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白细胞介素-2

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(重定向自白细胞介素2
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IL2
IL2 Crystal Structure.png
已知的結構
PDB Ortholog search: PDBe RCSB
識別號
别名 IL2;IL-2、​TCGF、​interleukin 2、​lymphokine
外部ID OMIM147680 MGI96548 HomoloGene488 GeneCardsIL2
相關疾病
过敏、​1型糖尿病[1]
RNA表达模式
PBB GE IL2 207849 at fs.png
更多參考(基因)表达數據
直系同源
物種 人類 小鼠
Entrez
Ensembl
UniProt
mRNA​序列

NM_000586

NM_008366

蛋白序列

NP_000577

NP_032392

基因位置​(UCSC) Chr 4: 122.45 – 122.46 Mb n/a
PubMed​查找 [2] [3]
維基數據
檢視/編輯 人類 檢視/編輯 小鼠

白细胞介素2 (英语:Interleukin 2IL-2)是细胞因子白细胞介素的一种,在免疫系统中起重要作用。它是一种蛋白质,负责调节白血球(白细胞,通常是淋巴细胞)的免疫活性。 IL-2的生成是机体受微生物感染免疫应答的一部分,以区别“自己”与“非己”。IL-2通过与淋巴细胞表面的IL-2 受体结合来发挥作用。

信号通路[编辑]

IL-2是拥有四个α螺旋束的细胞因子家族的一员,这一家族包括IL-4IL-7IL-9IL-15IL-21。IL-2 signals through the IL-2 receptor, a complex consisting of three chains, termed alpha, beta and gamma. The gamma chain is shared by all family members.[4]

The IL-2 Receptor (IL-2R) α subunit has low affinity for its ligand but has the ability (when bound to the β and ϒ subunit) to increase the IL-2R affinity 100-fold. Heterodimerization of the β and ϒ subunits of IL-2R is essential for signalling in T cells.[5]

历史[编辑]

作为免疫系统的一种水溶性分子,白细胞介素2是第一种被发现并被克隆的白细胞介素,其对应受体也是第一个被克隆并被解析结构的I型细胞因子受体[6]:712

在1960年代中期,有研究报道了白细胞条件培养基中有促进淋巴细胞增殖的“活性因子”[7]:16。在1970年代中期,又发现了正常的人骨髓细胞可在某种条件性培养基中选择性的使T细胞扩增,此条件性培养基用由植物血凝素刺激人正常淋巴细胞而来[6]:712。这其中的关键因子被称为白细胞介素2,源自鼠细胞的白介2于1979年分离纯化,人细胞源的分离纯化于1980年[8]。在多个实验室的激烈竞争中,人IL-2基因最终在1982年被克隆[9]:76

IL-2的促免疫活性使得其在20世纪八九十年代成为一种有希望进入医药市场的免疫增强药物。在1983年,Cetus公司制得了重组的人IL-2蛋白(去掉了氨基端的丙氨酸,125号位的丝氨酸换为半胱氨酸)并冠以商品名Aldesleukin(后期改为Proleukin)[9]:76–77[10]:201[11]。此后,安进公司也进入了这一领域,制得了自己的重组/突变蛋白,很快两家公司就对簿公堂,Cetus最终赢得了专利诉讼将安进逐出了此领域[9]:151。在1990年,Cetus的aldesleukin获得了九个欧洲国家的批准,但是在同年,美国食品药品监督管理局(FDA)拒绝了Cetus的aldesleukin上市申请[12]。这一失利导致了Cetus公司的破产,并于1991年被Chiron公司收购[13][14]。此后,Chiron公司继续开发IL-2,并在1992年以Proleukin为商品名获得了FDA的批准,用以治疗转移性的肾细胞癌[15]

截止1993年,Proleukin仍是唯一获得批准的IL-2药物,但此时罗氏也开发了自己的修饰重组的IL-2(在氨基端增加了甲硫氨酸)商品名为teceleukin,and Glaxo was developing a version called bioleukin, with a methionine added at is N-terminal and residue 125 replaced with alanine. Dozens of clinical trials had been conducted of recombinant or purified IL-2, alone, in combination with other drugs, or using cell therapies, in which cells were taken from patients, activated with IL-2, then reinfused.[11][16] Novartis acquired Chiron in 2006[17] and sold the aldesleukin business to Prometheus Laboratories in 2010.[18] [19]

参考文献[编辑]

  1. ^ 與IL2相關的疾病;在維基數據上查看/編輯參考. 
  2. ^ Human PubMed Reference:. 
  3. ^ Mouse PubMed Reference:. 
  4. ^ Liao W, Lin JX, Leonard WJ. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Current Opinion in Immunology. October 2011, 23 (5): 598–604. PMC 3405730. PMID 21889323. doi:10.1016/j.coi.2011.08.003. 
  5. ^ Gaffen SL, Liu KD. Overview of interleukin-2 function, production and clinical applications. Cytokine. November 2004, 28 (3): 109–23. PMID 15473953. doi:10.1016/j.cyto.2004.06.010. 
  6. ^ 6.0 6.1 Paul WE. Fundamental immunology 6th. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. 2008. ISBN 978-0-7817-6519-0. 
  7. ^ Chavez AR, Buchser W, Basse PH, Liang X, Appleman LJ, Maranchie JK, Zeh H, de Vera ME, Lotze MT. Pharmacologic administration of interleukin-2. Annals of the New York Academy of Sciences. December 2009, 1182: 14–27. PMID 20074271. doi:10.1111/j.1749-6632.2009.05160.x. 
  8. ^ Welte K, Wang CY, Mertelsmann R, Venuta S, Feldman SP, Moore MA. Purification of human interleukin 2 to apparent homogeneity and its molecular heterogeneity. The Journal of Experimental Medicine. August 1982, 156 (2): 454–64. PMC 2186775. PMID 6980256. doi:10.1084/jem.156.2.454. 
  9. ^ 9.0 9.1 9.2 Rabinow P. Making PCR: A story of biotechnology Paperback. Chicago, IL, USA: University of Chicago Press. 1997. ISBN 978-0226701479. 
  10. ^ Hugo Almeida. Drugs obtained by biotechnology processing Brazilian Journal of Pharmaceutical Sciences apr/jun 2011 47(2):199-207
  11. ^ 11.0 11.1 Whittington R, Faulds D. Interleukin-2. A review of its pharmacological properties and therapeutic use in patients with cancer. Drugs. September 1993, 46 (3): 446–514. PMID 7693434. doi:10.2165/00003495-199346030-00009. 
  12. ^ Pollack A. Cetus Drug Is Blocked By F.D.A.. New York Times. July 31, 1990.  This source mentions approval in 9 European countries.
  13. ^ 2 Biotech Pioneers To Merge. New York Times. July 23, 1991. 
  14. ^ Lehrman S. Cetus: A Collision Course With Failure. The Scientist Magazine. January 20, 1992. 
  15. ^ Dutcher JP. Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma. Oncology. November 2002, 16 (11 Suppl 13): 4–10. PMID 12469934. 
  16. ^ D02749 (Teceleukin). KEGG drug. 
  17. ^ Chiron shareholders approve Novartis deal. SWI swissinfo.ch. Apr 19, 2006. 
  18. ^ Shi VY, Tran K, Patel F, Leventhal J, Konia T, Fung MA, Wilken R, Garcia MS, Fitzmaurice SD, Joo J, Monjazeb AM, Burrall BA, King B, Martinez S, Christensen SD, Maverakis E. 100% Complete response rate in patients with cutaneous metastatic melanoma treated with intralesional interleukin (IL)-2, imiquimod, and topical retinoid combination therapy: results of a case series. Journal of the American Academy of Dermatology. October 2015, 73 (4): 645–54. PMID 26259990. doi:10.1016/j.jaad.2015.06.060. 
  19. ^ Novartis sells rights to Proleukin in the USA to Prometheus; gets license for vaccine from IIG; and pleads guilty over Trileptal. Pharmaletter. January 27, 2010. 

外部链接[编辑]