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研究生：	莊佳璋 Chuang, Chia-Chang
論文名稱：	血清巨噬細胞移行抑制因子於急重症疾病扮演之免疫調控角色 The immunoregulatory role of serum macrophage migration inhibitory factor in acute illnesses
指導教授：	何漣漪 Hor, Lien-I 莊銀清 Chuang, Yin-Ching
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2010
畢業學年度：	98
語文別：	中文
論文頁數：	79
中文關鍵詞：	巨噬細胞移行抑制因子、嚴重敗血症、嚴重鈍傷、早期死亡率、創傷弧菌、抑制劑ISO-1 、轉錄因子NF-kB活化
外文關鍵詞：	macrophage migration inhibitory factor, severe sepsis, severe blunt trauma, early mortalities, Vibrio vulnificus, ISO-1, NF-kB activation
相關次數：	點閱：141 下載：2
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巨噬細胞移行抑制因子(macrophage migration inhibitory factor, 簡稱MIF)在敗血症病患，特別是在革蘭氏陰性菌敗血症感染時，因具有調控急性發炎免疫反應而受到注意。由於它對巨噬細胞及T淋巴球具有抑制類皮質糖素(glucocorticoid)及抗發炎的作用，近年來在急重症醫學領域中被認為重要的上游調控因子(upstream mediator)。我們在臨床觀察到嚴重敗血症病患、甚至嚴重創傷病患於急診就醫時，其血中MIF值有明顯升高的現象，其與臨床嚴重度呈現有意義的相關性，尤其重要的是MIF似乎可以作為嚴重敗血症或嚴重創傷病患的預後指標。在此急重症病患中，我們觀察到嚴重病患於感染24 小時後，血中MIF值如持續升高，其早期死亡率(即入院後前3天或前7天內死亡者)將明顯增加；同樣的，血中MIF值持續升高者，此病患晚期死亡率(入院後28天內死亡者)亦有增加的趨勢。我們進一步以創傷弧菌感染小鼠模式來摹擬臨床嚴重敗血症情形。我們發現早期感染小鼠血中MIF值越高者，其死亡率越高，確認感染創傷弧菌後MIF較其他早期發炎激素如腫瘤壞死因子(tumor necrosis factor, TNF-α)或介白素(interleukin, IL-6, IL-8)更早被誘發，意謂MIF可能具有調控或促進其他下游激素的角色(enhancer)。同樣以創傷弧菌感染人類全血細胞後，我們觀察到施予MIF抑制劑ISO-1後，促發炎激素如TNF-α, IL-6及IL-8的釋出呈現明顯下降的現象，且此抑制現象隨著時間及劑量的增加而更加明顯。我們進一步想瞭解此機轉究竟透過Akt, p38 MAPK，抑或NF-kB pathway來調控。在使用Akt, p38 MAPK及NF-kB抑制劑後，証實創傷弧菌感染人類周邊血液細胞後細胞激素的釋出主要經由p38 MAPK及NF-kB pathway來調控，但不受Akt的調控。ISO-1的施予後，可以降低轉錄因子NF-kB的活性、降低IL-6mRNA的表現及抑制IkB蛋白的磷酸化。此結果證實，在創傷弧菌感染模式下，人類周邊血液細胞其發炎細胞激素IL-6的釋出應經由MIF來調控，亦即IL-6的釋出可經由MIF 來調控其轉錄因子NF-kB及mRNA的表現。經由上述實驗我們可以進一步瞭解創傷弧菌感染時MIF可能的作用機轉，此機轉或許有助於將來嚴重敗血症時發展標靶治療的方向。

Macrophage migration inhibitory factor (MIF) has been proposed to be a pivotal cytokine of the innate immune system and plays an important role during sepsis, especially in infections by the Gram-negative bacteria. The critical regulatory role of MIF was demonstrated by its ability to override the anti-inflammatory and immunosuppressive effects of glucocorticoids on macrophage and T cells. Thereby it was strongly suggested that MIF may be an upstream mediator during stress or severe sepsis in critical care medicine. We observed the significant elevation of MIF levels in clinical situations such as patients with severe sepsis or patients with severe blunt traumas. Moreover, serum MIF correlated with clinical severity score and seemed to be a valuable prognostic factor in traumatic patients. Among patients with severe sepsis, a high percentage of increase between serum MIF levels on first day and second day could predict higher 3- and 7-day mortalities (early mortality), as well as 28-day mortalities (late mortality). By using the sepsis model, we found that MIF increased the inflammation of Vibrio vulnificus (V. vulnificus) infection in vivo. In V. vulnificus-infected mice, MIF was induced earlier than tumor necrosis factor (TNF)-α and interleukin (IL)-6 and was time-dependently expressed. Early high MIF levels were also noted in mice which died within 48 hrs. ISO-1 ((S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester), a small molecule inhibitor of MIF, significantly, and both time- and dose-dependently, decreased IL-6, IL-8, and TNF-α induction in human peripheral blood cells infected with V. vulnificus. We further demonstrated that the induction of IL-6, IL-8, and TNF-α production by V. vulnificus infection was mediated via the NF-κB- and p38 MAPK-regulated pathways, but not the Akt pathway. ISO-1-treated human peripheral blood cells showed lower induced NF-κB activation, IL-6 mRNA expression, and IκB phosphorylation, but not of p38MAPK activation. These results suggest that MIF may regulate V. vulnificus-induced IL-6 production via NF-κB and mRNA activation. From our studies, we could have a better understanding of the molecular mechanisms of MIF modulating V. vulnificus-induced sepsis. These results may provide some recommendations of target therapy in severe sepsis in the future.

Abstract in Chinese........................................I
Abstract.................................................VII
Acknowledgements..........................................IX
Contents..................................................XI
Abbreviation............................................XIII
1.  Introduction...........................................1
1-1.Background.............................................1
1-2.Role of the macrophage in innate immune response of 
    sepsis.................................................2
1-3.Clinical significance of macrophage MIF and its 
    associated researches..................................3
1-4.Clinical significance of Vibrio vulnificus (V.   
    vulnificus) infection..................................5
1-5.MIF regulates critical intracellular signal 
    transduction involved in sepsis........................8
2.  Experimental Methods..................................11
2-1.Clinical study........................................11
2-1-1. Subjects and inclusion criteria...................11 
2-1-2. Clinical severity scores and evaluation............12
2-1-3. Immunological assays...............................13
2-2.Animal infection model................................15
2-2-1. V.vulnificus infection in the mouse................15
2-2-2. Measurement of MIF, IL-6, TNF-α and IL-1β levels in mouse serum...............................................15
2-3.In vitro studies with human blood cells...............16
2-3-1. Preparation of human peripheral blood cells........16
2-3-2. Measurement of proinflammatory cytokines produced   
       by human PBMCs.....................................16
2-3-3. Treatment of human PBMCs with inhibitors...........17
2-3-4. Measurement of Akt, p38 MAPK and IκB by Western 
       blotting analysis..................................17
2-3-5. Measurement of NF-κB binding activity by gel 
       electrophoretic mobility shift assays (EMSA).......18
2-3-6. Measurement of IL-6 mRNA by reverse-transcription 
       polymerase chain reaction (RT-PCR).................19
2-4.Statistical analysis..................................20
3.  Results...............................................21
3-1.Serum macrophage MIF levels in patients with severe 
    sepsis predict early and late mortalities.............21
3-1-1. Serum MIF levels measured in patients with severe 
       sepsis on day 1 and day 2..........................22
3-1-2. Correlation of changes of serum MIF levels and 
       early mortalities in severely septic patients.....22 
3-1-3. Correlation of serum MIF levels on day 1 and late 
       mortalities in severely septic patients............22
3-1-4. Correlation between serum MIF levels and clinical 
       severity scores in severely septic patients........23
3-2.Circulating serum macrophage MIF levels in patients 
    with severe blunt trauma correlates with clinical 
    severity score and fatal outcome......................23
3-2-1. Serum MIF levels in severe blunt trauma patients 
       and mild  traumatic patients.......................23
3-2-2. Correlation of serum MIF levels with clinical 
       severity scores....................................24
3-2-3. Serum MIF levels and other inflammatory cytokines 
       in surviviors  and nonsurvivors on day 1 and day 2
       ...................................................25
3-3.Induction of serum MIF, IL-6, TNF-α, and IL-1β in V. 
    vulnificus- infected mice.............................25
3-4.Effects of ISO-1 on IL-6 and TNF-α induction in V. 
    vulnificus-infected mice..............................26
3-5.Effects of ISO-1 on the induction of IL-6, IL-8, and 
    TNF-α in human whole blood cells......................27
3-6.Effects of ISO-1 on the induction of IL-6, IL-8, and 
    TNF-α in human PBMCs..................................27
3-7.Involvements of NF-κB and p38 MAPK on the induction 
    of IL-6, IL-8 and TNF-α during V. vulnificus infection 
    of human PBMCs........................................28
3-8.Effects of ISO-1 on the phosphorylation of IkB and 
    p38MAPK in human PBMCs infected with V. vulnificus....28
3-9.Effects of ISO-1 on the transcriptional level of IL-6 
    and binding NF-κB to the promoter of IL-6 gene........29
4.  Discussion............................................31
4-1.Serum MIF acts as a critical prognostic factor in  
    early mortality both in severe sepsis and blunt 
    traumas...............................................31
4-2.Serum MIF plays a facilitator rather than a upstream 
    cytokine in V. vulnificus infection...................35
4-3.Serum MIF modulates proinflammatory cytokine mainly 
    via NF-kB activation..................................37
4-4.Serum MIF regulates IL-6 production via NF-kB 
    activation in human PBMCs infected with V. vulnificus.38
5.  Conclusions...........................................41
6.  References............................................42
7. Tables................................................55 
8.  Figures...............................................59
9.  Resumes and publications..............................77
10. Refereed papers(related to this thesis)...............79
                                    

1. Abraham E, Anzueto A, Gutierrez G, et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 351: 929-933, 1998.
2. Al-Abed Y, Dabideen D, Aljabari B, et al. ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis. J Biol. Chem. 280: 36541-36544, 2005.
3. Alonso de Vega JM, Diaz J, Serrano ES, et al. Oxidative stress in critically ill patients with systemic inflammatory response syndrome. Crit. Care Med. 30: 1782-1786, 2002.
4. Baker SP, O'Neill B, Haddon W, et al. The injury severity score: A method for describing patients with multiple injuries and evaluating emergency care. J. Trauma. 14: 187-196, 1974.
5. Baugh JA and Bucala R. Macrophage migration inhibitory factor. Crit. Care Med. 30: S27-35, 2002.
6. Beishuizen A, Thijs LG, Haanen C, et al. MIF and hypothalamo-pituitary-adrenal function during critical illness. J. Clin. Endocrinol. Meta. 86: 2811-2816. 2001.
7. Bernhagen J, Mitchell RA, Calandra T, et al. Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor Biochemistry 33: 14144-14155, 1994.
8. Bernhagen J, Calandra T, Butala R. Regulation of the immune response by macrophage migration inhibitory factor: biological and structural features. J. Mol. Med. 76: 151-161, 1998.
9. Bisharat N, Agmon V, Finkelstein R, et al. Clinical, epidemiological, and microbiological features of Vibrio vulnificus biogroup 3 causing outbreaks of wound infection and bacteraemia in Israel. Lancet 354: 1421-1424, 1999.
10. Bloom BR and Bennett B. Mechanism of a reaction in-vitro associated with delayed-type hypersensitivity. Science 153: 80-82, 1966.
11. Borrelli E, Pascali RL, Grau G.E, et al. Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit. Care Med. 24: 392-397, 1996.
12. Boyd CR, Tolson MA and Copes WS. Evaluating trauma care: the TRISS method. J. Trauma 27: 370-378, 1987.
13. Bozza FA, Gomes RN, Japiassu AM, et al. Macrophage migration inhibitory factor levels correlate with fatal outcome in sepsis. Shock 22: 309-313, 2004.
14. Bozza M, Satoskar AR, Lin G, et al. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J. Exp. Med. 189: 341-346, 1999.
15. Branger J, van den Blink B, Weijer S, et al. Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J. Immunol. 168: 4070-4077, 2002.
16. Buchrieser C, Gangar VV, Murphree ML, et al. Multiple Vibrio vulnificus strains in oysters as demonstrated by clamped homogenous electric field gel electrophoresis. Appl. Environ. Microbiol. 61: 1163-1168, 1995.
17. Calandra T, Bernhagen J, Mitchell RA, et al. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J. Exp. Med. 179: 1895-1902, 1994.
18. Calandra T, Echtenacher B, Le Roy D, et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat. Med. 6: 164-170, 2000.
19. Calandra T, Froidevaux C, Martin C, et al. Macrophage migration inhibitory factor and host innate immune defenses against bacterial sepsis. J. Infect. Dis. 187(suppl 2): 385-390, 2003.
20. Calandra T and Roger T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat. Rev. Immunol. 3: 791-800, 2003.
21. Calandra T, Spiegel LA, Metz CN, et al. Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of gram-positive bacteria. Proc. Natl. Acad. Sci. USA 95: 11383-11388, 1998.
22. Castella X, Artigas A, Bion J, et al. A comparison of severity of illness scoring systems for intensive care unit patients: Results of a multicenter, multinational study. Crit. Care Med. 23: 1327-1335, 1995.
23. Champion HR, Sacco WJ, Copes WS, et al: A revision of the trauma score. J. Trauma 29: 623-629, 1989.
24. Chang WT, Huang AM. Pal/NRF-1 regulates the promoter of the human Integrin-associated protein/CD47 Gene. J. Biol. Chem. 279: 14542-14550, 2004.
25. Chiang SR, Tang HJ, Chang PC, et al. Synergistic antimicrobial effect of cefotaxime and minocyline on proinflammatory cytokine levels in a murine model of Vibrio vulnificus infection. J. Microbiol. Immunol. Infect. 40: 123-133, 2007.
26. Chuang CC, Wang ST, Chen WC, et al. Increases in serum macrophage migration inhibitory factor in patients with severe sepsis predict early mortality. Shock 27: 503-506, 2007.
27. Chuang CC, Hung CJ, Tsai MC, et al. High concentrations of circulating macrophage migration inhibitory factor in patients with severe blunt trauma: Is serum macrophage migration inhibitory factor concentration a valuable prognostic factor? Crit. Care Med. 323: 734-739, 2004.
28. Chuang CC, Shiesh SC, Chi CH, et al. Serum total antioxidant capacity reflects severity of illness in patients with severe sepsis. Crit. Care. 10(1): R36. 2006.
29. Chuang YC, Yuan CY Liu CY, et al. Vibrio Vulnificus infection in Taiwan: Report of 28 cases and review of clinical manifestations and treatment. Clin. Infect. Dis. 15: 1-6, 1992.
30. Cowley HC, Bacon PJ, Goode HF, et al. Plasma antioxidant potential in severe sepsis: A comparison of survivors and nonsurvivors. Crit. Care Med. 24: 1179-1183, 1996.
31. Damas P, Ledoux D, Nys M, et al. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann. Surg. 215: 356–362, 1992.
32. Damico RL, Chesley A, Johnston L, et al. Macrophage migration inhibitory factor governs endothelial cell sensitivity to LPS-induced apoptosis. Am. J. Respir. Cell Mol. Biol. 39: 77-85, 2008.
33. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit. Care Med. 32: 858-873. 2004.
34. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit. Care Med. 36: 296-327, 2008.
35. Donn RP, Plant D, Jury F, et al. Macrophage migration inhibitory factor gene polymorphism is associated with psoriasis. J Invest. Dermatol. 123: 484-487, 2004.
36. Donnelly SC, Haslett C, Reid PT, et al. Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat. Med. 3: 320-332, 1997.
37. Faust SN, Heyderman RS, Levin M. Coagulation in severe sepsis: a central role for thrombomodulin and activated protein C. Crit. Care Med. 29: S62-S68, 2001.
38. Froidevaux et al. Macrophage migration inhibitory factor and innate immune responses to bacterial infections. Crit. Care Med. 29: S13-S15. 2001.
39. Gando S, Nishihira J, Kobayashi S, et al. Macrophage migration inhibitory factor is a critical mediator of systemic inflammatory response syndrome. Intensive Care Med. 27: 1187-1193, 2001.
40. Ghosh S and Karin M. Missing pieces in the NF-kappaB puzzle. Cell 109: S81–S96, 2002.
41. Goo SY, Han YS, Kim WH, et al. Vibrio vulnificus ilpA-induced cytokine production is mediated by Toll-like receptor 2. J. Biol. Chem. 282: 27647-27658, 2007.
42. Gore Y, Starlets D, Maharshak N, et al. Macrophage migration inhibitory factor induces B cell survival by activation of a CD74-CD44 receptor complex. J. Biol. Chem. 283: 2784-2792, 2008.
43. Gulig PA, Bourdage KL, Straks AM. Molecular pathogenesis of Vibrio vulnificus. J. Microbiol. 43:118-131, 2005.
44. Hack Ec, Hart M, van Schijndel RJ, et al. Interleukin-8 in sepsis: relation to shock and inflammatory mediators. Infect. Immun. 60: 2835-2842, 1992.
45. Hlady WG and Klontz KC. The epidemiology of Vibrio infections in Florida, 1981-1993. J. Infect. Dis. 173: 1176-1183, 1996.
46. Hlady WG, Mullen RC and Hopkins RS. Vibrio vulnificus infections associated with raw oyster consumption-Florida. 1981-1992. Arch. Dermatol. 129: 957-958, 1993.
47. Hoch RC, Rodriguez R, Manning T, et al. Effects of accidental trauma on cytokine and endotoxin production. Crit. Care Med. 21: 839-845, 1993.
48. Hor LI, Chang TT and Wang ST. Survival of Vibrio vulnificus in whole blood from patients with chronic liver diseases: association with phagocytosis by neutrophils and serum ferritin levels. J. Infect. Dis. 179: 275-278, 1999.
49. Hor LI, Chang YK, Chung CC. et al. Mechanism of high susceptibility of lron-overloaded mouse to Vibrio vulnificus infection. Microbiol. Immun. 44: 871-878, 2000.
50. Hor LI, Gao CT, Wan L. Isolation and characterization of Vibrio vulnificus inhabiting the marine environment of the southwestern area of Taiwan. J. Biomed. Sci. 2: 384-389, 1995.
51. Hotchkiss RS and Karl IE. The pathophysiology and treatment of sepsis. New Engl. J. Med. 348: 138-150, 2003.
52. Hou LF, Tsai MC. Comparison between TRISS and ASCOT methods in Tainan area. Kaohsiung J. Med. Sci. 12: 691-698, 1996.
53. Hsieh YC, Frink M, Hsieh CH, et al. Downregulation of migration inhibitory factor is critical for estrogen-mediated attenuation of lung tissue damage following trauma-hemorrhage. Am. J. Physiol. Lung Cell Mol. Physiol. 292:L1227-1232, 2007.
54. Hsueh PR, Lin CY, Tang HJ, et al. Vibrio vulnificus in Taiwan. Emerg. Infect. Dis. 10: 1363-1368, 2004.
55. Jones MK and Oliver JD. Vibrio vulnificus: disease and pathogenesis. Infect. Immun. 77: 1723-1733, 2009.
56. Kawai T, Akira S. Signaling to NF-B by Toll-like receptors. Trends Mol. Med. 13: 460-469, 2007.
57. Kenzel S, Santos-Sierra S, Deshmukh SD, et al. Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus. Infect. Immnu. 77: 2474-2481, 2009.
58. Kellum JA, Kong L, Fink MP, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis. Arch. Intern. Med. 167: 1655-1663, 2007.
59. Kelly MT. Effect of temperature and salinity on Vibrio vulnificus occurrence in a Gulf Coast environment. Appl. Environ. Microbiol. 44: 820-824, 1982.
60. Kim YR, Lee SE, Kook H, et al. Vibrio vulnificus RTX toxin kills host cells only after contact of the bacteria with host cells. Cell. Microbiol. 10: 848-862, 2008.
61. Klein D, Einspanier R, Bolder U, et al. Differences in hepatic signal transcription pathway and cytokine expression between thermal and sepsis. Shock 20: 536-543, 2003.
62. Klontz KC, Lieb S, Schreiber MA, et al. Syndromes of Vibrio vulnificus infections. Ann. Intern. Med. 15: 318-323, 1988.
63. Knaus WA, Draper EA, Wagner DP, et al. APACHE II: A severity of disease classification system. Crit. Care Med. 13: 818-827, 1985.
64. Koebernick H, Grode L, David JR, et al. Macrophage migration inhibitory factor (MIF) plays a pivotal role in immunity against Salmonella typhimurium. Proc. Natl. Acad. Sci. USA 99: 13681-13686, 2002.
65. Kofoed K, Andersen O, Kronborg G, et al. Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinse-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study. Crit. Care11: R38, 2007.
66. Lai KN, Leung JCK, Metz CN, et al. Role for macrophage migration inhibitory factor in acute respiratory distress syndrome. J. Pathol. 199: 496-508, 2003.
67. Lally ET, Hill RB, Kieba IR, et al. The interaction between RTX toxins and target cells. Trends Microbiol. 1999; 7(9): 356-361, 1999.
68. Lan HY, Yang N, Nikolic-Paterson DJ, et al. Expression of macrophage migration inhibitory factor in human glomerulonephritis. Kidney Int. 57: 499-509, 2000.
69. Lee BC, Kim SH, Choi SH, et al. Induction of interleukin-8 production via nuclear factor-κB activation in human intestinal epithelial cells infected with Vibrio vulnificus. Immunology 115: 506-515, 2005.
70. Lee JH, Kim MW, Kim BS, et al. Identification and characterization of the Vibrio vulnificus rtxA essential for cytotoxicity in vitro and virulence in mice. J. Microbiol. 45: 146-152, 2007.
71. Lee SE, Ryu PY, Kim SY, et al. Production of Vibrio vulnificus hemolysin in vivo and its pathogenic significance. Biochem. Biophys. Res. Commun. 324: 86-91, 2004.
72. Lehmann LE, Weber SU, Fuchs D, et al. Intracellular detection of macrophage migration inhibitory factor in peripheral blood leukocytes. Free Radic. Biol. Med. 38: 1170-1179, 2005.
73. Li GQ, Xie J, Lei XY, et al. Macrophage migration inhibitory factor regulates proliferation of gastric cancer cells via the PI3K/Akt pathway. World J. Gastroenterol. 15: 5541-5548, 2009.
74. Liu JW, Lee IK, Tang HJ, et al. Prognostic factors and antibiotics in Vibrio vulnificus septicemia. Arch. Intern. Med. 166: 2117-2123, 2006.
75. Liu M, Alice AF, Naka H, et al. The HlyU protein is a positive regulator of rtxA1, a gene responsible for cytotoxicity and virulence in the human pathogen Vibrio vulnificus. Infect. Immun. 75: 3282-3289, 2007.
76. Liu SF and Malik AB. NF-B activation as a pathological mechanism of septic shock and inflammation, Am. J. Physiol. Lung Cell Mol. Physiol. 290: L622-L645, 2006.
77. Lubetsky JB, Dioa A, Han J, et al. The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents. J. Biol. Chem. 277: 24976-24982, 2002.
78. Lue H, Thiele M, Franz J, et al. Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. Oncogene 26: 5046-5049, 2007.
79. Martin TR. MIF mediation of sepsis. Nature Med. 6: 140-141. 2000.
80. Matsui H, Ihara Y, Fujio Y, et al. Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-B and NF-IL6 in cardiac myocytes. Cardiovasc. Res. 42: 104-112, 1999.
81. Mitchell RA, Metz CN, Peng T, et al. Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF): Regulatory role in cell proliferation and glucocorticoid action. J. Biol. Chem. 274: 18100-18106, 1999.
82. Mitchell RA, Liao H, Chesney J, et al. Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: Regulatory role in the innate immune response. Proc. Natl. Acad. Sci. USA. 99:345-350, 2002.
83. Moine P, Abraham E. Immunomodulation and sepsis: impact of the pathogen.
Shock 22: 297-308, 2004.
84. Ohkawara T, Nishihira J, Takeda H, et al. Pathophysiological roles of macrophage migration inhibitory factor in gastrointestinal, hepatic, and pancreatic disorders. J. Gastroenterol. 40: 117-122, 2005.
85. Opal, SM, Fisher, CJ. Jr, Dhainaut, JF. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A phase III, randomized, doubleblind, placebo-controlled, multicenter trial. Crit. Care Med. 25: 1115-1124, 1997.
86. O’Sullivan AW, Wang JH, Redmond HP, et al. NF-B and p38 MAPK inhibition improve survival in endotoxic shock and in a cecal ligation and puncture model of sepsis in combination with antibiotic therapy. J. Surg. Res. 152: 46-53, 2009.
87. Park SD, Shon HS, and Joh NJ. Vibrio vulnificus septicemia in Korea: Clinical and epidemiologic findings in seventy patients. J. Am. Acad. Dermatol. 24: 397-403, 1991.
88. Powell ND, Papenfuss TL, McClain MA, et al. Cutting edge: macrophage migration inhibitory factor is necessary for progression of experimental autoimmune encephalomyelitis. J. Immunol. 175: 5611-5614, 2005.
89. Reinhart, K and Karzai, W. Anti-tumor necrosis factor therapy in sepsis: Update on clinical trials and lessons learned. Crit. Care Med. 29: S121-S125, 2001.
90. Renner P, Roger T, Calandra T. Macrophage migration inhibitory factor: gene polymorphisms and susceptibility to inflammatory diseases. Clin. Infect. Dis. 42: S513-S519, 2005.
91. Riedemann NC, Guo RF, Ward PA, et al. Novel strategies for the treatment of sepsis. Nat. Med. 9: 517-524, 2003.
92. Roger T, David J, Glauser MP, et al. MIF regulates innate immune response
through modulation of Toll-like receptor 4. Nature 414: 920-924, 2001.
93. Roger T, Froidevaux C, Le Roy D, et al. Protection from lethal Gram-negative
bacterial sepsis by targeting Toll-like receptor 4. Proc. Natl. Acad. Sci. USA 106: 2348-2352, 2009.
94. Rossi AG, Haslett C, Hirani N, et al. Human circulating eosinophils secrete macrophage migration inhibitory factor- potential role in asthma. J. Clin. Invest. 101: 2869-2874, 1998.
95. Sanchez-Nino MD, Sanz AB, Ihalmo P, et al. The MIF receptor CD74 in diabetic podocyte injury. J. Am. Soc. Nephrol. 20: 353-362, 2009.
96. Sankoff JD, Goyal M, Gaieski DF, et al. Validation of the Mortality in Emergency Department Sepsis (MEDS) score in patients with the systemic inflammatory response syndrome (SIRS). Crit Care Med. 36: 421-426, 2008.
97. Santos LL, Morand EF. Macrophage migration inhibitory factor: a key cytokine in RA, SLE and atherosclerosis. Clinica. Chimica. Acta. 399: 1-7, 2009.
98. Sauaia A, Moore FA, Moore EE, et al. Early predictors of postinjury multiple organ failure. Arch. Surg. 129: 39-45, 1994.
99. Sauaia A, Moore FA, Moore EE, et al. Pneumonia related multiple organ failure is not a primary cause of death in head trauma. Pan. Am. J. Trauma. 3: 90-96, 1992.
100. Shin SH, Shin DH, Ryu PY, et al. Proinflammatory cytokine profile in Vibrio vulnificus septicemic patients’ sera. FEMS Immunol. Med. Microbiol. 33: 133-138, 2002.
101. Spiller S, Elson G, Ferstl R, et al. TLR4-induced IFN-r production increases
TLR2 sensitivity and drives Gram-negative sepsis in mice. J. Exp. Med. 205:
1747-1754, 2008.
102. Strom MS and Paranjpye RN. Epidemiology and pathogenesis of Vibrio vulnificus. Microbes Infect. 2: 177−188, 2000.
103. Svoboda P, Kantorova I, Ochmann J. Dynamics of interleukin 1, 2 and 6 and tumor necrosis factor alpha in multiple trauma patients. J. Trauma 36: 336-340, 1994.
104. Takahasi M, Nishihira J, Shimpo M, et al. Macrophage migration inhibitory factor as a redox-sensitive cytokine in cardiac myocytes. Cardiovasc. Res. 52: 438-445, 2001.
105. Talan DA, Moran GJ, Abrahamian FM, et al. Severe sepsis and septic shock in the emergency department. Infect. Dis. Clin. N. Am. 22: 1-31, 2008.
106. Toh ML, Aeberli D, Lacey, et al. Regulation of IL-1 and TNF receptor expression and function by endogenous macrophage migration inhibitory factor. J. Immunol. 177: 4818-4825, 2006.
107. Tsai CC, Kai JI, Huang WC, et al. Glycogen synthase kinase-3β facilitates IFN-γ-induced STAT1 activation by regulating Src homology-2 domain-containing phosphatase 2, J. Immunol. 183: 856-864, 2009.
108. Tschoeke SK, Oberholzer A, Moldawer LL. Interleukin-18: a novel prognostic cytokine in bacteria-induced sepsis. Crit. Care Med 34: 1225-1233, 2006.
109. Wang B, Huang X, Wolters PJ, et al. Cutting edge: deficiency of macrophage migration inhibitory factor impairs murine airway allergic responses. J. Immunol. 175: 5779-5784, 2006.
110. Wang HE, Shapiro NI, Angus DC, et al. National estimate of severe sepsis in the United States emergency departments. Crit. Care Med 35: 1928-1936, 2007.
111. West PW, Parker LC, Ward JR, et al. Differential and cell-type specific regulation of responses to Toll-like receptor agonists by ISO-1. Immunology 125: 101-110, 2008.
112. Whalen MJ, Carlos TM, Kochanek PM, et al. Interleukin-8 is increased in cerebrospinal fluid of children with severe head injury. Crit. Care Med. 28:
929-934, 2000.
113. Willams and Wilkins: American college of chest physicians/society of critical care medicine consensus conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit. Care Med. 20: 864-873, 1992.
114. Wright AC, Simpson LM, Oliver JD. Role of iron in the pathogenesis of Vibrio Vulnificus infections. Infect. Immun. 34: 503-507, 1981.
115. Yu CM, Lai KWH, Chen YX, et al. Expression of macrophage migration inhibitory factor in acute ischemic myocardial injury. J. Histochem. Cytochem. 51: 625-631, 2003.
116. Zhou Z, Gengaro P, Wang W, et al. Role of NF-κB and PI3-kinase/Akt in TNF-α- induced cytotoxicity in microvascular endothelial cells. Am. J. Physiol. Renal Physiol. 295: F932-F941, 2008.
117. Zubert S, Funk DJ, Kumar A. Antibiotics in sepsis and septic shock: like everything else in life, timimg is everything. Crit. Care Med. 38: 1211-1212, 2010.

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