白细胞介素22在结核性胸膜炎与恶性胸腔积液中生物学特性的研究进展

摘要/Abstract

摘要： 白细胞介素22（IL-22）是IL-10细胞因子家族成员之一，通过与IL-22R1、IL-10R2二聚体结合发挥作用。主要由T辅助细胞(T-helper cell)22（Th22）、Th17和Th1细胞表达，部分自然杀伤细胞（NK细胞）、γδT（T细胞受体的一种）细胞和淋巴组织可诱导（LTi）细胞也可表达。结核性胸腔积液和恶性胸腔积液中都存在显著升高的IL-22，主要来源于受趋化因子作用募集于胸膜腔的外周血CD4⁺ T淋巴细胞和胸膜腔局部在IL-6、IL-23、IL-1β和肿瘤坏死因子-α（TNF-α）等细胞因子作用下分化而来的CD4⁺ T细胞。在胸膜腔中，IL-22通过促进基质金属蛋白酶（matrix metalloproteinases，MMPs）的表达发挥免疫病理作用，并通过介导NK细胞产生溶解因子减少寄生于单核细胞来源的巨噬细胞内的结核分枝杆菌生长。在恶性胸腔积液中，IL-22可通过促进肿瘤细胞增殖、迁移，并且通过增加黏附分子的表达促进与胸膜间皮细胞（pleural mesothelial cells，PMCs）的黏附发挥作用。研究IL-22在上述两种疾病中的作用机制，将会为免疫诊断与治疗开辟新的途径。

关键词: 白细胞介素类, 结核,胸膜, 胸腔积液,恶性

Abstract: Interleukin-22 (IL-22)is a member of IL-10 cytokine family, and its biological activity is initiated by binding to a cell surface complex composed IL-22R1 and IL-10R2 receptor chains. IL-22 is expressed by most notably T-helper 22 (Th22),Th17 and Th1 cells, partly γδT cells, natural killer cells (NK cells) and lymphoid tissue inducer cells (LTi-like cells). Both of the concentration of IL-22 in tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) were increased. CD4⁺T cells recruitment from peripheral blood which induced by chemokine/CCR interaction and the differentiation of Th22 cells promoted by IL-1b, IL-6 or tumor necrosis factor-α(TNF-α) from native CD4⁺T cells contribute to the increase. IL-22 was involved in the immunopathology by promoting the expression of matrix metalloproteinases (MMPs) in pleural cavity, and IL-22 could mediate NK cells to produce soluble factors to reduce bacillary growth in M. tuberculosis infected monocyte-derived macrophages. In MPE pleural Th22 cells might be involved in the proliferation and migration of cancer cells,and promote intercellular adhesion of cancer cells to pleural mesothelial cells（PMCs） by upregulating the expression of cellular adhesion molecules. To explore the mechanism of IL-22 in these two diseases will provide new methods for immunodiagnosis and immunotherapy.

Key words: Interleukins, Tuberculosis,pleural, Pleural effusion, malignant

原艳明王仲元程小星. 白细胞介素22在结核性胸膜炎与恶性胸腔积液中生物学特性的研究进展[J]. 中国防痨杂志, 2013, 35(5): 379-383.

YUAN Yan-ming,WANG Zhong-yuan,CHENG Xiao-xing. Recent advances in the research on biological characteristics of interleukin-22 in tuberculous pleurisy and malignant pleural effusion[J]. Chinese Journal of Antituberculosis, 2013, 35(5): 379-383.

参考文献

［1］World Health Organization. Global tuberculosis control: WHO report 2011. Geneva：WHO, 2011：10.
［2］Dumoutier L, Van Roost E, Colau D, et al.Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor.Proc Natl Acad Sci USA,2000,97（18）:10144-10149.
［3］Commins S,Steinke JW,Borish L. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24,IL-26, IL-28, and IL-29. J Allergy Clin Immunol，2008,121（5）:1108-1111.
［4］Xie MH, Aggarwal S, Ho WH,et al.Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R.J Biol Chem,2000,275（40）:31335-31339.
［5］Jones BC, Logsdon NJ, Walter MR. Structure of IL-22 bound to its high-affinity IL-22R1 chain. Structure,2008,16（9）:1333-1344.
［6］孙奇. IL-22——炎症性疾病关键因子.免疫学杂志,2011，27(9):821-825.
［7］黎翠翠,蒋莉.Th22及其效应因子生物学特性相关研究.现代免疫学,2011，31(3)：258-261.
［8］Wolk K,Kunz S,Witte E,et al.IL-22 increases the innate immunity of tissues. Immunity, 2004,21（2）:241-254.
［9］Radaeva S,Sun R,Pan HN,et al.Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology, 2004,39（5）:1332-1342.
［10］Liang SC, Tan XY, Luxenberg DP, et al.Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med,2006,203（10）:2271-2279.
［11］Scriba TJ, Kalsdorf B, Abrahams DA, et al. Distinct, specific IL-17 and IL-22-producing CD4⁺T cell subsets contribute to the human anti-mycobacterial immune response. J Immunol, 2008, 180（3）:1962-1970.
［12］Duhen T,Geiger R,Jarrossay D,et al. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells.Nat Immunol, 2009,10（8）:857-863.
［13］Eyerich S,Eyerich K,Pennino D,et al.Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling.J Clin Invest,2009,119（12）:3573-3585.
［14］Trifari S,Kaplan C,Tran EH,et al.Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T（H）-17, T（H）1 and T（H）2 cells.Nat Immunol,2009,10（8）:864-871.
［15］Zheng Y,Danilenko DM,Valdez P,et al.Interleukin-22, a T（H）17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.Nature,2007,445（7128）:648-651.
［16］Ghoreschi K,Laurence A,Yang XP,et al.Generation of pathogenic T（H）17 cells in the absence of TGF-β signalling.Nature,2010,467（7318）:967-971.
［17］Volpe E,Servant N,Zollinger R,et al.A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T（H）-17 responses.Nat Immunol,2008,9（6）:650-657.
［18］Cella M, Fuchs A, Vermi W, et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.Nature, 2009, 457（7230）: 722-725.
［19］Dhiman R, Indramohan M, Barnes PF, et al. IL-22 produced by human NK cells inhibits growth of Mycobacterium tuberculosis by enhancing phagolysosomal fusion. J Immunol，2009, 183（10）:6639-6645.
［20］Martin B, Hirota K, Cua DJ, et al. Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals.Immunity,2009,31（2）:321-330.
［21］Simonian P,Wehrmann F,Roark C,et al.Gammadelta T cells protect against lung fibrosis via IL-22.J Exp Med,2010, 207（10）:2239-53.
［22］Mebius RE, Rennert P, Weissman IL.Developing lymph nodes collect CD4⁺CD3-LTbeta+cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells.Immunity,1997,7（4）:493-504.
［23］Van Maele L, Carnoy C, Cayet D, et al. TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3(neg)CD127+immune cells in spleen and mucosa.J Immunol,2010,185（2）:1177-1185.
［24］Zenewicz LA, Flavell RA. Recent advances in IL-22 biology. Int Immunol,2011,23（3）:159-163.
［25］Matthews K, Wilkinson KA, Kalsdorf B,et al. Predominance of interleukin-22 over interleukin-17 at the site of disease in human tuberculosis.Tuberculosis (Edinb)，2011,91（6）: 587-593.
［26］Annunziato F, Cosmi L, Santarlasci V, et al. Phenotypic and functional features of human Th17 cells. J Exp Med,2007, 204（8）: 1849-1861.
［27］Ye ZJ, Zhou Q, Yin W, et al. Interleukin 22-producing CD4⁺T cells in malignant pleural effusion. Cancer Lett,2012, 326（1）:23-32.
［28］Ye ZJ, Zhou Q, Gu YY, et al.Generation and differentiation of IL-17-producing CD4⁺T cells in malignant pleural effusion. J Immunol,2010, 185（10）: 6348-6354.
［29］Xirouchaki N, Tzanakis N, Bouros D, et al. Diagnostic value of interleukin-1alpha, interleukin-6, and tumor necrosis factor in pleural effusions.Chest, 2002,121（3）: 815-820.
［30］Ye ZJ, Zhou Q, Yuan ML, et al. Differentiation and recruitment of IL-22-producing helper T cells stimulated by pleural mesothelial cells in tuberculous pleurisy.Differentiation and recruitment of IL-22-producing helper T cells stimulated by pleural mesothelial cells in tuberculous pleurisy. Am J Respir Crit Care Med,2012,185（6）:660-669.
［31］江静.胸腔积液白细胞介素-20与白细胞介素-22的水平和意义.南宁:广西医科大学,2008.
［32］Aujla SJ, Chan YR, Zheng M, et al.IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med,2008,14（3）:275-281.
［33］Zenewicz LA, Yancopoulos GD, Valenzuela DM, et al. IL-22 but not IL-17 provides protection to hepatocytes during acute liver inflammation. Immunity,2007, 27（4）:647-659.
［34］Andoh A,Zhang Z,Inatomi O, et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology, 2005, 129（3）:969-984.
［35］Yao S,Huang D,Chen CY,et al. Differentiation, distribution and gammadelta T cell-driven regulation of IL-22-producing T cells in tuberculosis. PLoS Pathog,2010, 6（2）:e1000789.
［36］Amadi-Obi A,Yu CR,Liu X, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med, 2007,13（6）: 711-718.
［37］Qiao D, Yang BY, Li L, et al. ESAT-6-and CFP-10-specific Th1, Th22 and Th17 cells in tuberculous pleurisy may contribute to the local immune response against Mycobacterium tuberculosis infection. Scand J Immunol,2011,73（4）:330-337.
［38］Zucker S, Mirza H, Conner CE,et al. Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. Int J Cancer, 1998,75（5）:780-786.
［39］Bernardi RJ, Trump DL, Yu WD,et al.Combination of 1alpha,25-dihydroxyvitamin D(3) with dexamethasone enhances cell cycle arrest and apoptosis: role of nuclear receptor cross-talk and Erk/Akt signaling. Clin Cancer Res, 2001,7（12）:4164-4173.
［40］Romerio F,Zella D. MEK and ERK inhibitors enhance the anti-proliferative effect of interferon-alpha2b. FASEB J, 2002,16（12）:1680-1682.
［41］Wu JJ, Zhang XD, Gillespie S, et al. Selection for TRAIL resistance results in melanoma cells with high proliferative potential. FEBS Lett,2005, 579（9）:1940-1944.
［42］Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer. Lancet Oncol, 2005,6（5）: 322-327.
［43］Zhang W,Chen Y,Wei H,et al. Antiapoptotic activity of autocrine interleukin-22 and therapeutic effects of interleukin-22-small interfering RNA on human lung cancer xenografts. Clin Cancer Res,2008,14（20）: 6432-6439.
［44］Alkhamesi NA, Ziprin P, Pfistermuller K,et al. ICAM-1 mediated peritoneal carcinomatosis, a target for therapeutic intervention.Clin Exp Metastasis, 2005,22（6）: 449-459.
［45］Slack-Davis JK, Atkins KA, Harrer C,et al. Vascular cell adhesion molecule-1 is a regulator of ovarian cancer peritoneal metastasis. Cancer Res,2009, 69（4）:1469-1476.