臺灣博碩士論文加值系統

腫瘤壞死因子-a （Tumor Necrosis Factor，簡稱TNF-a）顧名思義，其可以殺死腫瘤細胞，抑制腫瘤的發展，是一種促進發炎的細胞激素，體內大部分的有核細胞皆可以製造產生，而其生物活性功能的表現，必須透過TNF-a專一性的接受體傳遞訊息來完成。腫瘤壞死因子-a有兩種接受器，第一型（TNF-RI，p55）與第二型（TNF-RII，p75），分別透過不同的訊號傳遞途徑，表現出的功能也不一致，進而影響各種免疫功能、正常生理或病理反應。 以上兩種接受體又分別可以細胞表面型（cell surface form）和可溶型（soluble form）表現。 可溶型a型腫瘤壞死因子接受器（sTNF-Rs）會與細胞表面型受體競爭TNF-a的結合，影響訊息傳遞，藉此調控TNF-α功能，一般認為具有抑制或穩定TNF-a的作用，其又可以分第一型及第二型（sTNF-RI and sTNF-RII）。 本研究透過探討嚼食檳榔口腔鱗狀細胞癌患者之TNF-a、 sTNF-RI、RII濃度和TNF-a/sTNF-Rs比值在不同治療時程的表現，期能提供口腔癌治療過程與預後預測的新方向，故以高雄醫學大學口腔顎面外科經主治醫師與口腔病理學判定為口腔鱗狀細胞癌的嚼食檳榔之男性病人為研究對象，共有116名病例。並選取有嚼食檳榔但無口腔黏膜疾病的男性19名作為對照，共得個案135人。並將癌症患者的治療時程分為「未接受治療」組、「治療1年內」組、「治療1年以上」組及「復發個案」組。收集周邊血液中單核球予以培養，取其上清液，以ELISA進行TNF-a、sTNF-RI、II的測定。
整體而言，菸、酒的使用在嚼食檳榔者對TNF-a與其兩種可溶型受體的濃度均無明顯相關；在疾病影響上，對照組的TNF-a平均值是40.2±59.1 pg/ml (mean±SE)顯著低於口腔癌疾病組88.2±14.8 pg/ml (p<0.01)。sTNF-RI在各治療時程間並無明顯差異的結果不同，而sTNF-RII在口腔癌者的平均濃度459.6 pg/ml顯著高於對照組的269.4pg/ml。經迴歸分析以「對照組」為參考組，控制年齡、菸與酒三因素的影響後，各治療時程的sTNF-RII濃度都比對照組表現還高。以「治療1年內」和「復發個案」尤其明顯。又發現(TNF-a/ sTNF-RII)*100比值的變化，各治療時程的數值都顯著低於「對照組」。
由我們研究結果發現sTNF-RII或TNF-a/ sTNF-RII比值的表現，或許可以用來作為臨床上診斷和預測口腔鱗狀細胞癌的參考數據。

Evaluation of tumor necrosis factor-alpha (TNF-a) and the expression of their soluble receptors (sTNF-Rs) in peripheral blood mononuclear cells (PBMC) may aid in the evaluation of immune potentials of cancer patients. Soluble receptors of tumor necrosis factor-alpha can have inhibiting effect against TNF-a. We examined the expression of TNF-a, sTNF-Rs, and the TNF-a/sTNF-Rs ratios in PBMC of betel quid-chewers with oral squamous cell carcinoma (OSCC), who were at different stages of the treatment.
PBMC were collected from 135 male subjects with betal quid chewing habit, including 116 patients with OSCC and 19 normal controls. Subjects with OSCC were further grouped according to the stages of treatment where they were at: untreated, treated for less than one year, treated for one or more years and in remission, and treated for one or more year but recurred. We used enzyme-linked immunosorbent assay (ELISA) to quantify the expression of TNF-a and its sTNF-Rs.
The expression of the TNF-a and its sTNF-Rs in the OSCC patients was higher than normal controls. Examination of levels of expression in groups at different treatment stages showed that average concentration of TNF-a and sTNF-Rs was the highest in the recurrent group and lowest in normal controls. Expression levels of sTNF-RII differed significantly over different groups, while TNF-a and sTNF-RI expressions did not. Using multiple linear regression and controlling for age, alcohol, and cigarette smoking, the TNF-a/sTNF-RII ratio showed distinct differences comparing OSCC patients at each treatment stage with normal controls.
Our data indicated that the expression of sTNF-RII and the ratio of TNF-a/sTNF-RII might have an informative value for diagnosis and prognosis of OSCC.

目次
中文摘要 …………………………………………………………………II
英文摘要…………………………………………………………………III
誌謝………………………………………………………………………IV
目次……………………………………………………………………V
表次…………………………………………………………………….. VII
圖次………………………………………………………………..…VIII
第一章 緒 論……………………………………………………………1
第一節 口腔癌及口腔鱗狀細胞癌的流行病學…………………1
第二節 TNF-a與sTNF-Rs介紹……………………………………4
第三節 TNF-a與sTNF-Rs和疾病關係之研究…………………9
第二章 研究目的………………………………………………………11
第三章 材料與方法……………………………………………………12
第一節 個案與血樣收集…………………………………………12
第二節 材料.………………………………………………………13
一、單核球分離………………………………………………13
二、細胞培養液………………………………………………13
三、酵素連結免疫分析………………………………………14
第三節 方法………………………………………………………14
一、單核球的分離及培養……………………………………14
二、單核球培養液中a型腫瘤壞死因子(TNF-a)及其接受器的釋出分析………………………………………………15
第四節 統計分析 …………………………………………………16
第四章 結果……………………………………………………………17
一、個案基本資料分布……………………………………17
二、菸、酒及檳榔使用與TNF-a、sTNF-Rs之關係………18
三、口腔鱗狀細胞癌病人TNF-a、sTNF-RI、sTNF-RII之分泌情形(表2) …………………………………………18
四、口腔鱗狀細胞癌病人在不同治療時程TNF-a、sTNF-RI、sTNF-RII之分泌情形(表2) …………………………18
五、以菸、酒、年齡及療程等變項進行TNF-a、sTNF-RI 和 sTNF-RII之迴歸分析模式……………………………20
六、TNF-a/sTNF-RI與TNF-a/sTNF-RII比值之分布….21
七、TNF-a與sTNF-Rs相關之探討…………………………22
八、口腔鱗狀細胞癌依臨床診斷各不同分期與TNF-a、sTNF-RI和sTNF-RII濃度變化之情形……………………23
第五章 討論……………………………………………………………24
參考文獻…………………………………………………………………40
附錄圖表…………………………………………………………………54

參考文獻
1. 韓良俊。檳榔健康的危害。台北，健康文化；2000年。
2. Silverman SJ. Early diagnosis of oral cancer. Cancer 1998; 62:1769-96.
3. Voles EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. New Engl J Med 1993; 328:184-94.
4. Sidransky D. Molecular genetics of head and neck cancer. Curr Opin Oncol 1995; 7:229-33.
5. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. Calif Cancer J Clin 2001; 51:15-36.
6. Cancer Registry. Department of Health, Taiwan, Republic of China, 2000.
7. Chen YK, Huang HC, Lin LM. Primary squamous cell carcinoma: An analysis of 703 cases in southern Taiwan. Eur J Cancer 1999; 35:173-9.
8. Cancer Registry. Department of Health, Taiwan, Republic of China, 2001.
9. Cancer Registry. Department of Health, Taiwan, Republic of China, 2002.
10. 蔡崇弘、邱清華。臺灣地區口腔癌發生率研究。中華牙誌1990；9：104-15。
11. Cancer Registry. Department of Health, Taiwan, Republic of China, 1996.
12. Health and Vital Statistics. Department of Health, Taiwan, Republic of China, 1999.
13. Lin SC, Chang KW, Chang CS, Liu TY, Tzeng YS, Yang FS, Wong YK. Alterations of p16/MTS1 gene in oral squamous cell carcinomas from Taiwanese. J Oral Pathol Med 2000; 29:159-66.
14. Cancer Registry. Department of Health, Taiwan, Republic of China, 1997.
15. 黃湧澧、林立民、葛應欽。檳榔塊與口腔癌。公共衛生1993；371-83。
16. Gupta PC, Nehta FS, Daftary DK, Pindborg JJ, Bhonsle RB, Jalnawalla PN, et al. Incidence rate of oral cancer and natural history of oral precancerous lesions in a 10-year follow-up study of Indian villagers. Commun Dent Oral Epidemiol 1980; 8:287-333.
17. Muir CS, Kirk R. Betel, tobacco, and cancer of the mouth. Br J Cancer 1960; 14:597-608.
18. Rajendran R, Sugathan CK, Remani P, Ankathil R, Vijayakumar T. Cell mediated and humoral immune responses in oral submucous fibrosis. Cancer 1986; 58:2628-30.
19. Ko YC, Chiang TA, Chang SJ, Hsieh SF. Prevalence of betel-quid chewing habit in Taiwan and related sociodemographic factors. J Oral Pathol Med 1992; 21:261-4.
20. Ko YC, Huang YL, Lee CH, Chen MJ, Lin LM, Tsai CC. Betel-quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Oathol Med 1995; 24:450-3.
21. Anonymous. Betel-quid and areca-nut chewing. International Agency for research on cancer. Lyon, Monographs 1985; 37:141-291.
22. Ranasinghe AW, Warnakulasuriya KA, Johnson NW. Low prevalence of expression of p53 oncoprotein in oral carcinomas from Sri Lanka associated with betel and tobacco chewing. Eur J Cancer B Oral Oncol 1993; 29B:147-50.
23. Saranath D, Bhoite LT, Deo MG. Molecular lesions in human oral cancer: the Indian scene. Eur J Cancer B Oral Oncol 1993; 29B: 107-12.
24. Neville BW, Damm DD, Allen CM, et al: Epithelial Pathology. In: Oral and Maxilliofacial Pathology. 1st ed. Philadelphia: Saunders, 1995: 259-321.
25. Thomas SJ, MacLennan R. Slaked lime and betel-nut cancer in Papua New Guinea. Lancet 1992; 340:577-8.
26. Macfarlane GJ, Boyle P, Evstifeeva TV, et al. Rising trends of oral cancer mortality among males worldwide: the return of an old public health problem. Cancer Causes Control 1994; 5:259-65.
27. Macfarlane GJ, Evstifeeva TV, Robertson C, et al. Trends of oral cancer mortality among females worldwide. Cancer Causes and Control 1994; 5:255-8.
28. Muir CS, Nectoux J. International patterns of cancer. Cancer Epidemiology and Prevention, 2nd ed. In: Schottenfeld D, Fraumeni JF eds. New York: Oxford University Press, 1996; 141-67.
29. Nair MK, Sankaranarayanan R, Padmanabhsan TK, et al. Clinical profile of 2007 oral cancer in Kerala, India. Ann Dent 1988; 47:23-6.
30. Ng KH, Siar CH, Ramanarhan K, et al. Squamous cell carcinoma of the oral mucosa in Malaysia- any change? Southeast Asian J Trop Med Public Health 1985; 16:602-6.
31. 陳金勝、陳中和。口腔鱗狀上皮細胞癌之統計分析報告。高醫醫誌1995；11：582-8。
32. Chen CH. An epidemiology study of oral squamous cell carcinoma in southern Taiwan. J Formosan Dent Assoc 1987; 10:268-74.
33. Shanta V, Krishnamurthis. A study of etiologic factors in oral squamous cell carcinoma. Br J Cancer 1959; 13:387-9.
34. Kumar V, Cotran RS, Robbins SL. Basic Pathology, 6th ed, WB Saunders Co, Philadelphia; 1997:473-4.
35. Wustrow TP, Mahnke CG. Causes of immunosuppression in squamous cell carcinoma of the head and neck. Anticancer Res 1996; 16:2433-68.
36. Dietz A, Heimlich F, Daniel V, Polarz H, Weidauer H, Maier H. Immunomodulating effects of surgical intervention in tumors of the head and neck. Otolaryngol Head Neck Surg 2000; 123:132-9.
37. Kim J, Shin DM. Biomarkers of squamous cell carcinoma of the head and neck. Histol Histopathol 1997; 12:205-18.
38. Lippman SM, Hong WK. Molecular markers of the risk of oral cancer. N Engl J Med 2001; 344:1323-6.
39. Fernandez-Botran R. Soluble cytokine receptors: their role in immunoregulation. FASEB J 1991; 5:2567-74.
40. Jablonska E, Kiluk M, Piotrowski L, Grabowska Z, Markiewicz W, Jablonski J. Tumor necrosis factor-alpha and soluble tumor necrosis factor receptors in the culture supernatants of polymorphonuclear cells and peripheral blood mononuclear cells from cancer patients. Eur Cytokine Netw 1998; 9:155-9.
41. Gallo O, Pinto S, Boccuzzi S. Monocyte tumor necrosis factor production in head and neck squamous cell carcinoma. Laryngoscope 1992; 102:447-50.
42. Parks RR, Yan SD, Huang CC. Tumor necrosis factor-alpha production in human head and neck squamous cell carcinoma. Laryngoscope 1994; 104:860-4.
43. Hsu HJ, Shieh TY, Chang KL. The effects of arecoline on the release of cytokines using cultured peripheral blood mononuclear cells from patients with oral mucous diseases. Kaohsiung J Med Sci 2001; 17:175-82.
44. McDermott MF. TNF and TNF-R biology in health and disease. Cell Mol Biol 2001; 47:619-35.
45. Loro LL, Vintermyr OK, Johannessen AC. Cell death regulation in oral squamous cell carcinoma: methodological considerations and clinical significance. J Oral Pathol Med 2003; 32:125-38.
46. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin- induced serum factor that cause necrosis of tumor. Proc Natl Acad Sci USA 1975; 72:3666-70.
47. Helson L, Green S, Carswell E, Old LJ. Effect of TNF on cultured human melanoma cells. Nature 1975; 258:731-2.
48. Beutler B, Cerami A. Tumor necrosis, cachexia, shock, and inflammation: a common mediator. Annu Rev Biochem 1988; 57:505-18.
49. Aggarwal BB, Kohr WJ, Hass PE, Moffat B, Spencer SA, Henzel WJ, et al. Human necrosis factor production. Purification and characterization. J Biol Chem 1985; 260:2345-54.
50. Aggarwal BB, Moffat B, Harkins RN. Human lymphotoxin. Production by a lymphoblastoid cell line, purification, and initial characterization. J Biol Chem 1984; 259:686-91.
51. Oppenheim JJ, Feldmann M. Cytokine reference: A compendium of cytokine and other mediators of host defense. In: Aggarwal BB, Samanta A, Feldmann M eds. TNFa. London: Academic Press, 2001: 413-34.
52. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104:487-501.
53. Aggarwal BB, Natarajan K. Tumor necrosis factors: developments during the last decade. Eur Cytokine Netw 1996; 7:93-124.
54. Tracey KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med 1994; 45:491-503.
55. Orosz P, Echtenacher B, Falk W, Ruschoff J, Weber D, Mannel DN. Enhancement of experimental metastasis by tumor necrosis factor. J Exp Med 1993; 177:1391-8.
56. Beutler BA. The role of tumor necrosis factor in health and disease. J Rheumatol 1999; 26:16-21.
57. Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N, et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 1999; 5:828-31.
58. Tracey KJ, Vlassara H, Cerami A. Cachectin/tumour necrosis factor. Lancet 1989; 1:1122-6.
59. Beutler B. TNF in pathophysiology: biosynthetic regulation. J Invest Dermatol 1990; 95:81S-84S.
60. Duncombe AS, Brenner MK. Is circulating tumor necrosis factor bioactive? N Engl J Med 1988; 319:1277-8.
61. Oppenheim JJ, Feldmann M. Cytokine reference: A compendium of cytokine and other mediators of host defense. In: Aggarwal BB, Samanta A, Feldmann M eds. TNF Receptors. London: Academic Press, 2001:1619-32.
62. Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med 1996; 334:1717-25.
63. Beutler B, Van Huffel C. Unraveling function in the TNF ligand and receptor families. Science 1994; 264:667-8.
64. Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends in Cell Biol 2001; 11:372-7.
65. Tartaglia LA, Rothe M, Hu YF, Goeddel DV. Tumor necrosis factor''s cytotoxic activity is signaled by the p55 TNF receptor. Cell 1993; 73:213-6.
66. Tartaglia LA, Goeddel DV, Reynolds C, Figari IS, Weber RF, Fendly BM, et al. Stimulation of human T-cell proliferation by specific activation of the 75-kDa tumor necrosis factor receptor. J Immunol 1993; 151:4637-41.
67. Weiss T, Grell M, Hessabi B, Bourteele S, Muller G, Scheurich P, et al. Enhancement of TNF receptor p60-mediated cytotoxicity by TNF receptor p80: requirement of the TNF receptor-associated factor-2 binding site. J Immunol 1997; 158:2398-404.
68. Pinckard JK, Sheehan KC, Schreiber RD. Ligand-induced formation of p55 and p75 tumor necrosis factor receptor heterocomplexes on intact cells. J Biol Chem 1997; 272:10784-9.
69. Li X, Yang Y, Ashwell JD. TNF-RII and c-LAP1 mediate ubiquitination and degradation of TRAF2. Nature 2002; 416:345-7.
70. Akassoglou K, Douni E, Bauer J, Lassmann H, Kollias G, Probert L. Exclusive tumor necrosis factor (TNF) signaling by the p75 TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice. Proc Natl Acad Sci USA 2003; 100:709-14.
71. Nagata S. Apoptosis by death factor. Cell 1997; 88:355-65.
72. Tartaglia LA, Goeddel DV. Two TNF receptors. Immunology Today 1992; 13:151-3.
73. Haridas V, Darnay BG, Natarajan K, Heller R, Aggarwal BB. Overexpression of the p80 TNF receptor leads to TNF-dependent apoptosis, nuclear factor-kappa B activation, and c-Jun kinase activation. J Immunol 1998; 160:3152-62.
74. Guicciardi ME, Gores GJ. AIP1: a new player in TNF signaling. J Clin Invest 2003; 111:1813-5.
75. Novick D, Engelmann H, Wallach D, Rubinstein M. Soluble cytokine receptors are present in normal human urine. J Exp Med 1989; 170:1409-14.
76. Porteu F, Nathan C. Shedding of tumor necrosis factor receptors by activated human neutrophils. J Exp Med 1990; 172:599-607.
77. Smith KJ, Skelton HG. Rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis after starting tumor necrosis factor alpha receptor IgG1-Fc fusion complex therapy. J Am Acad Dermatol 2001; 45:953-6.
78. Engelmann H, Novick D, Wallach D. Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J Biol Chem 1990; 265:1531-6.
79. Aderka D, Wysenbeek A, Engelmann H, Cope AP, Brennan F, Molad Y, et al. Correlation between serum levels of soluble tumor necrosis factor receptor and disease activity in systemic lupus erythematosus. Arthritis Rheum 1993; 36:1111-20.
80. Weber JC, Korganow AS, Ginsbourger M, Lehr L, Hauptmann G, Muller S, et al. Soluble tumor necrosis factor receptors in patients with systemic lupus erythematosus. Presse Med 1998; 27:1941-5.
81. Cope AP, Aderka D, Doherty M, Engelmann H, Gibbons D, Jones AC, et al. Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases. Arthritis Rheum 1992; 35:1160-9.
82. Roux-Lombard P, Punzi L, Hasler F, Bas S, Todesco S, Gallati H, Guerne PA, Dayer JM. Soluble tumor necrosis factor receptors in human inflammatory synovial fluids. Arthritis Rheum 1993; 36:485-9.
83. Godfried MH, Van der Poll T, Weverling GJ, Mulder JW, Jansen J, Van Deventer SJ, et al. Soluble receptors for tumor necrosis factor as predictors of progression to AIDS in asymptomatic human immunodeficiency virus type 1 infection. J Infect Dis 1994; 169:739-45.
84. Girardin E, Roux-Lombard P, Grau GE, Suter P, Gallati H, Dayer JM. Imbalance between tumour necrosis factor-alpha and soluble TNF receptor concentrations in severe meningococcaemia. Immunology 1992; 76:20-3.
85. Aderka D, Englemann H, Hornik V, Skornick Y, Levo Y, Wallach D, Kushtai G. Increased serum levels of soluble receptors for tumor necrosis factor in cancer patients. Cancer Res 1991; 51:5602-7.
86. Tracey KJ, Chrami A. Tumor necrosis factor: an updated review of its biology. Crit Care Med 1993; 21:S415-22.
87. Von Biberstein SE, Spiro JD, Lindquist R, Kreutzer DL. Enhanced tumor cell expression of tumor necrosis factor receptors in head and neck squamous cell carcinoma. Am J Surg 1995; 170:416-22.
88. Higuchi Y, Herrera P, Muniesa P, Huarte J, Belin D, Ohashi P, et al. Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes. J Exp Med 1992; 176:1719-31.
89. Picarella DE, Kratz A, Li CB, Ruddle NH, Flavell RA. Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice. J Immunol 1993; 150:4136-50.
90. Ferrari R. The role of TNF in cardiovascular disease. Pharmacol Res 1999; 40:97-105.
91. Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 1991; 10:4025-31.
92. Elsasser-Beile U, Gallati H, Weber W, Wild ED, Schulte Monting J, Von Kleist S. Increased plasma concertrations for type I and type II tumor necrosis factor receptors and IL-2 receptors in cancer patients. Tumor Biol 1994; 15:17-24.
93. Gadducci A, Ferdeghini M, Fanucchi A, Annicchiarico C, Prato B, Prontera C, et al. Serum levels of soluble receptors for tumor necrosis factor (p55 and p75 sTNFR) in endometrial cancer. Anticancer Res 1996; 16:3125-8.
94. Vinante F, Rigo A, Tecchio C, Morosato L, Nadali G, Ricetti MM, et al. Serum levels of p55 and p75 soluble TNF receptors in adult acute leukaemia at diagnosis: correlation with clinical and biological features and outcome. Br J Haematol 1998; 102:1025-34.
95. Jablonska E, Kiluk M, Markiewicz W, Piotrowski L, Grabowska Z, Jablonski J. TNF-alpha, IL-6 and their soluble receptor serum levels and secretion by neutrophils in cancer patients. Arch Immunol Ther Exp 2001; 49:63-9.
96. Nakano Y, Kobayashi W, Sugai S, Kimura H, Yagihashi S. Expression of tumor necrosis factor-alpha and interleukin-6 in oral squamous cell carcinoma. Jpn J Cancer Res 1999; 90:858-66.
97. Heller RA, Kronke M. Tumor necrosis factor receptor-mediated signaling pathways. J Cell Biol 1994; 126:5-9.
98. Fiers W. Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level. FEBS Lett 1991; 285:199-212.
99. Palladino MA Jr, Shalaby MR, Kramer SM, Ferraiolo BL, Baughman RA, Deleo AB, et al. Characterization of the antitumor activities of human tumor necrosis factor-alpha and the comparison with other cytokines: induction of tumor-specific immunity. J Immunol 1987; 138:4023-32.
100. Creasey AA, Reynolds MT, Laird W. Cures and partial regression of murine and human tumors by recombinant human tumor necrosis factor. Cancer Res 1986; 46:5687-90.
101. Old LJ. Tumor necrosis factor (TNF). Science 1985; 230:630-2.
102. Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA Jr, Shepard HM. Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science 1985; 230:943-5.
103. Frater-Schroder M, Risau W, Hallmann R, Gautschi P, Bohlen P. Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Natl Acad Sci USA 1987; 84:5277-81.
104. Mannel DN, Ruschoff J, Orosz P. The role of TNF in tumour growth and metastasis. Res Immunol 1993; 144:364-9.
105. Elsasser-Beile U, Von Kleist S, Sauther W, Gallati H, Monting JS. Impaired cytokine production in whole blood cell cultures of patients with gynaecological carcinomas in different clinical stages. Br J Cancer 1993; 68:32-6.
106. Zielinski CC, Mueller C, Tyl E, Tichatschek E, Kubista E, Spona J. Impaired production of tumor necrosis factor in breast cancer. Cancer 1990; 66:1944-8.
107. Engelmann H, Holtmann H, Brakebusch C, Avni YS, Sarov I, Nophar Y, et al. Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J Biol Chem 1990; 265:14497-504.
108. Seckinger P, Isaaz S, Dayer JM. Purification and biologic characterization of a specific tumor necrosis factor alpha inhibitor. J Biol Chem 1989; 264:11966-73.
109. Aderka D, Engelmann H, Wysenbeek AJ, Levo Y. The possible role of tumor necrosis factor (TNF) and its natural inhibitors, the soluble-TNF receptors, in autoimmune diseases. Isr J Med Sci 1992; 28:126-30.
110. Oppenheim JJ, Feldmann M. Cytokine reference: A compendium of cytokine and other mediators of host defense. In: Feldmann M, Brennan FM eds. Cytokines and disease. London: Academic Press, 2001:35-52.
111. Jablonska E. Soluble IL-6 and TNF receptors release by polymorphonuclear and mononuclear cells in cancer patients. Neoplasma 1999; 46:35-9.
112. Aggarwal S, Gollapudi S, Gupta S. Increased TNF-alpha-induced apoptosis in lymphocytes from aged humans: changes in TNF-alpha receptor expression and activation of caspases. J Immunol 1999; 162:2154-61.
113. Powell JL, Strauss KA, Wiley C, Zhan M, Morris JG Jr. Inflammatory cytokine response to Vibrio Vulnificus elicited by peripheral blood mononuclear cells from chronic alcohol users is associated with biomarkers of cellular oxidative stress. Infect Immun 2003; 71:4212-6.
114. Zhao XJ, Marrero L, Song K, Oliver P, Chin SY, Simon H, Schurr JR, Zhang Z, Thoppil D, Lee S, Nelson S, Kolls JK. Acute alcohol inhibits TNF-alpha processing in human monocytes by inhibiting TNF/TNF-alpha-converting enzyme interactions in the cell membrane. J Immunol 2003; 170:2923-31.
115. Ryder MI, Saghizadeh M, Ding Y, Nguyen N, Soskolne A. Effects of tobacco smoke on the secretion of interleukin-1beta, tumor necrosis factor-alpha, and transforming growth factor-beta from peripheral blood mononuclear cells. Oral Microbiol Immunol 2002; 17:331-6.
116. Van der Poll T, Calvano SE, Kumar A, Braxton CC, Coyle SM, Barbosa K, Moldawer LL, Lowry SF. Endotoxin induces downregulation of tumor necrosis factor receptors on circulating monocytes and granulocytes in humans. Blood 1995; 86:2754-9.
117. Heilig B, Mapara M, Brockhaus M, Krauth K, Dorken B. Two types of TNF receptors are expressed on human normal and malignant B lymphocytes. Clin Immunol Immunopathol 1991; 61:260-7.
118. Porteu F, Brockhaus M, Wallach D, Engelmann H, Nathan CF. Human neutrophil elastase releases a ligand-binding fragment from the 75-kDa tumor necrosis factor (TNF) receptor. Comparison with the proteolytic activity responsible for shedding of TNF receptors from stimulated neutrophils. J Biol Chem 1991; 266:18846-53.
119. Dembic Z, Loetscher H, Gubler U, Pan YC, Lahm HW, Gentz R, Brockhaus M, Lesslauer W. Two human TNF receptors have similar extracellular, but distinct intracellular, domain sequences. Cytokine 1990; 2(4):231-7.
120. Brockhaus M, Schoenfeld HJ, Schlaeger EJ, Hunziker W, Lesslauer W, Loetscher H. Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci USA 1990; 87:3127-31.
121. Xing L, Remick DG. Relative cytokine and cytokine inhibitor production by mononuclear cells and neutrophils. Shock 2003; 20:10-6.
122. Bemelmans MH, Abramowicz D, Gouma DJ, Goldman M, Buurman WA. In vivo T cell activation by anti-CD3 monoclonal antibody induces soluble TNF receptor release in mice. Effects of pentoxifylline, methylprednisolone, anti-TNF, and anti-IFN-gamma antibodies. J Immunol 1994; 153:499-506.
123. Bemelmans MH, Gouma DJ, Buurman WA. LPS-induced sTNF-receptor release in vivo in a murine model. Investigation of the role of tumor necrosis factor, IL-1, leukemia inhibiting factor, and IFN-gamma. J Immunol 1993; 151:5554-62.
124. Cope AP, Aderka D, Wallach D, Kahan M, Chu NR, Brennan FM, Feldmann M. Soluble TNF receptor production by activated T lymphocytes: differential effects of acute and chronic exposure to TNF. Immunology 1995; 84:21-30.
125. Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med 1992; 175:323-9.
126. Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci USA 1992; 89:4845-9.
127. Tartaglia LA, Pennica D, Goeddel DV. Ligand passing: the 75kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55kDa TNF receptor. J Biol Chem 1993; 268:18542-8.
128. Grell M, Douni E, Wajant H, Lohden M, Clauss M, Maxeiner B, et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80kDa tumor necrosis factor receptor. Cell 1995; 83:793-802.
129. Green DM, Trial J, Birdsall HH. TNF-alpha released by comigrating monocytes promotes transendothelial migration of activated lymphocytes. J of Immunol 1998; 161:2481-9.
130. Oppenheim JJ, Feldmann M. Cytokine reference: A compendium of cytokine and other mediators of host defense. In: Ruddle N, Ware CF. Lymphotoxin a and b. London: Academic Press, 2001:435-47.
131. Jablonska E. Changes in sIL-6R and sTNF-Rs release by PMNs and the serum levels in breast cancer patients at different stages of treatment. Cytokine 1998; 10:540-3.
132. Mantovani A, Bussolino F, Dejana E. Cytokine regulation of endothelial cell function. FASEB J 1992; 6:2591-9.
133. Knerer B, Hulla W, Martinek H, Formanek M, Temmel A, Kornfehl J. IL-1 and TNF-alpha but no IL-2 expression is found in squamous cell carcinomas of the head and neck by RT-PCR. Acta Otolaryngol 1996; 116:132-6.
134. Schroder J, Stuber F, Gallati H, Schade FU, Kremer B. Pattern of soluble TNF receptors I and II in sepsis. Infection 1995; 23:143-8.
135. Yamamoto T, Kimura T, Ueta E, Tatemoto Y, Osaki T. Characteristic cytokine generation patterns in cancer cells and infiltrating lymphocytes in oral squamous cell carcinomas and the influence of chemoradiation combined with immunotherapy on these patterns. Oncology 2003; 64:407-15.
136. Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, Schreiber RD, et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med 1997; 185:1573-84.