四、白细胞介素-8的生物学功能

(一)趋化和激活中性粒细胞

IL-8的趋化和激活中性粒细胞作用无明显种属特异性,动物腹腔或静脉注射IL-8可引起外周血中性粒细胞增加。IL-8可促使中性粒细胞形态改变,促进脱颗粒,激活中性粒细胞并使其产生呼吸爆发(respiratory burst)。局部注射IL-8可趋化中性粒细胞,并刺激中性粒细胞产生白三烯B4(LTB4);IL-8还可诱导中性粒细胞上调Mac-1,促进中性粒细胞黏附到内皮细胞和内皮下基质。

(二)趋化嗜碱性粒细胞

IL-8可趋化嗜碱性粒细胞发生胞吐作用(exocytosis),并刺激释放组胺(histamine),与速发超敏反应有关。此外,IL-8还可刺激GM-CSF和IL-5预先处理的嗜酸性粒细胞脱颗粒。

(三)趋化淋巴细胞

IL-8在单核细胞存在的情况下可趋化CD4 +T细胞和CD8 +T细胞。局部注射IL-8可使局部淋巴结T细胞明显增多,同时,IL-8还可趋化IL-2活化的NK细胞。

五、白细胞介素-8与疾病

(一)IL-8与急性炎症

IL-8在炎症情况下参与中性粒细胞招募和脱颗粒,如作为牙周炎(periodontitis)的促炎性介质。败血症休克、急性脑膜炎患者血清中IL-8显著升高。

(二)IL-8与慢性炎症

肺囊性纤维化时,IL-8水平升高,招募中性粒细胞至肺组织中,导致促炎性细胞因子释放。胃炎、酒精性肝炎患者血清中IL-8明显高于正常对照组。因此,抗IL-8抗体用于治疗囊性纤维化等炎性疾病。

(三)IL-8与自身免疫性疾病

类风湿关节炎患者关节滑液中含有IL-8,IL-8可诱导中性粒细胞促进软骨降解,引起软骨损伤。检测分析发现,银屑病(psoriasis)患者的皮屑中含有IL-8。同时,炎性肠病患者血清中IL-8水平明显高于正常对照组。

(四)IL-8在肿瘤细胞微环境中的作用

1.促进肿瘤细胞增殖
肿瘤组织及癌旁组织IL-8表达可诱导肿瘤细胞内上述多条信号转导通路活化,导致肿瘤细胞增殖和存活能力增强。Kamohara等研究发现,胰腺癌中IL-8过表达,可促进肿瘤细胞增殖;Mac Manus等证实前列腺癌组织中的IL-8可促进癌细胞周期素D1和细胞周期素B的表达,这2种周期素是细胞从G1期向S期转变的关键因素,它们的高表达表明IL-8有促进前列腺癌细胞增殖的作用。
2.促进肿瘤组织中血管的形成
研究表明,肿瘤来源的IL-8可调节肿瘤血管内皮细胞的生长状态及血管壁的通透性,促进肿瘤组织血管的生成,诱导肿瘤内部中性粒细胞的趋化渗透。Merritt等运用小RNA干扰技术抑制卵巢癌细胞IL-8表达,显著降低癌组织中微血管的密度;Huang等通过特异性抗体抑制瘤内IL-8的表达可明显降低黑色素瘤的微血管形成;Karashima等在研究IL-8对膀胱癌的作用时发现,IL-8可通过激活NF-κB对血管形成发挥作用。

(五)IL-8与代谢性疾病

氧化应激可促进IL-8释放,招募炎性细胞到局部,炎性细胞又进一步加重氧化应激,IL-8在动脉粥样硬化局部炎症的恶性循环中起重要作用。

(六)IL-8与生殖病理生理

IL-8是一种属于趋化因子家族的细胞因子,近年来,人们在研究中发现,IL-8几乎参与哺乳动物的整个生殖过程如排卵、黄体形成、子宫内膜增殖、蜕膜化、胚胎着床及其生长发育等过程。许多临床研究表明,IL-8还与某些生殖病理过程有关,如子宫内膜异位症,不明原因的自然流产等。妊娠女性体内分泌高水平的IL-8,可增加后代患精神分裂症的风险,高水平IL-8降低子代对抗精神分裂症的能力。
总之,IL-8在急性炎症、慢性炎症、自身免疫性疾病、肿瘤、代谢性疾病和生殖病理生理有重要作用,检测血清IL-8对疾病病程判断、炎症消退和疾病诊断以及拮抗IL-8治疗提供重要参考。
(饶亚华 曹文操)

参考文献

1.金伯泉.细胞和分子免疫学.西安:世界图书出版公司,1998
2.张晓雷,毛立群,葛新,等.白细胞介素-8在肿瘤中的作用研究现状.武警后勤学院学报(医学版),2014,23(1):69-72
3.Takayuki Y,Tomohiro Y. Cytokine Frontiers. Japan:Springer,2014
4.Baggiolini M,Walz A,Kunkel SL. Neutrophil-activating peptide-1/interleukin 8,a novel cytokine that activates neutrophils. J Clin Invest,1989,84(4):1045-1049
5.Bacon K,Baggiolini M,Broxmeyer H,et al. IUIS/WHO Subcommittee on Chemokine Nomenclature. Chemokine/chemokine receptor nomenclature. J Interferon Cytokine Res,2002,22(10):1067-1068
6.Bhaumik D,Scott GK,Schokrpur S,et al. MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8.Aging(Albany NY),2009,1(4):402-411
7.Brown AS,Hooton J,Schaefer CA,et al. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry,2004,161(5):889-895
8.Harada A,Sekido N,Akahoshi T,et al. Essential involvement of interleukin-8(IL-8)in acute inflammation.J Leukoc Biol,1994,56(5):559-564
9.Kamohara H,Ogawa M,Ishiko T,et al. Leukemia inhibitory factor functions as a growth factor in pancreas carcinoma cells:Involvement of regulation of LIF and its receptor expression. Int J Oncol,2007,30(4):977-983
10.Kownatzki E,Uhrich S,Grüninger G. Functional properties of a novel neutrophil chemotactic factor derived from human monocytes. Immunobiology,1988,177(4-5):352-362
11.Luger TA,Uchida A,Köck A,et al. Human epidermal cells and squamous carcinoma cells synthesize a cytokine that augments natural killer cell activity. J Immunol,1985,134(4):2477-2483
12.Luger TA,Charon JA,Colot M,et al. Chemotactic properties of partially purified human epidermal cell-derived thymocyte-activating factor(ETAF)for polymorphonuclear and mononuclear cells. J Immunol,1983,131(2):816-820
13.Lüttge M,Fulde M,Talay SR,Nerlich A,Rohde M,Preissner KT,Hammerschmidt S,Steinert M,Mitchell TJ,Chhatwal GS,et al. Streptococcus pneumoniae induces exocytosis of Weibel-Palade bodies in pulmonary endothelia cells. Cell Microbiol,2012,14(2):210-225
14.Matsumoto T,Yokoi K,Mukaida N,et al. Pivotal role of interleukin-8 in the acute respiratory distress syndrome and cerebral reperfusion injury. J Leukoc Biol,1997,62(5):581-587
15.Oglesby IK,Vencken SF,Agrawal R,et al.miR-17 overexpression in cystic fibrosis airway epithelial cells decreases interleukin-8 production. Eur Respir J,2015,46(5):1350-1360
16.Reeves EP,Williamson M,O′Neill SJ,et al. Nebulized hypertonic saline decreases IL-8 in sputum of patients with cystic fibrosis. Am J Respir Crit Care Med,2011,183(11):1517-1523
17.Sauder DN,Mounessa NL,Katz SI,et al. Chemotactic cytokines:the role of leukocytic pyrogen and epidermal cell thymocyte-activating factor in neutrophil chemotaxis. J Immunol,1984,132(2):828-832
18.Sharabiani MT,Vermeulen R,Scoccianti C,et al. Immunologic profile of excessive body weight. Biomarkers,2011,16(3):243-251
19.Turner NA,Moake JL. Factor VIII Is Synthesized in Human Endothelial Cells,Packaged in Weibel-Palade Bodies and Secreted Bound to ULVWF Strings. PLoS One,2015,10(10):e0140740
20.Utgaard JO,Jahnsen FL,Bakka A,et al. Rapid secretion of prestored interleukin 8 from Weibel-Palade bodies of microvascular endothelial cells. J Exp Med,1998,188(9):1751-1756
21.Weiss E,Mamelak AJ,La Morgia S,et al. The role of interleukin 10 in the pathogenesis and potential treatment of skin diseases. J Am Acad Dermatol,2004,50(5):657-675
22.Yoshimura T. Discovery of IL-8/CXCL8(The Story from Frederick).Front Immunol,2015,6:278