自然杀伤细胞对肝星状细胞的调控及其在肝纤维化中的作用

李天阳; 涂正坤; 苏立山

doi:10.3969/j.issn.1001-5256.2017.03.036

自然杀伤细胞对肝星状细胞的调控及其在肝纤维化中的作用

DOI: 10.3969/j.issn.1001-5256.2017.03.036

吉林大学第一医院转化医学研究院

基金项目:

国家自然科学基金(81373143,81571535)；

详细信息

中图分类号: R575.2
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出版历程
- 收稿日期: 2016-12-15
- 出版日期: 2017-03-20

Regulatory effect of natural killer cells on hepatic stellate cells and their role in liver fibrosis

Research Institute of Translational Medicine, The First Hospital of Jilin University

Research funding:

摘要

摘要: 肝星状细胞(HSC)的激活与肝纤维化进展有至关重要的联系。作为固有免疫的重要组分,自然杀伤细胞(NK细胞)在肝内的富集程度更高,在机体防御病毒感染和肿瘤中发挥关键作用,而且其抗肝纤维化的功能也得到证实。NK细胞可以通过直接杀伤早期激活或衰老的HSC,或通过分泌IFNγ抑制肝纤维化。总结了最近几年的相关研究进展,以NK细胞和HSC的功能与表型为基础,介绍了NK细胞调控HSC的分子免疫学机制及其潜在的抗肝纤维化作用。
- 肝硬化 /
- 杀伤细胞,天然 /
- 肝星状细胞 /
- 综述
Abstract: Hepatic stellate cell (HSC) activation is closely associated with the progression of liver fibrosis.As an important component of the innate immune system, natural killer (NK) cells are enriched in the liver and play a key role in host defense against viral infection and tumor, and their anti-fibrotic effect has also been confirmed.NK cells can reduce liver fibrosis by killing early-activated or senescent HSCs or secreting interferon-γ.This article summarizes related research advances in recent years, and introduces the molecular immunological mechanism of NK cells in regulating HSCs and their potential anti-fibrotic effect based on the function and phenotype of NK cells and HSCs.
- liver cirrhosis /
- killer cells /
- natural /
- hepatic stellate cells

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参考文献(60)

[1]ATTA HM.Reversibility and heritability of liver fibrosis:implications for research and therapy[J].World J Gastroenterol, 2015, 21 (17) :5138-5148.

[2]FRIEDMAN SL.Evolving challenges in hepatic fibrosis[J].Nat Rev Gastroenterol Hepatol, 2010, 7 (8) :425-436.

[3]FRIEDMAN SL, ROLL FJ, BOYLES J, et al.Hepatic lipocytes:the principal collagen-producing cells of normal rat liver[J].Proc Natl Acad Sci U S A, 1985, 82 (24) :8681-8685.

[4]RIPPE RA, BRENNER DA.From quiescence to activation:Gene regulation in hepatic stellate cells[J].Gastroenterology, 2004, 127 (4) :1260-1262.

[5]ELPEK GO.Cellular and molecular mechanisms in the pathogenesis of liver fibrosis:an update[J].World J Gastroenterol, 2014, 20 (23) :7260-7276.

[6]DUARTE S, BABER J, FUJII T, et al.Matrix metalloproteinases in liver injury, repair and fibrosis[J].Matrix Biol, 2015, 44-46:147-156.

[7]IREDALE JP.Models of liver fibrosis:exploring the dynamic nature of inflammation and repair in a solid organ[J].J Clin Invest, 2007, 117 (3) :539-548.

[8]CANBAY A, FRIEDMAN S, GORES GJ.Apoptosis:the nexus of liver injury and fibrosis[J].Hepatology, 2004, 39 (2) :273-278.

[9]BRUNATI AM, PAGANO MA, BINDOLI A, et al.Thiol redox systems and protein kinases in hepatic stellate cell regulatory processes[J].Free Radic Res, 2010, 44 (4) :363-378.

[10]WATANABE A, HASHMI A, GOMES DA, et al.Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9[J].Hepatology, 2007, 46 (5) :1509-1518.

[11]SALLOUM S, HOLMES JA, JINDAL R, et al.Exposure to human immunodeficiency virus/hepatitis C virus in hepatic and stellate cell lines reveals cooperative profibrotic transcriptional activation between viruses and cell types[J].Hepatology, 2016, 64 (6) :1951-1968.

[12]BRYCESON YT, MARCH ME, LJUNGGREN HG, et al.Activation, coactivation, and costimulation of resting human natural killer cells[J].Immunol Rev, 2006, 214:73-91.

[13]MOROSO V, METSELAAR HJ, MANCHAM S, et al.Liver grafts contain a unique subset of natural killer cells that are transferred into the recipient after liver transplantation[J].Liver Transpl, 2010, 16 (7) :895-908.

[14]LUO D, VANDERKERKEN K, BOUWENS L, et al.The role of adhesion molecules in the recruitment of hepatic natural killer cells (pit cells) in rat liver[J].Hepatology, 1996, 24 (6) :1475-1480.

[15]TAKEDA K, CRETNEY E, HAYAKAWA Y, et al.TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver[J].Blood, 2005, 105 (5) :2082-2089.

[16]SOJKA DK, PLOUGASTEL-DOUGLAS B, YANG L, et al.Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells[J].Elife, 2014, 3:e01659.

[17]SHARMA R, DAS A.Organ-specific phenotypic and functional features of NK cells in humans[J].Immunol Res, 2014, 58 (1) :125-131.

[18]PENG H, SUN R, TANG L, et al.CD62L is critical for maturation and accumulation of murine hepatic NK cells in response to viral infection[J].J Immunol, 2013, 190 (8) :4255-4262.

[19]TOSELLO-TRAMPONT AC, KRUEGER P, NARAYANAN S, et al.NKp46 (+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice[J].Hepatology, 2016, 63 (3) :799-812.

[20]SUBLESKI JJ, WILTROUT RH, WEISS JM.Application of tissuespecific NK and NKT cell activity for tumor immunotherapy[J].J Autoimmun, 2009, 33 (3-4) :275-281.

[21]SUN C, SUN HY, XIAO WH, et al.Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy[J].Acta Pharmacol Sin, 2015, 36 (10) :1191-1199.

[22]SUN C, SUN H, ZHANG C, et al.NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma[J].Cell Mol Immunol, 2015, 12 (3) :292-302.

[23]BJORKSTROM NK, LJUNGGREN HG, SANDBERG JK.CD56 negative NK cells:origin, function, and role in chronic viral disease[J].Trends Immunol, 2010, 31 (11) :401-406.

[24]LI F, WEI H, WEI H, et al.Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice[J].Gastroenterology, 2013, 144 (2) :392-401.

[25]MELHEM A, MUHANNA N, BISHARA A, et al.Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC[J].J Hepatol, 2006, 45 (1) :60-71.

[26]RADAEVA S, SUN R, JARUGA B, et al.Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners[J].Gastroenterology, 2006, 130 (2) :435-452.

[27]FASBENDER F, WIDERA A, HENGSTLER JG, et al.Natural killer cells and liver fibrosis[J].Front Immunol, 2016, 7:19.

[28]ONG S, LIGONS DL, BARIN JG, et al.Natural killer cells limit cardiac inflammation and fibrosis by halting eosinophil infiltration[J].Am J Pathol, 2015, 185 (3) :847-861.

[29]MITRA A, SATELLI A, YAN J, et al.IL-30 (IL27p28) attenuates liver fibrosis through inducing NKG2D-rae1 interaction between NKT and activated hepatic stellate cells in mice[J].Hepatology, 2014, 60 (6) :2027-2039.

[30]GLASSNER A, EISENHARDT M, KRAMER B, et al.NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL-and NKG2D-dependent manner[J].Lab Invest, 2012, 92 (7) :967-977.

[31]MUHANNA N, ABU TAIR L, DORON S, et al.Amelioration of hepatic fibrosis by NK cell activation[J].Gut, 2011, 60 (1) :90-98.

[32]FRIEDMAN SL.Hepatic stellate cells:protean, multifunctional, and enigmatic cells of the liver[J].Physiol Rev, 2008, 88 (1) :125-172.

[33]MEHAL W, IMAEDA A.Cell death and fibrogenesis[J].Semin Liver Dis, 2010, 30 (3) :226-231.

[34]FENG X, YAN J, WANG Y, et al.The proteasome inhibitor bortezomib disrupts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and natural killer (NK) cell killing of TRAIL receptor-positive multiple myeloma cells[J].Mol Immunol, 2010, 47 (14) :2388-2396.

[35]GAO B, RADAEVA S, JEONG WI.Activation of natural killer cells inhibits liver fibrosis:a novel strategy to treat liver fibrosis[J].Expert Rev Gastroenterol Hepatol, 2007, 1 (1) :173-180.

[36]JEONG WI, PARK O, RADAEVA S, et al.STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity[J].Hepatology, 2006, 44 (6) :1441-1451.

[37]ULLOA L, DOODY J, MASSAGUE J.Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway[J].Nature, 1999, 397 (6721) :710-713.

[38]VIVIER E, TOMASELLO E, BARATIN M, et al.Functions of natural killer cells[J].Nat Immunol, 2008, 9 (5) :503-510.

[39]PENG H, WISSE E, TIAN Z.Liver natural killer cells:subsets and roles in liver immunity[J].Cell Mol Immunol, 2016, 13 (3) :328-336.

[40]LI Q, YAN Z, LI F, et al.Corrigendum:the improving effects on hepatic fibrosis of interferon-γliposomes targeted to hepatic stellate cells[J].Nanotechnology, 2014, 25 (7) :079501.

[41]TU Z, HAMALAINEN-LAANAYA HK, CRISPE IN, et al.Synergy between TLR3 and IL-18 promotes IFN-gamma dependent TRAILexpression in human liver NK cells[J].Cell Immunol, 2011, 271 (2) :286-291.

[42]GRESSNER AM, WEISKIRCHEN R, BREITKOPF K, et al.Roles of TGF-beta in hepatic fibrosis[J].Front Biosci, 2002, 7:d793-d807.

[43]NIETO N.Oxidative-stress and IL-6 mediate the fibrogenic effects of[corrected]Kupffer cells on stellate cells[J].Hepatology, 2006, 44 (6) :1487-1501.

[44]FRIEDMAN SL, ARTHUR MJ.Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium.Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors[J].J Clin Invest, 1989, 84 (6) :1780-1785.

[45]ROCKEY DC, MAHER JJ, JARNAGIN WR, et al.Inhibition of rat hepatic lipocyte activation in culture by interferon-gamma[J].Hepatology, 1992, 16 (3) :776-784.

[46]BARRON L, WYNN TA.Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages[J].Am J Physiol Gastrointest Liver Physiol, 2011, 300 (5) :g723-g728.

[47]MENTINK-KANE MM, CHEEVER AW, WILSON MS, et al.Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin (IL) -10, IL-12p40, and IL-13Ralpha2[J].Gastroenterology, 2011, 141 (6) :2200-2209.

[48]GLASSNER A, EISENHARDT M, KOKORDELIS P, et al.Impaired CD4 (+) T cell stimulation of NK cell anti-fibrotic activity may contribute to accelerated liver fibrosis progression in HIV/HCV patients[J].JHepatol, 2013, 59 (3) :427-433.

[49]LANGHANS B, ALWAN AW, KRAMER B, et al.Regulatory CD4+T cells modulate the interaction between NK cells and hepatic stellate cells by acting on either cell type[J].J Hepatol, 2015, 62 (2) :398-404.

[50]JIAO J, OOKA K, FEY H, et al.Interleukin-15 receptor alpha on hepatic stellate cells regulates hepatic fibrogenesis in mice[J].JHepatol, 2016, 65 (2) :344-353.

[51]NEL I, LUCAR O, PETITDEMANGE C, et al.Accumulation of intrahepatic TNF-alpha-producing NKp44+NK cells correlates with liver fibrosis and viral load in chronic HCV infection[J].Medicine (Baltimore) , 2016, 95 (19) :e3678.

[52]WAN Z, XIE G, WU Y, et al.Cytokines elevated in patients with HBV-related acute-on-chronic liver failure promote NK cell mediated cytotoxicity through TRAIL[J].Dig Liver Dis, 2016, 48 (5) :528-535.

[53]DUNN C, BRUNETTO M, REYNOLDS G, et al.Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage[J].J Exp Med, 2007, 204 (3) :667-680.

[54]MORISHIMA C, PASCHAL DM, WANG CC, et al.Decreased NKcell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing[J].Hepatology, 2006, 43 (3) :573-580.

[55]INAGAKI Y, NEMOTO T, KUSHIDA M, et al.Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice[J].Hepatology, 2003, 38 (4) :890-899.

[56]BECKER PS, SUCK G, NOWAKOWSKA P, et al.Selection and expansion of natural killer cells for NK cell-based immunotherapy[J].Cancer Immunol Immunother, 2016, 65 (4) :477-484.

[57]GLAVAN TM, PAVELIC J.The exploitation of Toll-like receptor3 signaling in cancer therapy[J].Curr Pharm Des, 2014, 20 (42) :6555-6564.

[58]RELJIC R.IFN-gamma therapy of tuberculosis and related infections[J].J Interferon Cytokine Res, 2007, 27 (5) :353-364.

[59]GIRART MV, FUERTES MB, DOMAICA CI, et al.Engagement of TLR3, TLR7, and NKG2D regulate IFN-gamma secretion but not NKG2D-mediated cytotoxicity by human NK cells stimulated with suboptimal doses of IL-12[J].J Immunol, 2007, 179 (6) :3472-3479.

[60]BRACCI L, PROIETTI E, BELARDELLI F.IFN-alpha and novel strategies of combination therapy for cancer[J].Ann N Y Acad Sci, 2007, 1112:256-268.

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