1、IL-21與腫瘤治療目錄Il-21&IL-21RIl-21介導(dǎo)的信號(hào)通路IL-21對(duì)免疫細(xì)胞的作用Il-21在腫瘤治療的應(yīng)用IL-212000年命名IL-2家族基因位于4q26-q27133個(gè)氨基酸四螺旋結(jié)構(gòu)CD4+T細(xì)胞分泌（1）功能多樣http:/www.ebi.ac.uk/pdbe/entry/pdb/2OQPIL-21R孤獨(dú)受體受體復(fù)合體包括IL21R與c受體鏈IL-2家族公用激活方式（2）酪氨酸殘基Janus kinase1（JAK1）和JAK3http:/pdb/ngl/ngl.do?pdbid=3TGX&preset=validationReport信號(hào)通路JAK/STAT通路（

2、3）Signal transducers and activators of transcription（STAT）STAT1，STAT3，STAT5停靠JAK激酶磷酸化脫離，組成二聚體入核，活化特異基因啟動(dòng)子Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015

3、, Article ID 696578, 15 pages信號(hào)通路phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)調(diào)節(jié)細(xì)胞周期（3）ras/raf/Mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinases (MAPK)細(xì)胞分裂（3）interferon-regulatory factor 4 (IRF4)+STAT3細(xì)胞凋亡（4）B細(xì)胞只有IL-21（5）激活toll like receptor（TLR）介導(dǎo)凋亡IL-21+BCR/CD

4、40促進(jìn)增殖（5）激活Blimp1（6）促進(jìn)分化Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pagesB細(xì)胞IL-21+IL-4（7）CD40+B細(xì)胞促進(jìn)IgG1和IgG3分泌長(zhǎng)效漿細(xì)胞的產(chǎn)生IL-21信號(hào)

5、的STAT3促進(jìn)抗腫瘤抗體表達(dá)Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pagesB細(xì)胞IL21R缺失的小鼠（8）B細(xì)胞調(diào)節(jié)異常IgG1降低，IgE升高與自身免疫疾病的B細(xì)胞應(yīng)答有關(guān)T細(xì)胞激活Bcl6和M

6、AF轉(zhuǎn)錄因子（9）促進(jìn)濾泡輔助T細(xì)胞分化IRF-4DC抗原呈遞后Tfh產(chǎn)生大量細(xì)胞因子，包括IL-21刺激B細(xì)胞二次免疫應(yīng)答Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pagesT細(xì)胞促進(jìn)CTL分化成熟 I

7、L-21+IL-15（10）可維持CTL的CD28表達(dá)與反應(yīng)性增強(qiáng)IL-15介導(dǎo)的CTL增殖增強(qiáng)記憶CD8+T和原始CD8+T的擴(kuò)增Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pagesT細(xì)胞L21R缺陷的

8、小鼠（10）CTL反應(yīng)下降STAT1激活CD8+T細(xì)胞中的轉(zhuǎn)錄因子T-bet穿孔素和粒酶B的表達(dá)增強(qiáng)CTL運(yùn)輸CCR7有關(guān)C-C chemokine receptorMichela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 1

9、5 pagesT細(xì)胞IL-21+IL-2（11）刺激產(chǎn)生IL-10的type 1 regulatory T (Tr1)增殖和分化STAT3刺激Il-10的產(chǎn)生抑制APC和T細(xì)胞對(duì)抗原的反應(yīng)Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article I

10、D 696578, 15 pagesNK細(xì)胞僅是調(diào)節(jié)功能（12）只有IL-21不會(huì)刺激NK細(xì)胞增殖IL-21+IL-2/IL-15（12）共刺激可促進(jìn)NK細(xì)胞增殖已激活的NK高效的效應(yīng)細(xì)胞更多的IFN-，穿孔素細(xì)胞毒素效應(yīng)增強(qiáng)Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Vol

11、ume 2015, Article ID 696578, 15 pagesNK細(xì)胞STAT3（12）提高natural killer group 2, member D (NKG2D) 受體的表達(dá)STAT3缺失降低NKG2D的表達(dá)量IL-21+IL-7+IL-15+干細(xì)胞因子（SCF）激活KIRs，CD2和細(xì)胞裂解反應(yīng)介導(dǎo)骨髓中CD34+的前細(xì)胞分化為成熟的NK細(xì)胞刺激NK凋亡限制NK反應(yīng)的持續(xù)時(shí)間NK細(xì)胞IL-21不是NK細(xì)胞成熟分化的必要條件（12）IL21R缺失只是會(huì)降低針對(duì)NK敏感抗原的細(xì)胞毒作用，不會(huì)影響antibody-dependent cell-mediated cytotox

12、icity（ADCC）腫瘤中失去功能NK細(xì)胞IL-21刺激可以重新喚醒ADCC樹(shù)突狀細(xì)胞（DC）抑制作用（13）STAT3和Bim激活凋亡Granulocyte macrophage colony-stimulating factor（GM-CSF）可以部分抑制凋亡作用Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of I

13、mmunology Research Volume 2015, Article ID 696578, 15 pagesB-10/BregB-10分泌IL-10的B細(xì)胞亞群Il-20+CD40+T細(xì)胞（14） 刺激B細(xì)胞分化為T(mén)reg細(xì)胞分泌大量Il-10抑制免疫反應(yīng)Michela Croce, Valentina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Imm

14、unology Research Volume 2015, Article ID 696578, 15 pagesB-10/BregB細(xì)胞白血病小鼠（14）注入誘導(dǎo)出的B-10細(xì)胞病情被抑制Il-21+TLR/BCR（14）可誘導(dǎo)出CD19+CD38+CD1d+IgM+CD147+ granzyme B+ Treg細(xì)胞與人類(lèi)腫瘤周?chē)淖儺怋reg細(xì)胞同型與腫瘤的免疫逃逸有關(guān)Treg抑制Treg的功能（15）刺激T細(xì)胞的生長(zhǎng)中和Treg的抑制作用抑制 IL-2/TGF-信號(hào)（15）抑制Treg生長(zhǎng)STAT3抑制分化的激活物Smad2/3負(fù)向調(diào)節(jié)Treg分化Michela Croce, Valen

15、tina Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pagesTreg導(dǎo)致CD4+CD25 T 細(xì)胞對(duì)Treg細(xì)胞產(chǎn)生耐性與T細(xì)胞白血病相關(guān)（15）阻斷IL-21/IL-21R軸有效抑制自身免疫疾病（15）Michela Croce, Valentina

16、 Rigo, and Silvano Ferrini,IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology, Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 696578, 15 pages慢性B細(xì)胞淋巴白血病JAK/STAT （16）激活caspase-8 and caspase-3激活poly (ADP-ribose) polymerase (PARP) 激活p27Kip-1正向調(diào)節(jié)

17、Bcl-2 interacting mediator (BIM)B細(xì)胞凋亡慢性B淋巴細(xì)胞白血病CD40L和CpG oligodeoxynucleotide（16）正向調(diào)節(jié)IL-21R的表達(dá)IL-21+CpG oligodeoxynucleotide（16）凋亡分泌粒酶B抑制絲蛋白酶抑制劑B9治療有效不只是本身凋亡，也會(huì)殺傷周?chē)?xì)胞慢性B淋巴細(xì)胞白血病效果會(huì)被其他信號(hào)干擾（16）IL-21+IL-4 導(dǎo)致CLL增殖對(duì)B-CLL的微環(huán)境建立有促進(jìn)作用治療效果有待改進(jìn)濾泡狀淋巴瘤（FL）JAK/STAT（17）促進(jìn)Caspase-8 and -3 激活降低Bcl-2 表達(dá)增加proapoptotic

18、 Bax 表達(dá)細(xì)胞凋亡只對(duì)IL-21敏感細(xì)胞有效濾泡狀淋巴瘤彌散性大B細(xì)胞淋巴癌（DLBCL）阻礙細(xì)胞周期激活caspase介導(dǎo)的細(xì)胞凋亡STAT激活C-Myc（18）刺激凋亡抑制抗凋亡蛋白Bcl-2 and Bcl-XL 蛋白表達(dá)套細(xì)胞淋巴癌（MCL）STAT1信號(hào)通路（18）增加BIK, NIP3, 和 HARAKIRI抑制抗凋亡蛋白BCL-2 and BCLXL/S抑制nuclear factor-kappaB (NF-B)信號(hào)促進(jìn)細(xì)胞凋亡細(xì)胞疫苗表達(dá)IL-21的癌細(xì)胞（19）旁分泌效應(yīng)刺激CTL，NK，B，效果強(qiáng)于IL-2 or IL-15IFN-，CXCL-9,10,11抗血管生成作

19、用抑制腫瘤形成，增強(qiáng)對(duì)同型腫瘤抗性細(xì)胞疫苗除了腫瘤細(xì)胞，其他細(xì)胞也能做成疫苗（19）DC-hgp100/mIL21對(duì)抗B16黑素瘤表達(dá)鼠IL-21的人臍帶血干細(xì)胞（hUCBSC）抑制卵巢癌腫瘤治療性分子IL-21可以加強(qiáng)治療效應(yīng)anti-CD25 mAb+分泌IL-21的乳腺癌細(xì)胞（20）增強(qiáng)抗原特異的T細(xì)胞反應(yīng)以及IFN-的分泌有效率達(dá)到70%anti-CD4 mAb+分泌IL-21的神經(jīng)膠質(zhì)瘤細(xì)胞Treg（-）&CD8+細(xì)胞（+）免疫檢查點(diǎn)與腫瘤細(xì)胞的免疫逃逸相關(guān)PD-1和PD-1LPD-1：激活的T細(xì)胞表面PD-1L：實(shí)體瘤細(xì)胞表面結(jié)合后抑制CTL的增殖轉(zhuǎn)基因?qū)氡磉_(dá)IL-21和可溶性P

20、D-1（21）治療H22肝癌其他治療方法雞尾酒療法其他治療性單抗DNA疫苗IL-21治療腫瘤的缺點(diǎn)作用的兩面性NK細(xì)胞凋亡，抑制B細(xì)胞作用的復(fù)雜性不同的共刺激信號(hào)產(chǎn)生不同的效果效果不穩(wěn)定副作用可溶性會(huì)在全身分布，產(chǎn)生不良反應(yīng)，甚至自身免疫病總結(jié)IL-21可以激活與增強(qiáng)抗腫瘤免疫反應(yīng)通過(guò)不同共刺激信號(hào)可以增強(qiáng)免疫療法的效果需要提高效果的可控性參考文獻(xiàn)（1）J. Parrish-Novak, S. R. Dillon, A. Nelson et al., “Interleukin 21 and its receptor are involved in NK cell expansion and r

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