Structural characterization and chromosomal location of the mouse macrophage migration inhibitory factor gene and pseudogenes. Genomics 1995; 27: 412-419.
5. Sato A, Uinuk-ool TS, Kuroda N et al. Macrophage migration inhibitory factor (MIF) of jawed and jawless fishes: implications for its evolutionary origin. Dev Comp Immunol 2003; 27: 401-412.
6. Pastrana DV, Raghavan N, FitzGerald P et al. Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor. Infect Immun 1998; 66: 5955-5963.
7. Jaworski DC, Jasinskas A, Metz CN et al. Identification and characterization of a homologue of the pro-inflammatory cytokine Macrophage Migration Inhibitory Factor in the tick, Amblyomma americanum. Insect Mol Biol 2001; 10: 323-331.
8. Jin HJ, Xiang LX, Shao JZ. Molecular cloning and identification of macrophage migration inhibitory factor (MIF) in teleost fish. Dev Comp Immunol 2007;31: 1131-1144.
9. 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: 1895-1902.
10. Fingerle-Rowson G, Koch P, Bikoff R et al. Regulation of macrophage migration inhibitory factor expression by glucocorticoids in vivo. Am J Pathol 2003; 162: 47-56.
11. Bernhagen J, Calandra T, Mitchell RA et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 1993; 365: 756-759.
12. Calandra T, Bernhagen J, Metz CN et al. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 1995; 377: 68-71.
13. Donnelly CA, Ghani AC, Ferguson NM, Anderson RM. Recent trends in the BSE epidemic. Nature 1997; 389: 903.
14. Leech M, Metz C, Bucala R, Morand EF. Regulation of macrophage migration inhibitory factor by endogenous glucocorticoids in rat adjuvant-induced arthritis. Arthritis Rheum 2000; 43: 827-833.
15. Rossi AG, Haslett C, Hirani N et al. Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma. J Clin Invest 1998; 101: 2869-2874.
16. Mizue Y, Ghani S, Leng L et al. Role for macrophage migration inhibitory factor in asthma. Proc Natl Acad Sci U S A 2005; 102: 14410-14415.
17. Baugh JA, Chitnis S, Donnelly SC et al. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 2002; 3: 170-176.
18. Plant BJ, Gallagher CG, Bucala R et al. Cystic fibrosis, disease severity, and a macrophage migration inhibitory factor polymorphism. Am J Respir Crit Care Med 2005; 172: 1412-1415.
19. Daun JM, Cannon JG. Macrophage migration inhibitory factor antagonizes hydrocortisone-induced increases in cytosolic IkappaBalpha. Am J Physiol Regul Integr Comp Physiol 2000; 279: R1043-1049.
20. Roger T, Chanson AL, Knaup-Reymond M, Calandra T. Macrophage migration inhibitory factor promotes innate immune responses by suppressing glucocorticoid-induced expression of mitogen-activated protein kinase phosphatase-1. Eur J Immunol 2005; 35: 3405-3413.
21. Roger T, David J, Glauser MP, Calandra T. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 2001; 414: 920-924.
22. Calandra T, Echtenacher B, Roy DL et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 2000; 6: 164-170.
23. Meyer-Siegler KL, Iczkowski KA, Leng L et al. Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells. J Immunol 2006; 177: 8730-8739.
24. Bourguignon LY, Singleton PA, Zhu H, Diedrich F. Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. JBiol Chem 2003; 278: 29420-29434.
25. Liu R, Wang X, Chen GY et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 2007; 356: 217-226.
26. Chesney J, Metz C, Bacher M et al. An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma. Mol Med 1999; 5: 181-191.
27. Shimizu T, Abe R, Nakamura H et al. High expression of macrophage migration inhibitory factor in human melanoma cells and its role in tumor cell growth and angiogenesis. Biochem Biophys Res Commun 1999; 264: 751-758.
28. White ES, Strom SR, Wys NL, Arenberg DA. Non-small cell lung cancer cells induce monocytes to increase expression of angiogenic activity. J Immunol 2001; 166: 7549-7555.
29. Ren Y, Tsui HT, Poon RT et al. Macrophage migration inhibitory factor: roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinoma. Int J Cancer 2003; 107: 22-29.
30. Wilson JM, Coletta PL, Cuthbert RJ et al. Macrophage migration inhibitory factor promotes intestinal tumorigenesis. Gastroenterology 2005; 129: 1485-1503.
31. Amin MA, Volpert OV, Woods JM et al. Migration inhibitory factor mediates angiogenesis via mitogen-activated protein kinase and phosphatidylinositol kinase. Circ Res 2003; 93: 321-329.
32. Holmquist L, Lofstedt T, Pahlman S. Effect of hypoxia on the tumor phenotype: the neuroblastoma and breast cancer models. Adv Exp Med Biol 2006; 587: 179-193.
33. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006; 441: 437-443.
34. Koong AC, Denko NC, Hudson KM et al. Candidate genes for the hypoxic tumor phenotype. Cancer Res 2000; 60: 883-887.
35. Bando M, Hasegawa M, Tsuboi Y et al. The mycotoxin penicillic acid inhibits Fas ligand-induced apoptosis by blocking self-processing of caspase-8 in death-inducing signaling complex. J Biol Chem 2003; 278: 5786-5793.
36. Yao K, Shida S, Selvakumaran M et al. Macrophage migration inhibitory factor is a determinant of hypoxia-induced apoptosis in colon cancer cell lines. Clin Cancer Res 2005; 11: 7264-7272.
37. Winner M, Koong AC, Rendon BE et al. Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization. Cancer Res 2007; 67: 186-193.
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