摘要
研究背景:脑梗死发病率、致死率和致残率均高,严重危害人类的健康。动脉粥样硬化是其主要病因之一,近来研究发现炎症和免疫反应在动脉粥样硬化形成中发挥关键作用。白细胞介素-4和13(IL-4和IL-13)是一种生物活性相似的多效细胞因子,具有抗炎作用,脑梗死后其变化目前研究较少,且有争议。同时,IL-4和IL-13参与动脉粥样硬化形成,IL-4与IL-13及其受体基因有多个影响其生物活性的基因多态位点,这些位点的基因多态性与脑梗死的相关性目前国内外鲜有报道。
第一部分白细胞介素-4、13与动脉粥样硬化性脑梗死的关系
目的:动态观察脑梗死后血清IL-4和IL-13的变化,以明确IL-4和IL-13是否参与脑梗死的病理生理过程。
方法:采用病例对照研究设计,纳入28例动脉粥样硬化性脑梗死患者和151例对照者,其中对照组分为有颈动脉粥样硬化和无颈动脉粥样硬化两个亚组。脑梗死病人分别在第1、3、7和14天收集血标本,对照组收集一次血标本。采用ELISA方法测定血清IL-4、IL-13水平。
结果:
1.对照组中有颈动脉粥样硬化和无颈动脉粥样硬化两个亚组血清IL-4水平无差别。与对照组相比,脑梗死后第1天血清IL-4水平无变化(p>0.05);第3天开始增高,第7天时达高峰,为基础水平的3.4倍;14天时仍高于对照组(p<0.01)。同时,脑梗死后第3、7和14天的血清IL-4水平均高于对照组中的颈动脉粥样硬化亚组(p<0.01)。
2.对照组中有颈动脉粥样硬化和无颈动脉粥样硬化两个亚组IL-13水平无差别。与对照组相比,脑梗死后第1天血清IL-13水平无变化(p>0.05);第3天开始增高,第7天时达高峰,为基础水平的2倍,14天时仍高于对照组(p<0.01)。同时,脑梗死后第3、7和14天的血清IL-13水平均高于对照组中的颈动脉粥样硬化亚组(p<0.01)。
结论:
脑梗死后,血清IL-4和13水平升高,可能抑制脑梗死后的炎症反应,减轻脑损伤。
第二部分白细胞介素-4、13及其受体基因多态性与动脉粥样硬化性脑梗死的关系
目的:1.探讨IL-4 C-590T和C+33T、IL-13 C+1923T基因多态性与血清IL-4、IL-13水平的关系。2.探讨IL-4 C-590T和C+33T、IL-4RQ576R、IL-13 C+1923T基因多态性与动脉粥样硬化性脑梗死发病的关系。
方法:采用病例对照研究设计,纳入159例动脉粥样硬化性脑梗死患者和151例对照者。采用PCR-限制性片段长度多态性(PCR-RFLP)方法检测对照组人群、动脉粥样硬化性脑梗死患者IL-4 C-590T和C+33T、IL-4R Q576R、IL-13 C+1923T基因的单核苷酸多态性。
结果:
1.IL-4 C-590T和C+33T位点呈连锁不平衡,TT基因型的IL-4血清水平高于TC和CC基因型,TC基因型高于CC基因型。其基因型和等位基因频率在两组中分布无差异。
2.IL-13 C+1923T基因的TC型和TT型的血清IL-13水平无统计学差异,两者的血清IL-13水平均高于CC型。其基因型和等位基因频率在两组中分布无差异。
3.IL-4R Q576R的各种基因型及其等位基因频率在两组中分布无差异。
4.脑梗死组中携带IL-4 590T/IL-4R 576R或IL-4 33T/IL-4R 576R基因型的比例较对照组高;IL-13 1923T/IL-4R 576R基因型在两组间无显著性差异。
结论:
1.IL-4 C-590T与C+33T位点呈连锁不平衡,T等位基因与高血清IL-4水平有关,IL-4 C-590T与C+33T基因多态与中国湖南汉族人动脉粥样硬化性脑梗死的发病无关。
2.IL-13+1923T基因与高血清IL-13水平相关,IL-13 C+1923T基因多态与中国湖南汉族人动脉粥样硬化性脑梗死的发病无关。
3.IL-4R Q576R基因多态与中国湖南汉族人动脉粥样硬化性脑梗死的发病无关。
4.IL-4 590T/IL-4R 576R和IL-4 33T/IL-4576R基因型可作为中国湖南汉族人动脉粥样硬化性脑梗死的独立预知因子。
Background: Cerebral infarction is a common cerebrovascular diseasewith high disease incidence, morbidity and mortality. Atherosclerosis isone of the main causes of cerebral infarction. It has been known thatinflammation plays a key role in atherosclerosis. Interleukin 4 (IL-4) andIL-13(IL-13) are pleiotropic cytokines exerting similar biological activity.As an anti-inflammation cytokine, the change of IL-4 and IL-13 in braininfarction is controversy. Meanwhile, IL-4 and IL-13 play an importantrole in atherogenesis. There are several genetic polymorphisms locus inIL-4, IL-13 and their receptor which alter their biological activity.Unfortunately, the association of those gene polymorphisms with braininfarction hasn't been reported almost.
Part 1The association of IL-4 and IL-13 with atherothrombotic cerebralinfarction
Objects:
To be comprehensive understanding the alternation of the IL-4 andIL-13 serum level in the patients with cerebral infarction, the serialchanges of serum IL-4 and IL-13 in atherothrombotic cerebral infarctionpatients will be measured.
Methods: A case-control study was carded out in this research, in which28 patients with atherothrombotic cerebral infarction, as well as 151control subjects were recruited. Control subjects with or without carotidartery atherosclerosis were divided into 2 subgroups. 28 cerebralinfarction patients' blood was serially obtained at four times: within 24hours, at day 3, at day 7 and at day 14. The control subjects' blood was collected only once. IL-4 and IL-13 levels in serum samples weredetermined with ELISA method using human IL-4 and IL-13immunoassay kit.
Results:
1. The serum level of IL-4 was not different among subjects with carotidartery atherosclerosis and no- carotid artery atherosclerosis (P>0.05).Compared with the control value, the serum IL-4 level obtained at day1 was not increase (P>0.05). It began to increase at day 3, and peakedat day 7 (3.4 times of control value). The high level of IL-4 lasted today 14(P<0.01). Meanwhile, the serum levels of IL-4 obtained at day3, 7, and 14 in patients with cerebral infarction were significantlyhigher than the control subjects with carotid atherosclerosis (P<0.01).
2. The serum level of IL-13 was not different among subjects withcarotid artery atherosclerosis and no- carotid artery atherosclerosis(P>0.05). Compared with the control value, the serum IL-13 levelobtained at day 1 was not increase (P>0.05). It began to increase atday 3, and peaked at day 7 (2 times of control value). The high levellasted to day 14(P<0.01). Meanwhile, the serum levels of IL-4obtained at day 3, 7, and 14 in patients with cerebral infarction weresignificantly higher than the control subjects with carotidatherosclerotic (P<0.01).
Conclusion:
The serum levels of IL-4 and IL-13 are elevated after cerebralinfarction. This supposes that IL-4 and IL-13 play an anti-inflammationrole in brain ischemic injury and ameliorate brain ischemic injury.
Part 2The association of gene polymorphisms of IL-4, IL-13 and IL-4Rwith atherothrombotic cerebral infarction
Objects:
1. To elucidate the associations of genetic polymorphism of IL-4 C-590Tand C+33T, IL-13 C+1923T with the serum levels of IL-4 and IL-13.
2. To elucidate the associations ofgene polymorphisms of C-590T andC+33T in IL-4, C+1923T in IL-13 and Q576R in IL-4R withatherothrombotic cerebral infarction.
Methods: A case-control study was carried out in this research, in which159 patients with atherothrombotic cerebral infarction, as well as 151control subjects were recruited. Genotyping among study subjects wascarried out by polymerase chain reaction (PCR)-restriction fragmentlength polymorphism (RFLP).
Results:
1. The IL-4 C+33T was in strong linkage disequilibrium with C-590T.The serum IL-4 level in TT genotype was higher than TC and CCgenotype, TC genotype higher than CC genotype. But those genotypesand allele frequencies in IL-4 were found no difference amongpatients with cerebral infarction and control subjects.
2. The serum IL-13 level in TT genotype of IL-13 C+1923Tpolymorphism was not different from TC genotype. The serum IL-13level in TT and TC genotype were higher than CC genotype. But thosegenotypes and allele frequencies were found no difference amongpatients with cerebral infarction and control subjects.
3. IL-4R Q576R polymorphisms were found no difference amongpatients with cerebral infarction and control subjects.
4. The genotype of IL-4 590T/IL-4R 576R and IL-4 33T/IL-4 576R butnot IL-13 1923T/IL-4R 576R had a significantly increased risk forcerebral infarction.
Conclusion:
1. IL-4 C+33T is in strong linkage disequilibrium with C-590T. T allelewas associated with high serum IL-4 level. The C-590T and C+33Tpolymorphism are not associated with the risk of atherothromboticcerebral infarction in Chinese Han population.
2. The serum IL-13 level depends on IL-13 C+1923T polymorphism, Tallele was associated with high serum IL-13 level. The IL-13C+1923T polymorphism is not associated with the risk ofatherothrombotic cerebral infarction in Chinese Han population.
3. The IL-4R Q576R polymorphism is not associated with the risk ofatherothrombotic cerebral infarction in Chinese Han population.
4. The genotype of IL-4 590T/IL-4R 576R and IL-4 33T/IL-4 576R arefound to be independent predictors of atherothrombotic cerebralinfarction in Chinese Han population.
引文
1. Thomas J, DeGraba MD. The role of inflammation after acute stroke, Neurology, 1998,51(suppl 3):s62-s67.
2. Abehsira-Amar O., Gibert M., Joliy M., et al. IL-4 plays a dominant role in the differential development of Th0 into Th1 and Th2 cells. J Immunol 148 (1992), p. 3820.
3. Essner R., Rhoades K., McBride W.H, et al. IL-4 down-regulates IL-1 and TNF gene expression in human monocytes. J Immunol. 1989 (142): 3857.
4. Damle N. and Doyle LV. Distinct regulatory effects of IL-4 and TNF-alpha during CD3-dependent and CD3-independent initiation of human T-cell activation. Lymphokine Res. 1989 (8): 85.
5. Chaitidis P, O'Donnell V, Kuban RF, et al. Gene expression alterations of human peripheral blood monocytes induced by medium-term treatment with the TH2-cytokines interleukin-4 and -13. Cytokine, 2005; 30(6): 366-377.
6. Rocken M, Rack M, Shevach E. IL-4 induced immune deviation as antigen specific therapy for inflammatory autoimmune disease. Immunol Today. 1996; 17:225-231.
7. Femke J. Bijlsmaa, Joyce van Kuika. Acute cardiac transplant rejection is associated with low frequencies of interleukin-4 producing helper T-Lymphocytes rather than with interleukin-4 promoter or splice variants. Human Immunology. 2002, 63(4): 317-323
8. Shirakawa T, Klaus A. Deichmannb. Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunology Today. 2000, 21(2): 60-64.
9. Wojta J., Gallicchio M., Zoellner H., et al. Interleukin-4 stimulates expression of urokinase-type-plasminogen activator in cultured human foreskin microvascular endothelial cells. Blood 1993, 81:3285.
10. Bochner BS, Klunk DA, Sterbinsky SA, et al. IL-13 selectively induces vascular cell adhesion molecule-1 expression in human endothelial cells. J. Immunol. 1995.154:799.
11. Toi M, Harris AL, Bicknell R. Interleukin-4 is a potent mitogen for capillary endothelium. Biochem. Biophys. Res. Commun. 1991.174:1287.
12. Fukushi J, Morisaki T, Shono T, et al. Novel biological functions of interleukin-4: formation of tube-like structures by vascular endothelial cells in vitro and angiogenesis in vivo. Biochem. Biophys. Res. Commun. 1998.250:444.
13. George J, Shoenfeld Y, Gilburd B. Requisite Role for Interleukin-4 in the Acceleration of Fatty Streaks Induced by Heat Shock Protein 65 or Mycobacterium tuberculosis. Circulation Research. 2000; 86:1203.
14. Elkarim RA, Mustafa M, Kivisakk P, et al. Cytokine autoantibodies in multiple sclerosis, aseptic meningitis and stroke. Eur. J. Clin. Invest, 1998,28,295-299.
15. Kim HM, Shin HY, Jeong HJ, et al. Reduced IL-2 but elevated IL-4, IL-6, and IgE serum levels in patients with cerebral infarction during the acute stage. J. Mol. Neurosci., 2000,14,191-196.
16. Pelidou SH, Kostulas N, Matusevicius DHigh levels of IL-10 secreting cells are present in blood in cerebrovascular diseases. Eur J Neurol. 1999,6(4):437-42.
17. Minty A, Chalon P, Derocq JM, et al. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature, 1993; 362(6417): 248-50.
18. de Waal Malefyt R, Figdor CG., Huijbens R, et al. Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes: comparison with IL-4 and modulation by IFN-γ or IL-10. J. Immunol. 1993; 151:6370.
19. Foteinos G, Afzal AR, Mandal K, et al. Anti-Heat Shock Protein 60 Autoantibodies Induce Atherosclerosis in Apolipoprotein E-Deficient Mice via Endothelial Damage. Circulation. 2005; 112: 1206-1213.
20. Shin WH, Lee DY, Park KW, et al. Microglia expressing interleukin-13 undergo cell death and contribute to neuronal survival in vivo. Glia. 2004; 46(2):142-52.
21. Yang MS, Park EJ, Sohn S, Interleukin-13 and -4 induce death of activated microglia. Glia. 2002; 38(4): 273-80.
22.唐红宇,杨期东,张智博等,脑卒中患者血浆白细胞介素13水平的动态变化.中华神经科杂志,2002,35(3):151-153.
23. Tetickovic E, Marchetti M, Matela J, et al. Three-dimensional ultrasonography for the evaluation of atherosclerotic stenoses of the carotid trunk. Coll Antropol. 2001; 25: 511-20.
24. Corry DB and Kheradmand F. Induction and regulation of the IgE response. Nature, 1999; 402(6760 Suppl): B18-23.
25. Parronchi P, Tiri A, Maccia D, et al. Noncognate contact-dependent B cell activation can promote IL-4-dependent in vitro human IgE synthesis. J Immunol.1990 Mar 15;144(6):2102-8.
26. Mckezie AN. Regulation of T helper type 2 cell immunity by interleukin-4 and interleukin-13. Pharmacol Ther, 2000; 88(2): 143-51.
27. Prue H, Hart, Gerard F. et al. Potential Antiinflammatory Effects of Interleukin 4: Suppression of Human Monocyte Tumor Necrosis Factor α, Interleukin 1, and Prostaglandin E2 PNAS, 1989; 86:3803-3807.
28. Oppenheim JJ, and Neta, R. Pathophysiological roles of cytokines in development, immunity, and inflammation[news]. FASEB J. 1994; 8, 158-162.
29. Street NE and Mosmann TR. Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J. 1991; 5, 171-177.
30. Abbas AK, Murphy KM, and Sher A. Functional diversity of helper T lymphocytes. Nature, 1996; 383(6603): 787-93.
31. Serhan CN, Jain A, Marleau S, et al. Reduced Inflammation and Tissue Damage in Transgenic Rabbits Overexpressing 15-Lipoxygenase and Endogenous Anti-inflammatory Lipid Mediators J. Immunol. 2003; 171: 6856-6865.
32. te Velde AA, Huijbens RJ, de Vries JE, et al. IL-4 decreases Fc gamma R membrane expression and Fc gamma R-mediated cytotoxic activity of human monocytes J. Immunol., 1990; 144: 3046.
33. Renkonen R, Mattila P, Majuri ML, et al. IL-4 decreases IFN-gamma-induced endothelial ICAM-1 expression by a transcriptional mechanism. Scand J Immunol, 1992; 35(5): 525-30.
34. Ohmori Y, and Hamilton TA. IL-4-induced expression of the IL-1 receptor antagonist gene is mediated by STAT6J. Immunol. 1997; 157,2058-2065.
35. Kato A, Yoshidome H, Edwards MJ, et al. Reduced hepatic ischemia/reperfusion injury by IL-4: potential anti-inflammatory role of STAT6. Inflamm. res. 2000 , (49): 275-279.
36. Stoll G, Jander S, Schroeter M. Inflammation and glial response in ischemic brain lesions. Prog Neurobiol. 1998; 56(2): 149-171.
37. Clark RK, Lee EV, Fish CJ, et al. Development of tissue damage, inflammation and resolution following stroke: an immunohistochemical and quantitative planimetric study. Brain Res. Bull. 1993,31(5): 565-572.
38. Banati RB, Gehrmann J, Wiessner C, et al. Glial expression of the beta-amyloid precursor protein (APP) in global ischemia. J. Cereb. Blood Flow Metabol. 1995, 15(4): 647-654.
39. Lees GJ. The possible contribution of microglia and macropahges to delayed neuronal death after ischemia. J. Neurol. Sci. 1993,114(2): 119-122.
40. Paul WE. Interleukin-4: a prototypic immunoregulatory lymphokine. Blood, 1991, 77:1859-1870.
41. Zhou X, Paulsson G, Stemme S, et al. Hypercholesterolemia is associated with a T helper (Th)1/Th2 switch of the autoimmune response in atherosclerotic apoE-knockout mice. J Clin Invest 1998; 101(8): 1717.
42. Khew-Goodal Y, Wadham C, Stein BN, etal. Stat6 activation is essential for interleukin-4 induction of P-selectin transcription in Human umbilical vein endothelia lcells. Arterioscler Throm Vasc. Biol. 1999; 19(6):1421.
43. Greaves DR, HakkinenT, LucasAD, et al. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fracta lkine, and thymus- and activation- regulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler Thromb Vase Biol. 2001; 21(6): 923.
44. Lee YW, Kuhn H, Kaiser S, et al. Interleukin 4 induces transcription of the 15-lipoxygenase 1 gene in human endothelial cells. J Lipid Res. 2001:42(5): 783.
45. Barks JL, Mc Quillan JJ, Iademarco MF. INF-alpha and IL-4 synergistically increase vascular cell adhesion molecule-1 expression in cultured vascular smooth muscle cells. J Immunol. 1997; 159(9): 4532.
46. Sasaguri T, Arima N, Tanimoto A, et al. A role for interleukin 4 in production of matrix metalloproteinase 1 by human aortic smooth muscle cells. Atherosclerosis. 1998;138(2):247-53.
47. Cornicelli JA, Butteiger D, Rateri DL, et al. Interleukin-4 augments acetylated LDL-induced cholesterol esterification in macrophages.J Lipid Res. 2000 41:376-383.
48. Brubaker JO, Montaner LJ. Role of interleukin-13 in innate and adaptive immunity. Cell. Mol. Biol. 2001; 47:637.-651.
49. Wang YH, Shen BJ, and Sebald W. A mixed-charge pair in human interleukin 4 dominates high-affinity interaction with the receptor α chain. Proc. Natl. Acad. Sci. USA. 1997, (94): 1657-1662.
50. Letzelter F, Wang Y and Sebald W. The interleukin-4 site-2 epitope determining binding of the common receptor gamma chain. European Journal of Biochemistry, 1998, (257): 11-20.
51.冯振伟.江黎明.陈孝文.IL-13对大鼠急性肾缺血再灌注时IL-1β表达的影响.中国病理生理杂志,2003,19(7):930-934.
52. Virginia A. Folcik; Rozina Aamir; Martha K. Cathcart. Cytokine Modulation of LDL Oxidation by Activated Human Monocytes. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997; 17: 1954-1961.
53. Brassss LM, Isaacohn JL, Merikanga KR, etal. A study of twins and stroke. Stroke, 1992, 23(2): 221-223.
54. Bak S, Gaist D, Sindrup SH, etal. Genetic liability in stroke: long-term follow-up study of Danish twins. Stroke, 2002, 3(3): 769-774.
55. Hassan A, Markush S. Genetics and ischemic stroke. Brain, 2000, 123: 1784-1812.
56. Kiely DK, Wolf PA, Cupples LA, et al. Familial aggregation of stroke. The Framingham Study. Stroke, 1993, 24(9): 1366-1371.
57. Thoravldsen P, Aplund K, Kuulasmaa K, etal. Stroke incidence, case fatality, and mortality in the WHO MONICA project. World Health Organization Monitoring Trends and Determinants in cardiovascular disease. Stroke, 1995, 26(3): 361-367.
58. Rastenyte D, Tuomilehto J, Sarti C. Genetics of stroke -a review. J of NeurolSci, 1998, 153: 132-145.
59. Grover SA, Coupal PM, Hu XP. Identifying adults at increased risk of coronary disease. How well do the current cholesterol guidelines work. JAMA. 1995; 274: 801-806.
60. Libby P. Inflammation in atherosclerosis. Nature. 2002; 420: 866-874.
61. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685-1695
62. Rosenwasser LJ,. Klemm DJ, Dresback JK, et al. Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy, Clin. Exp. Allergy 1995; 25: 74-78 (discussion) 95-76.
63. Lanny J. Rosenwasser LJ, and Borish L. Genetics of Atopy and Asthma: The Rationale behind Promoter-based Candidate Gene Studies (IL-4 and IL-10). Am. J. Respir. Crit. Care Med., 1997; 156: 152-5.
64. Kawashima T, Noguchi E, Arinami T, et al. Linkage and association of an interleukin 4 gene polymorphism with atopic dermatitis in Japanese families J. Med. Genet. 1998; 35: 502.
65. Cantagrel A, Navaux F, Loubet-Leseoulie P, et al. Interleukin-lbeta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 gene polymorphisms: relationship to occurrence and severity of rheumatoid arthritis, Arthritis Rheum. 1999; 42: 1093-1100.
66. Odbileg R, Lee SI, Onuma M. Cloning and sequence analysis of llama (lama glama) Th2 (IL-4, IL-10 and IL-13) cytokines. Vet Immunol Immunolpathol. 2005, 104: 145-53.
67. Graves PE, Kabesch M, Halonen M, et al. A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children. J Allergy Clin Immunol 2000; 105: 506-513.
68.陈吉庆,孙海平,郭锡熔,陈荣华.白细胞介素-13基因多态性对哮喘患儿血清白细胞介素-13及总免疫球蛋白E水平的影响。中国实用儿科杂志2004年4月第19卷第4期:209-211.
69. Kommann M, Kleeff J, Debinski W, et al. Pancreatic cancer cells express interleukin-13 and -4 receptors, and their growth is inhibited by Pseudomonas exotoxin coupled to interleukin-13 and -4. Anticancer Res, Jan 1999; 19(1A): 125-31.
70. Montaner LJ, Bailer RT, Gordon S. IL-13 acts on macrophages to block the completion of reverse transcription, inhibit virus production, and reduce virus infectivity. J. Leukocyte Biol. 1997.62: 126.-132.
71. Carballido JM, Schols D, Namikawa R, et al. IL-4 induces human B cell maturation and IgE synthesis in SCID-hu mice. Inhibition of ongoing IgE production by in vivo treatment with an IL-4/IL-13 receptor antagonist. J. Immunol., 1995; 155: 4162.
72. Idzerda RL, March CJ, Mosley B, et al. Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily J. Exp. Med. 1990; 171: 861-873.
73. Bodo Grimbacher, Steven M. Holland, Jennifer M. Puck, Gurjit K. Khurana Hershey, and Talal A. Chatila The Interleukin-4 Receptor Variant Q576R in Hyper-IgE Syndrome N. Engl. J. Med. Apr 1998; 338: 1073-1074.
74. Hershey GKK, Friedrich MF, Esswein LA, et al. The Association of Atopy with a Gain-of-Function Mutation in the Subunit of the Interleukin-4 Receptor N. Engl. J. Med.1997; 337: 1720-1725.
75. Nakayama EE, Hoshino Y, Xin XM, et al. Polymorphism in the Interleukin-4 Promoter Affects Acquisition of Human Immunodeficiency Virus Type 1 Syncytium-Inducing Phenotype J. Virol. 2000; 74:5452-5459.
76.刘东方,刘日明,崔天盆等.白细胞介素4及肿瘤坏死因子-α基因多态性与湖北汉族儿童哮喘相关性研究.华中科技大学学报医学版,2004,33(2):196-198.
77. Sandford AJ, Chagani T, Zhu S, et al. Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol, 2000; 106(1 Pt 1): 135-40.
78. Tsai MH, Chen WC, Tsai CH, et al. Interleukin-4 gene, but not the interleukin-1 beta gene polymorphism, is associated with oral cancer. J Clin Lab Anal. 2005; 19:93-98.
79. Noguchi E, Shibasaki M, Arinami T, et al. Association of asthma and the interleukin-4 promoter gene in Japanese. Clin Exp Allergy 1998; 28: 449-453.
80. Verra F, Luoni G, Calissano C, et al. IL4-589C/T polymorphism and IgE levels in severe malaria. Acta Trop 2004; 90:205-209.
81. Beghe B, Barton S, Rorke S, et al. Polymorphisms in the interleukin- 4 and interleukin-4 receptor alpha chain genes confer susceptibility to asthma and atopy in a Caucasian population. Clin Exp Allergy 2003; 33: 1111-1117.
82. Nagarkatti R, Kumar R, Sharma SK, et al. Association of IL4 gene polymorphisms with asthma in North Indians. Int Arch Allergy Immunol 2004; 134:206-212.
83. Gervaziev YV, Kaznacheev VA, Gervazieva VB. Allelic Polymorphisms in the Interleukin-4 Promoter Regions and Their Association with Bronchial Asthma among the Russian Population. Int Arch Allergy Immunol. 2006; 141:257-264.
84. Choi EH, Lee HJ, Yoo T, et al. A common haplotype of interleukin-4 gene IL4 is associated with severe respiratory syncytial virus disease in Korean children. J Infect Dis2002;186: 1207-1211.
85. Suzuki I, Yamaguchi E, Hizawa N, et al. A new polymorphism in the 5' flanking region of the human interleukin (IL)-4 gene. Immunogenetics, 1999; 49(7-8): 738-9.
86. Zhou G, Zhai Y, Dong XJ,e t al. Haplotype Structure and Evidence for Positive Selection at the Human IL13 Locus. Molecular Biology and Evolution , 2004, vol. 21 no. 1:29-35
87. Hoebee B, RietveldE, Bont L,et.al. Association of Severe Respiratory Syncytial Virus Bronchiolitis with Interleukin-4 and Interleukin-4 Receptor a Polymorphisms The Journal of Infectious Diseases 2003; 187:2-11.
88. Nakamura E, Megumi Y, Kobayashi T, et al. Genetic Polymorphisms of the Interleukin-4 Receptor _ Gene Are Associated with an Increasing Risk and a Poor Prognosis of Sporadic Renal Cell Carcinoma in a Japanese Population. Clinical Cancer Research. 2002(8): 2620-2625.
89. Zhang WD, Zhang XZ, Qiu DW, et al. IL-4 receptor genetic polymorphisms and asthma in Asian populations. Respiratory Medicine, 2007,101(1): 186-190.
90. Lewontin RC. On measures of gametic disequilibrium. Genetics 1988; 120:849-852.
91. Moffatt MF, Traherne JA, Abecasis GR, et al. Single nucleotide polymorphism and linkage disequilibrium within the TCR/ locus. Hum Mol Genet 2000; 9:1011-1019.
92. Monica J. Basehore BS, Timothy D. A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects. Journal of Allergy and Clinical Immunology. 2004:114: 80-87.
93. Hunt J, Marshall SE, Weetma AP, et al. Cytokine gene polymorphisms in autoimmune thyroid disease, J. Clin. Endocrinol. Metab. 2000; 85: 1984-1988.
94. Bugawan TL, Mirel DB, Valdes AM, et al. Association and interaction of the IL4R, IL4, and IL13 loci with type 1 diabetes among Filipinos, Am. J. Hum. Genet. 2003; 72:1505-1514.
95. Aithal GP, Day CP, Leathart J, et al. Association of single nucleotide polymorphisms in the interleukin-4 gene and interleukin-4 receptor gene with Crohn's disease in a British population, Genes Immun. 2001,2:44-47.
96. Urcelaya E, Santiagoa JL, Masa A, et al. Role of interleukin 4 in Spanish multiple sclerosis patients. 2005; 168:164-167.
97. Zee RY, Cook NR, Cheng S. Polymorphism in the P-selectin and interleukin-4 genes as determinants of stroke: a population-based, prospective genetic analysis. Hum Mol Genet. 2004 Feb 15; 13(4):389-96.
98. Rosenwasser, LJ. The genetics of atopy. Allergy, 1998; 53(Suppl. 46):8-11.
99. Uboldi de Capei MU, Dametto E, Fasano ME, et al. Genotyping for cytokine polymorphisms: allele frequencies in the Italian population. Eur J Immunogenet 2003; 30: 5-10.
100. Scarel-Caminaga RM, Trevilatto PC, Souza AP, et al. Frequencies of the -330 (T-G) IL-2 and -590 (T- C) IL-4 gene polymorphisms in a population from south-eastern Brazil. Eur J Immunogenet 2002; 29:293-296.
101. Rosenwasser LJ. Genetics of atopy and asthma: promoter-based candidate gene studies for IL-4, Int. Arch. Allergy Immunol. 1997; 113: 61-64.
102. Choi EH, Foster CB, Taylor JG, et al. Association between chronic disseminated candidiasis in adult acute leukemia and common IL4 promoter haplotypes. J Infect Dis 2003; 187: 1153-1156.
103. Deichmann K, Bardutzky J, Forster J, et al. Common polymorphisms in the coding part of the IL4-receptor gene. Biochem Biophys Res Commun, 1997; 231(3): 696-7.
104. Rosand JR, Altshuler D.Human genome sequence variation and the search for gene sinfluencing stroke. Stroke, 2003, 34: 2512-2517.
1. Fort MM, Cheung J, Yen D, J Li, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity, 2001; 15(6): 985-95.
2. Karulin AY, Hesse MD, Hualin C. Yip, et al. Cellular immunology and immune regulation: Indirect IL-4 Pathway in Type 1 Immunity. J. Immunol., 2002; 168: 545-553.
3. Corry DB and Kheradmand F. Induction and regulation of the IgE response. Nature, 1999; 402(6760 Suppl): B18-23.
4. Venkayya R, Lam M, Willkom M, et al. The Th2 Lymphocyte Products IL-4 and IL-13 Rapidly Induce Airway Hyperresponsiveness Through Direct Effects on Resident Airway Cells Am. J. Respir. Cell Mol. Biol. 2002; 26: 202.
5. Cron RQ, Zhou B, Brunvand MW, et al. Octamer proteins inhibit IL-4 gene transcription in normal human CD4 T cells. Genes Immun, 2001; 2(8): 464-8.
6. Jiang H, Harris MB, and P Rothman. IL-4/IL-13 signaling beyond JAK/STAT. J Allergy Clin Immunol, 2000; 105(6 Pt 1): 1063-70.
7. Zamorano J, Wang HY, Wang LM, et al. IL-4 protects cells from apoptosis via the insulin receptor substrate pathway and a second independent signaling pathway J. Immunol. 1996; 157: 4926
8.王志华.IL-4的研究及其进展.国外医学·免疫学分册,1989,(3):113-116.
9. Daher S, Santo LM s, Sole D, et al. Interleukin-4 and soluble CD23 serum levels in asthmatic atopic children. J Investig Allergol Clin Immunol, 1995; 5(5): 251-4.
10. Walker C, Bauer W, Braun RK, et al. Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia Am. J. Respir. Crit. Care Med., 1994; 150: 1038.
11.王华强,张世明,李强.哮喘患者外周血淋巴细胞产生白细胞介素一4等水平的变化..中华结核和呼吸杂志,1997,20(1):32.
12. Leonard C, Tormey V, Burke C, et al. Allergen-induced cytokine production in atopic disease and its relationship to disease severity Am. J. Respir. Cell Mol. Biol., 1997; 17: 368.
13. Urban JF, Noben-Trauth N, Donaldson DD, et al. IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity, 1998; 8(2): 255-64
14. Parronchi P, Tiri A, Maccia D, et al. Noncognate contact-dependent B cell activation can promote IL-4-dependent in vitro human IgE synthesis. J Immunol. 1990 Mar 15; 144(6): 2102-8.
15. Mckezie AN. Regulation of T helper type 2 cell immunity by interleukin-4 and interleukin-13. Pharmacol Ther, 2000; 88(2): 143-51.
16. Chanez P, Vignola AM, Paul-Eugene N, et al. Modulation by interleukin-4 of cytokine release from mononuclear phagocytes in asthma. J Allergy Clin Immunol, 1994; 94(6 Pt 1): 997-1005.
17. Prue H, Hart, Gerard F. et al. Potential Antiinflammatory Effects of Interleukin 4: Suppression of Human Monocyte Tumor Necrosis Factor α, Interleukin 1, and Prostaglandin E_2 PNAS, 1989; 86:3803-3807.
18. Essner R, Rhoades K, McBride WH, et al. IL-4 down-regulates IL-1 and TNF gene expression in human monocytes J. Immunol., 1989; 142(11): 3857-61.
19.王立波.人类Th1细胞亚群与支气管哮喘.国外医学·免疫学分册.1995,18(1):21-23.
20. Vella A, Teague TK, Ihle J, et al. Interleukin 4 (IL-4) or IL-7 Prevents the Death of Resting T Cells: Stat6 Is Probably Not Required for the Effect of IL-4 J. Exp. Med., 1997; 186: 325-330.
21. Kuhn R, Rajewsky K, and W Muller. Generation and analysis of interleukin-4 deficient mice Science, 1991; 254: 707-710.
22. Paul WE and Seder RA. Lymphocyte responses and cytokines. Cell, 1994; 76(2): 241-51.
23. Oriss TB, McCarthy SA, Campana MAK, et al. Evidence of Positive Cross-Regulation on Th1 by Th2 and Antigen-Presenting Cells: Effects on Th1 Induced by IL-4 and IL-12 J. Immunol., 1999; 162: 1999-2007.
24. Castro A, Sengupta TK, Ruiz DC, et al. IL-4 Selectively Inhibits IL-2-Triggered Stat5 Activation, But Not Proliferation, in Human T Cells J. Immunol., Feb 1999; 162: 1261-9.
25.修方明,于益芝.白细胞介素4受体及其临床意义.国外医学·免疫学分册 1994,17(4):208-211.
26. Cavaillon JM. Pro- versus anti-inflammatory cytokines: myth or reality. Cell Mol Biol 2001; 47:695-702.
27. Rocken M, Rack M, Shevach E. IL-4 induced immune deviation as antigen specific therapy for inflammatory autoimmune disease. Immunol Today. 1996; 17:225-231.
28. Femke J. Bijismaa, Joyce van Kuika. Acute cardiac transplant rejection is associated with low frequencies of interleukin-4 producing helper T-Lymphocytes rather than with interleukin-4 promoter or splice variants. Human Immunology. 2002, 63(4): 317-323.
29. ShirakawaT, Klaus A. Deichmannb. Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunology Today. 2000,21(2): 60-64.
30. Wang L, Teng W, and Z Shan. Effect of IFN-gamma, IL-4 on proliferation and synthesis of hyaluronic acid and collagen in cultured human retroorbital fibroblasts in vitro. Chin Med J (Engl), 2000; 113(10): 907-10.
31. Chaitidis P, O'Donnell V, Kuban RF, et al. Gene expression alterations of human peripheral blood monocytes induced by medium-term treatment with the TH2-cytokines interleukin-4 and -13. Cytokine, 2005; 30(6): 366-377.
32. Serhan CN, Jain A, Marleau S, et al. Reduced Inflammation and Tissue Damage in Transgenic Rabbits Overexpressing 15-Lipoxygenase and Endogenous Anti-inflammatory Lipid Mediators J. Immunol. 2003; 171: 6856-6865
33. Levy BD, Clish CB, Schmidt B, et al. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol. 2001; 2(7): 612- 9
34. Goh J, Godson C, Brady HR, et al. Lipoxins: pro-resolution lipid mediators in intestinal inflammation. Gastroenterology, 2003; 124(4): 1043-54.
35. Huang JT, Welch JS, Ricote M, et al. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature, 1999; 400(6742): 378-82.
36. Singer TP and Ramsay RR. Flauoprotein structure and mechanism 2. Monoamine oxidases: old friends hold many surprises FASEB J, 1995; 9: 605-10.
37. Pichler R, Maschek W, Krieglsteiner S, et al. Pro-inflammatory role of serotonin and interleukin-6 in arthritis and spondyloarthropathies—measurement of disease activity by bone scan and effect of steroids. Scand J Rheumatol, 2002; 31(1): 41-3.
38. Mossner R and Lesch KP. Role of serotonin in the immune system and in neuroimmune interactions. Brain Behav Immun, 1998; 12(4): 249-71.
39. Oppenheim JJ, and Neta, R. Pathophysiological roles of cytokines in development, immunity, and inflammation [news]. FASEB J. 1994; 8,158-162.
40. Street NE and Mosmann TR. Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J. 1991; 5,171-177.
41. Abbas AK, Murphy KM, and Sher A. Functional diversity of helper T lymphocytes. Nature, 1996; 383(6603): 787-93.
42. te Velde AA, Huijbens RJ, de Vries JE, et al. IL-4 decreases Fc gamma R membrane expression and Fc gamma R-mediated cytotoxic activity of human monocytes J. Immunol., 1990; 144: 3046.
43. Renkonen R, Mattila P, Majuri ML, et al. IL-4 decreases IFN-gamma-induced endothelial ICAM-1 expression by a transcriptional mechanism. Scand J Immunol, 1992; 35(5): 525-30.
44. Darnell JE, Jr. Kerr IM, and Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994; 264,1415-1421.
45. DarnellJE, Jr. STATs and Gene Regulation Science. 1997; 277,1630-1635
46. Seidel HM, Milocco LH, Lamb, P, et al. Spacing of Palindromic Half Sites as a Determinant of Selective STAT (Signal Transducers and Activators of Transcription) DNA Binding and Transcriptional Activity. Proc. Natl. Acad. Sci. U. S. A. 1995; 92, 3041-3045
47. Ohmori Y, and Hamilton TA. IL-4-induced expression of the IL-1 receptor antagonist gene is mediated by STAT6J. Immunol. 1997; 157,2058-2065
48. Schindler C, Shuai K, Prezioso VR, et al. Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science, 1992; 257, 809-813.
49. Hou J, Schindler U, Henzel W J, et al. An interleukin-4-induced transcription factor: IL-4 Stat. Science, 1994; 265,1701-1706.
50. Ohmori Y and Hamilton HA. STAT6 Is Required for the Anti-inflammatory Activity of Interleukin-4 in Mouse Peritoneal Macrophages.J Biol Chem, 1998; 273: 29202-29209.
51. Parronchi P, Carli MD, Manetti R, et al. Aberrant interleukin (IL)-4 and IL-5 production in vitro by CD4+ helper T cells from atopic subjects. Eur J Immunol, 1992; 22(6): 1615-20
52. Brusselle GG, Kips JC, Tavernier JH, et al. Attenuation of allergic airway inflammation in IL-4 deficient mice Clin Exp Allergy, 1994; 24(1): 73-80.
53. Ying S, Durham SR, Corrigan CJ, et al. Phenotype of cells expressing mRNA for TH2-type (interleukin 4 and interleukin 5) and TH1-type (interleukin 2 and interferon gamma) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic and normal control subjects Am. J. Respir. Cell Mol. Biol., 1995; 12: 477-8.
54. Dabbagh K, Takeyama K, Lee HM, et al. IL-4 Induces Mucin Gene Expression and Goblet Cell Metaplasia In Vitro and In VivoJ. Immunol. 1999; 162: 6233-6237.
55. Doucet C, Brouty-Boye D, Pottin-Clemenceau C, et al. IL-4 and IL-13 specifically increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts Int. Immunol., 1998; 10: 1421 -1433.
56. Paul WE. Interleukin-4: a prototypic immunoregulatory lymphokine. Blood, 1991, 77:1859-1870.
57. Zhou X, Paulsson G, Stemme S, et al. Hypercholesterolemia is associated with a T helper (Th)l/Th2 switch of the autoimmune response in atherosclerotic apoE-knockout mice. J Clin Invest 1998; 101(8): 1717
58. Khew-Goodal Y, Wadham C, Stein BN, etal. Stat6 activation is essential for interleukin-4 induction of P-selectin transcription in Human umbilical vein endothelia lcells. Arterioscler Throm Vasc. Biol. 1999; 19 (6):1421
59. George J, Shoenfeld Y, Gilburd B, et al. Requisite role for interleukin-4 in the acceleration of fatty streaks induced by heat shock protein 65 or Mycobacterium tuberculosis. Circ Res. 2000;86(12):1203
60. GreavesDR, HakkinenT, LucasAD, et al. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fracta lkine, and thymus- and activation- regulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2001; 21(6): 923
61. Conrad DJ, Lu M. Regulation of human 12/15-lipoxygenase by Stat6-dependent transcription. Am J Respir Cell Mol Biol. 2000; 22(2): 226
62. Lee YW, Kuhn H, Kaiser S, et al. Interleukin 4 induces transcription of the 15-lipoxygenase 1 gene in human endothelial cells. J Lipid Res. 2001:42(5): 783
63. Barks JL, Mc Quillan JJ, Iademarco MR INF-alpha and IL-4 synergistically increase vascular cell adhesion molecule-1 ex pression in cultured vascular smooth muscle cells. J Immunol. 1997; 159(9): 4532
64. Sasaguri T, Arima N, Tanimoto A, et al. A role for interleukin 4 in production of matrix metalloproteinase 1 by human aortic smooth muscle cells. Atherosclerosis. 1998,138:247-253
65. Cornicelli JA, Butteiger D, Rateri DL, et al. Interleukin-4 augments acetylated LDL-induced cholesterol esterification in macrophages.J Lipid Res. 2000 41:376-383.
66. Monica J. Basehore BS, Timothy D. A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects. Journal of Allergy and Clinical Immunology. 2004: 80-87
67. Cantagrel A, Navaux F, Loubet-Lescoulie P, et al. Interleukin-1 beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 gene polymorphisms: relationship to occurrence and severity of rheumatoid arthritis, Arthritis Rheum. 1999; 42:1093-1100
68. Hunt J, Marshall SE, Weetma AP, et al. Cytokine gene polymorphisms in autoimmune thyroid disease, J. Clin. Endocrinol. Metab. 2000; 85: 1984-1988.
69. Beghe B, Barton S, Rorke S, et al. Polymorphisms in the interleukin-4 and interleukin-4 receptor alpha chain genes confer susceptibility to asthma and atopy in a Caucasian population, Clin. Exp. Allergy 2003; 33: 1111-1117.
70. Bugawan TL, Mirel DB, Valdes AM, et al. Association and interaction of the IL4R, IL4, and IL13 loci with type 1 diabetes among Filipinos, Am. J. Hum. Genet. 2003; 72:1505-1514.
71. Urcelaya E, Santiagoa JL, Masa A, et al. Role of interleukin 4 in Spanish multiple sclerosis patients. 2005; 168:164-167.
72. Zee RY, Cook NR, Cheng S. Polymorphism in the P-selectin and interleukin-4 genes as determinants of stroke: a population-based, prospective genetic analysis. Hum Mol Genet. 2004 Feb 15; 13(4):389-96.
73. Rosenwasser LJ, Klemm DJ, Dresback JK, et al. Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy, Clin. Exp. Allergy 1995; 25: 74-78 (discussion 95-76)
74. Rosenwasser, LJ. The genetics of atopy. Allergy, 1998; 53(Suppl. 46): 8-11.
75. Aithal GP, Day CP, Leathart J, et al. Association of single nucleotide polymorphisms in the interleukin-4 gene and interleukin-4 receptor gene with Crohn's disease in a British population, Genes Immun. 2001, 2: 44-47.
76. Rosenwasser LJ. Genetics of atopy and asthma: promoter-based candidate gene studies for IL-4, Int. Arch. Allergy Immunol. 1997; 113: 61-64.
77. Gervaziev YV, Kaznacheev VA, and VB Gervazieva. Allelic polymorphisms in the interleukin-4 promoter regions and their association with bronchial asthma among the Russian population. Int Arch Allergy Immunol, 2006; 141(3): 257-64.
1. Brubaker JO, Montaner LJ. Role of interleukin-13 in innate and adaptive immunity. Cell. Mol. Biol. 2001; 47: 637.-651.
2. Zurawski SM, Vega FJ, Huyghe B, et al. Receptors for interleukin-13 and interleuldn-4 are complex and share a novel component that functions in signal transduction. EMBO J, 1993; 12(7): 2663-70.
3. Schmid-grendelmeier P, et al. Eosinophils express functional IL-13 in eosinophilic inflammatory disease. J Immunol, 2002,169:1021-1027.
4. Gessner, A. Rollinghoff, M. Biologic functions and signaling of the interleukin-4 receptor complexes. Immunobiology, 2000, 201: 285-307.
5. Odbileg R, Lee SI, Onuma M. Cloning and sequence analysis of llama (lama glama) Th2 (IL-4, IL-10 and IL-13) cytokines. Vet Immunol Immunolpathol. 2005, 104:145-53.
6. de Waal Malefyt R, Figdor CG, Huijbens R, et al. Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes: comparison with IL-4 and modulation by IFN-1 or IL-10. J. Immunol. 1993; 151:6370.
7. Zurawski, G, de Vries JE. Interleukin 13, an interleukin 4-1ike cytokine that acts on monocytes and B cells, but not on T cells. Immunol. Today 1994; 15:19.
8. Minty A, Sebastein S, Bensussan A, et al. The related cytokines interleukin-13 and interleukin-4 are distinguished by differential production and differential effects on T lymphocytes. Eur. Cytokine Netw. 1997.8:203.
9. Mosmann T, Coffman R. Thl and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 1989.7:145.
10. de Waal Malefyt R ,. Abrams JS, Zurawsk SM.et al. Differential regulation of IL-13 and IL-4 production by human CD8+ and CD4+ ThO, Thl and Th2 T cell clones and EBV-transformed B cells. Int. Immunol. 1995.7:1405.
11. Jung, T, Wijdenes J, Neumann C. et al. Interleukin-13 is produced by activated human CD45RA+ and CD45RO+ T cells: modulation by interleukin-4 and interleukin-12. Eur. J. Immunol. 1996.26:571.
12. van der Pouw Kraan TC,. Boeije LC, Troon JT, et al. Human IL-13 production is negatively influenced by CD3 engagement: enhancement of IL-13 production by cyclosporin A. J. Immunol. 1996.156:1818.
13. McKenzie AN, Li DA, Largaespada X, et al. Structural comparison and chromosomal localization of the human and mouse IL-13 genes. J. Immunol. 1993.150:5436.
14. Punnomen J, de-Vries JE. Effect of IL-13on phonetype cytokine production and cytotoxic function of human monocytes. Comparison with IL-4 and modulation INF-gama or IL-10.J Immunol, 1994,152(3): 1094-1-2].
15. Bochner BS, Klunk DA, Sterbinsky SA. Et al. IL-13selectively induces vascular cell adhesion molecule-1 expression in human endothelial cells. J Immunol, 1995, 154(2):799-803.
16. Mckenzie AN, Gulpepper JA, de-Wal MR, et al. Interleukin-13, a T-cell-derive cytokine regulate human monocyte and B-cell function. PNAS. 1993, 90(8): 375-9.
17. Rogan DF, Cousins DJ, and Staynov DZ. Intergenic transcription occurs throughout the human IL-4/IL-13 gene cluster. Biochem Biophys Res Commun, 1999; 255(3): 556-61.
18. Zurawski G and de Vries JE. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 1994; 15(1): 19-26.
19. Punnonen, Aversa G, Cocks BG, et al. Interleukin 13 Induces Interleukin 4-Independent IgG4 and IgE Synthesis and CD23 Expression by Human B Cells. PNAS, 1993; 90: 3730.
20. Rolling C, Treton D, Beckmann P, et al. JAK3 associates with the human interleukin 4 receptor and is tyrosine phosphorylated following receptor triggering. Oncogene, 1995; 10(9): 1757-61
21. Minty A, Sebastein S, Bensussan A, et al. The related cytokines interleukin-13 and interleukin-4 are distinguished by differential production and differential effects on T lymphocytes. Eur. Cytokine Netw. 1997.8:203.
22. Alters SE, Gadea JR, Holm B, et al. IL-13 can substitute for IL-4 in the generation of dendritic cells for the induction of cytotoxic T lymphocytes and gene therapy. J Immunother, 1999; 22(3): 229-36.
23. Takeda K, Kamanaka M, Tanaka T, et al. Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. J. Immunol. 1996; 157: 3220.
24. Goebeler M, Schnarr B, Toksoy A, et al. Interleukin-13 selectively induces monocyte chemoattractant protein-1 synthesis and secretion by human endothelial cells. Involvement of IL-4R alpha and Stat6 phosphorylation. Immunology, 1997; 91(3): 450-7.]"
25. Zhou Zhu, Robert J. Homer, Z. et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest, 1999; 103: 779
26. Prieto J, Lensmar C, Roquet A,et al. Increased interleukin-13 mRNA expression in bronchoalveolar lavage cells of atopic patients with mild asthma after repeated low-dose allergen provocations. Respir Med, Aug 2000; 94(8): 806-14
27. Heinzmann A, Mao X, Akaiwa M, et al. Genetic variants of IL-13 signalling and human asthma and atopy. Hum Mol Genet 2000; 9:549-559.
28. Graves PE, Kabesch M, Halonen M, et al. A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children. J Allergy Clin Immunol 2000; 105:506-513.
29. Ober C, Leavitt SA, Tsalenko A, et al. Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations.Am J Hum Genet, Feb 2000; 66(2): 517-26
30. Kornmann M, Kleeff J, Debinski W, et al. Pancreatic cancer cells express interleukin-13 and -4 receptors, and their growth is inhibited by Pseudomonas exotoxin coupled to interleukin-13 and -4. Anticancer Res, Jan 1999; 19(1A): 125-31.
31. Montaner LJ, Bailer RT, Gordon S. IL-13 acts on macrophages to block the completion of reverse transcription, inhibit virus production, and reduce virus infectivity. J. Leukocyte Biol. 1997.62:126.-132.
32. Papasavvas E, Sun JW, Luo Q, et al. IL-13 Acutely Augments HIV-Specific and Recall Responses from HIV-1-Infected Subjects In Vitro by Modulating Monocytes J. Immunol. 2005; 175: 5532 - 5540.
33. Shin WH, Lee DY, Park KW, et al. Microglia expressing interleukin-13 undergo cell death and contribute to neuronal survival in vivo. Glia, April 15,2004; 46(2): 142-52.
34. Guo J, Apiou F, Mellerin MP, et al. Chromosome mapping and expression of the human interleukin-13 receptor.Genomics, 1997; 42(1): 141-5.
35. Carballido JM, Schols D, Namikawa R, et al. IL-4 induces human B cell maturation and IgE synthesis in SCID-hu mice. Inhibition of ongoing IgE production by in vivo treatment with an IL- 4/IL-13 receptor antagonist. J. Immunol., 1995; 155: 4162..
36. Hong Jiang, Harris MB, Rothman. IL-4/IL-13signaling beyond JAK/STAT. [J]. JAllergy Clin Immunol, 2000,105 :1063-1070]
37. Harris MB, Chang CH, Berton MT, et al. Transcriptional Repression of Stat6-Dependent Interleukin-4-Induced Genes by BCL-6: Specific Regulation of I(?) Transcription and Immunoglobulin E Switching. Mol. Cell. Biol., 1999; 19: 7264 - 7275.
38. Schindler U, Wu P, Rothe M, et al. Components of a Stat recognition code: evidence for two layers of molecular selectivity.Immunity, 1995; 2(6): 689-97.
39. Liu X, Nickel R, Beyer K, et al. An IL13 coding region variant is associated with a high total serum IgE level and atopic dermatitis in the German multicenter atopy study (MAS-90). JAllergy Clin Immunol 2000; 106:167-170.
40. Thompson JP, Debinski W. Mutants of interleukin-13 with altered reactivity toward interleukin-13 receptors. J Biol Chem 1999; 274:29944-29950.
41. Moy FJ, Diblasio E, Wilhelm J, Powers R. Solution structure of human IL-13 and implication for receptor binding. J Mol Biol 2001; 310:219-230.
42. Oshima Y, Joshi BH, Puri RK. Conversion of interleukin-13 into a high affinity agonist by a single amino acid substitution. J Biol Chem 2000; 275: 14375-14380.
43. 43. Arima K, Umeshita-Suyama R, Sakata Y, et al. Upregulation of IL-13 concentration in vivo by the IL-13 variant associated with bronchial asthma. J Allergy Clin Immunol 2002; 109: 980-987.
44. 44. van der Pouw Kraan TC, van Veen A, Boeije LC, et al. An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun, 1999; 1(1): 61-5.