Kupffer Cells in Health and Disease

  • Andrea M. Woltman
  • Andre Boonstra
  • Makoto Naito
  • Pieter J. M. Leenen


Kupffer cells (KC), the resident macrophages of the liver, represent the largest population of mononuclear phagocytes in the body. Phenotypic, developmental, and functional aspects of these cells in steady state and in different diseases are the focus of this review. Recently it has become evident that KC precursors seed the liver already early in fetal development, and the population can be maintained independently from circulating monocytes. However, inflammatory conditions allow rapid differentiation of monocytes into mature cells that are indistinguishable from genuine KC. KC are located in the lumen of sinusoids that receive blood both from the portal vein, carrying nutrients and microbial products from the gut, and from the hepatic artery. This positions KC ideally for their prime function, namely surveillance and clearance of the circulation. As such, they are important in iron recycling by phagocytosing effete erythrocytes, for instance. The immunophenotype of KC, characterized by a wide variety of endocytic receptors, is indicative of this scavenger function. In maintaining homeostasis, KC have an ambivalent response to exogenous triggers. On the one hand, their surveillance function requires alert responses to potentially hazardous substances. On the other hand, continuous exposure of the cells to the trigger-rich content of blood originating from the gut dampens their responsiveness to further stimuli. This ambivalence is also reflected in their diverse roles in disease pathogenesis. For the latter, we sketch the contribution of KC by giving examples of their role in metabolic disease, infections, and liver injury.


Liver Fibrosis Kupffer Cell Fatty Liver Disease Hepatic Stellate Cell Liver Infection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Aono K, Isobe K, Nakashima I, Kondo S, Miyachi M, Nimura Y (1994) Kupffer cells cytotoxicity against hepatoma cells is related to nitric oxide. Biochem Biophys Res Commun 201(3):1175–1181. doi: 10.1006/bbrc.1994.1829 PubMedGoogle Scholar
  2. Asabe S, Wieland SF, Chattopadhyay PK, Roederer M, Engle RE, Purcell RH et al (2009) The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol 83(19):9652–9662. doi: 10.1128/JVI.00867-09 PubMedCentralPubMedGoogle Scholar
  3. Baer K, Roosevelt M, Clarkson AB Jr, van Rooijen N, Schnieder T, Frevert U (2007) Kupffer cells are obligatory for Plasmodium yoelii sporozoite infection of the liver. Cell Microbiol 9(2):397–412. doi: 10.1111/j.1462-5822.2006.00798.x PubMedGoogle Scholar
  4. Baffy G (2009) Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol 51(1):212–223. doi: 10.1016/j.jhep.2009.03.008 PubMedCentralPubMedGoogle Scholar
  5. Baratta JL, Ngo A, Lopez B, Kasabwalla N, Longmuir KJ, Robertson RT (2009) Cellular organization of normal mouse liver: a histological, quantitative immunocytochemical, and fine structural analysis. Histochem Cell Biol 131(6):713–726. doi: 10.1007/s00418-009-0577-1 PubMedCentralPubMedGoogle Scholar
  6. Barsig J, Flesch IE, Kaufmann SH (1998) Macrophages and hepatocytic cells as chemokine producers in murine listeriosis. Immunobiology 199(1):87–104. doi: 10.1016/S0171-2985(98)80066-1 PubMedGoogle Scholar
  7. Bartocci A, Mastrogiannis DS, Migliorati G, Stockert RJ, Wolkoff AW, Stanley ER (1987) Macrophages specifically regulate the concentration of their own growth factor in the circulation. Proc Natl Acad Sci U S A 84(17):6179–6183PubMedCentralPubMedGoogle Scholar
  8. Beschin A, De Baetselier P, Van Ginderachter JA (2013) Contribution of myeloid cell subsets to liver fibrosis in parasite infection. J Pathol 229(2):186–197. doi: 10.1002/path.4112 PubMedGoogle Scholar
  9. Bieghs V, Walenbergh SM, Hendrikx T, van Gorp PJ, Verheyen F, Olde Damink SW et al (2013) Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation. Liver Int 33(7):1056–1061. doi: 10.1111/liv.12170 PubMedCentralPubMedGoogle Scholar
  10. Body-Malapel M, Dharancy S, Berrebi D, Louvet A, Hugot JP, Philpott DJ et al (2008) NOD2: a potential target for regulating liver injury. Lab Invest 88(3):318–327. doi: 10.1038/labinvest.3700716 PubMedGoogle Scholar
  11. Breiner KM, Schaller H, Knolle PA (2001) Endothelial cell-mediated uptake of a hepatitis B virus: a new concept of liver targeting of hepatotropic microorganisms. Hepatology 34(4 Pt 1):803–808. doi: 10.1053/jhep.2001.27810 PubMedGoogle Scholar
  12. Burgio VL, Ballardini G, Artini M, Caratozzolo M, Bianchi FB, Levrero M (1998) Expression of co-stimulatory molecules by Kupffer cells in chronic hepatitis of hepatitis C virus etiology. Hepatology 27(6):1600–1606. doi: 10.1002/hep.510270620 PubMedGoogle Scholar
  13. Byun JS, Suh YG, Yi HS, Lee YS, Jeong WI (2013) Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice. J Hepatol 58(2):342–349. doi: 10.1016/j.jhep.2012.09.016 PubMedGoogle Scholar
  14. Canbay A, Feldstein AE, Higuchi H, Werneburg N, Grambihler A, Bronk SF et al (2003) Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology 38(5):1188–1198. doi: 10.1053/jhep.2003.50472 PubMedGoogle Scholar
  15. Castilla A, Prieto J, Fausto N (1991) Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med 324(14):933–940. doi: 10.1056/NEJM199104043241401 PubMedGoogle Scholar
  16. Chang S, Dolganiuc A, Szabo G (2007) Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins. J Leukoc Biol 82(3):479–487. doi: 10.1189/jlb.0207128 PubMedGoogle Scholar
  17. Chatterjee S, Ganini D, Tokar EJ, Kumar A, Das S, Corbett J et al (2013) Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. J Hepatol 58(4):778–784. doi: 10.1016/j.jhep.2012.11.035 PubMedCentralPubMedGoogle Scholar
  18. Chen X, Xu C, Zhang F, Ma J (2010) Comparative analysis of expression profiles of chemokines, chemokine receptors, and components of signaling pathways mediated by chemokines in eight cell types during rat liver regeneration. Genome 53(8):608–618. doi: 10.1139/g10-040 PubMedGoogle Scholar
  19. Cousens LP, Wing EJ (2000) Innate defenses in the liver during Listeria infection. Immunol Rev 174:150–159PubMedGoogle Scholar
  20. Crispe IN (2011) Liver antigen-presenting cells. J Hepatol 54(2):357–365. doi: 10.1016/j.jhep.2010.10.005 PubMedCentralPubMedGoogle Scholar
  21. Czaja MJ, Weiner FR, Flanders KC, Giambrone MA, Wind R, Biempica L et al (1989) In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis. J Cell Biol 108(6):2477–2482PubMedGoogle Scholar
  22. Dao T, Mehal WZ, Crispe IN (1998) IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells. J Immunol 161(5):2217–2222PubMedGoogle Scholar
  23. de las Casas-Engel M, Dominguez-Soto A, Sierra-Filardi E, Bragado R, Nieto C, Puig-Kroger A et al (2013) Serotonin skews human macrophage polarization through HTR2B and HTR7. J Immunol 190(5):2301–2310. doi: 10.4049/jimmunol.1201133 PubMedGoogle Scholar
  24. Deodhar KP, Tapp E, Scheuer PJ (1975) Orcein staining of hepatitis B antigen in paraffin sections of liver biopsies. J Clin Pathol 28(1):66–70PubMedCentralPubMedGoogle Scholar
  25. Dixon JE, Allan JE, Doherty PC, Hume DA (1986) Immunohistochemical analysis of the involvement of F4/80 and Ia-positive macrophages in mouse liver infected with lymphocytic choriomeningitis virus. J Leukoc Biol 40(5):617–628PubMedGoogle Scholar
  26. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S et al (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115(1):56–65. doi: 10.1172/JCI22675 PubMedCentralPubMedGoogle Scholar
  27. Ebe Y, Hasegawa G, Takatsuka H, Umezu H, Mitsuyama M, Arakawa M et al (1999) The role of Kupffer cells and regulation of neutrophil migration into the liver by macrophage inflammatory protein-2 in primary listeriosis in mice. Pathol Int 49(6):519–532PubMedGoogle Scholar
  28. Ebrahimkhani MR, Mohar I, Crispe IN (2011) Cross-presentation of antigen by diverse subsets of murine liver cells. Hepatology 54(4):1379–1387. doi: 10.1002/hep.24508 PubMedCentralPubMedGoogle Scholar
  29. Ehlers S, Mielke ME, Blankenstein T, Hahn H (1992) Kinetic analysis of cytokine gene expression in the livers of naive and immune mice infected with Listeria monocytogenes. The immediate early phase in innate resistance and acquired immunity. J Immunol 149(9):3016–3022PubMedGoogle Scholar
  30. Farrell GC, van Rooyen D, Gan L, Chitturi S (2012) NASH is an inflammatory disorder: pathogenic, prognostic and therapeutic implications. Gut Liver 6(2):149–171. doi: 10.5009/gnl.2012.6.2.149 PubMedCentralPubMedGoogle Scholar
  31. Friedman SL, Arthur MJ (1989) 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 Clin Invest 84(6):1780–1785. doi: 10.1172/JCI114362 PubMedCentralPubMedGoogle Scholar
  32. Gaillard T, Mulsch A, Busse R, Klein H, Decker K (1991) Regulation of nitric oxide production by stimulated rat Kupffer cells. Pathobiology 59(4):280–283PubMedGoogle Scholar
  33. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S et al (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13(11):1118–1128. doi: 10.1038/ni.2419 PubMedCentralPubMedGoogle Scholar
  34. Gehring S, Sabo E, San Martin ME, Dickson EM, Cheng CW, Gregory SH (2009) Laser capture microdissection and genetic analysis of carbon-labeled Kupffer cells. World J Gastroenterol 15(14):1708–1718. doi: 10.3748/wjg.15.1708 PubMedCentralPubMedGoogle Scholar
  35. Goncalves LA, Rodrigues-Duarte L, Rodo J, Vieira de Moraes L, Marques I, Penha-Goncalves C (2013) TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection. Proc Natl Acad Sci U S A 110(48):19531–19536. doi: 10.1073/pnas.1306873110 PubMedCentralPubMedGoogle Scholar
  36. Gorgani NN, Ma Y, Clark HF (2008) Gene signatures reflect the marked heterogeneity of tissue-resident macrophages. Immunol Cell Biol 86(3):246–254. doi: 10.1038/sj.icb.7100131 PubMedGoogle Scholar
  37. Gregory SH, Cousens LP, van Rooijen N, Dopp EA, Carlos TM, Wing EJ (2002) Complementary adhesion molecules promote neutrophil-Kupffer cell interaction and the elimination of bacteria taken up by the liver. J Immunol 168(1):308–315PubMedGoogle Scholar
  38. Hara M, Kono H, Furuya S, Hirayama K, Tsuchiya M, Fujii H (2013) Interleukin-17A plays a pivotal role in cholestatic liver fibrosis in mice. J Surg Res 183(2):574–582. doi: 10.1016/j.jss.2013.03.025 PubMedGoogle Scholar
  39. He Y, Sadahiro T, Noh SI, Wang H, Todo T, Chai NN et al (2009) Flow cytometric isolation and phenotypic characterization of two subsets of ED2(+) (CD163) hepatic macrophages in rats. Hepatol Res 39(12):1208–1218. doi: 10.1111/j.1872-034X.2009.00528.x PubMedGoogle Scholar
  40. Heuff G, van de Loosdrecht AA, Betjes MG, Beelen RH, Meijer S (1995) Isolation and purification of large quantities of fresh human Kupffer cells, which are cytotoxic against colon carcinoma. Hepatology 21(3):740–745. doi: 10.1016/0270-9139(95)90527-8 PubMedGoogle Scholar
  41. Holub M, Cheng CW, Mott S, Wintermeyer P, van Rooijen N, Gregory SH (2009) Neutrophils sequestered in the liver suppress the proinflammatory response of Kupffer cells to systemic bacterial infection. J Immunol 183(5):3309–3316. doi: 10.4049/jimmunol.0803041 PubMedGoogle Scholar
  42. Hosel M, Quasdorff M, Wiegmann K, Webb D, Zedler U, Broxtermann M et al (2009) Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatology 50(6):1773–1782. doi: 10.1002/hep.23226 PubMedGoogle Scholar
  43. Hosomura N, Kono H, Tsuchiya M, Ishii K, Ogiku M, Matsuda M et al (2011) HCV-related proteins activate Kupffer cells isolated from human liver tissues. Dig Dis Sci 56(4):1057–1064. doi: 10.1007/s10620-010-1395-y PubMedGoogle Scholar
  44. Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K et al (2008) The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology 48(4):1224–1231. doi: 10.1002/hep.22470 PubMedGoogle Scholar
  45. Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ et al (2010) Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59(2):347–357. doi: 10.2337/db09-0016 PubMedCentralPubMedGoogle Scholar
  46. Huang HF, Zeng Z, Chen MQ (2012) Roles of Kupffer cells in liver transplantation. Hepatogastroenterology 59(116):1251–1257. doi: 10.5754/hge12046 PubMedGoogle Scholar
  47. Huang H, Chen HW, Evankovich J, Yan W, Rosborough BR, Nace GW et al (2013) Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury. J Immunol 191(5):2665–2679. doi: 10.4049/jimmunol.1202733 PubMedCentralPubMedGoogle Scholar
  48. Hussain SP, Harris CC (2007) Inflammation and cancer: an ancient link with novel potentials. Int J Cancer 121(11):2373–2380. doi: 10.1002/ijc.23173 PubMedGoogle Scholar
  49. Iimuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG (1997) Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 26(6):1530–1537. doi: 10.1002/hep.510260621 PubMedGoogle Scholar
  50. Ikarashi M, Nakashima H, Kinoshita M, Sato A, Nakashima M, Miyazaki H et al (2013) Distinct development and functions of resident and recruited liver Kupffer cells/macrophages. J Leukoc Biol 94(6):1325–1336. doi: 10.1189/jlb.0313144 PubMedGoogle Scholar
  51. Imaizumi T, Sashinami H, Mori F, Matsumiya T, Yoshida H, Nakane A et al (2006) Listeria monocytogenes induces the expression of retinoic acid-inducible gene-I. Microbiol Immunol 50(10):811–815PubMedGoogle Scholar
  52. Imamura M, Ogawa T, Sasaguri Y, Chayama K, Ueno H (2005) Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats. Gastroenterology 128(1):138–146PubMedGoogle Scholar
  53. Imran M, Waheed Y, Manzoor S, Bilal M, Ashraf W, Ali M et al (2012) Interaction of hepatitis C virus proteins with pattern recognition receptors. Virol J 9:126. doi: 10.1186/1743-422X-9-126 PubMedCentralPubMedGoogle Scholar
  54. Ishino T, Yano K, Chinzei Y, Yuda M (2004) Cell-passage activity is required for the malarial parasite to cross the liver sinusoidal cell layer. PLoS Biol 2(1):E4. doi: 10.1371/journal.pbio.0020004 PubMedCentralPubMedGoogle Scholar
  55. Jacques A, Bleau C, Martin JP, Lamontagne L (2008) Intrahepatic endothelial and Kupffer cells involved in immunosuppressive cytokines and natural killer (NK)/NK T cell disorders in viral acute hepatitis. Clin Exp Immunol 152(2):298–310. doi: 10.1111/j.1365-2249.2008.03628.x PubMedCentralPubMedGoogle Scholar
  56. Jenkins SJ, Ruckerl D, Thomas GD, Hewitson JP, Duncan S, Brombacher F et al (2013) IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1. J Exp Med 210(11):2477–2491. doi: 10.1084/jem.20121999 PubMedCentralPubMedGoogle Scholar
  57. Jilbert AR, Miller DS, Scougall CA, Turnbull H, Burrell CJ (1996) Kinetics of duck hepatitis B virus infection following low dose virus inoculation: one virus DNA genome is infectious in neonatal ducks. Virology 226(2):338–345. doi: 10.1006/viro.1996.0661 PubMedGoogle Scholar
  58. John B, Crispe IN (2004) Passive and active mechanisms trap activated CD8+ T cells in the liver. J Immunol 172(9):5222–5229PubMedGoogle Scholar
  59. Kamps JA, Kruijt JK, Kuiper J, Van Berkel TJ (1991) Uptake and degradation of human low-density lipoprotein by human liver parenchymal and Kupffer cells in culture. Biochem J 276(Pt 1): 135–140PubMedCentralPubMedGoogle Scholar
  60. Kan Z, Ivancev K, Lunderquist A, McCuskey PA, McCuskey RS, Wallace S (1995) In vivo microscopy of hepatic metastases: dynamic observation of tumor cell invasion and interaction with Kupffer cells. Hepatology 21(2):487–494PubMedGoogle Scholar
  61. Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C et al (2009) Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50(1):261–274. doi: 10.1002/hep.22950 PubMedGoogle Scholar
  62. Kinoshita M, Uchida T, Sato A, Nakashima M, Nakashima H, Shono S et al (2010) Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice. J Hepatol 53(5):903–910. doi: 10.1016/j.jhep.2010.04.037 PubMedGoogle Scholar
  63. Klein I, Cornejo JC, Polakos NK, John B, Wuensch SA, Topham DJ et al (2007) Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages. Blood 110(12):4077–4085. doi: 10.1182/blood-2007-02-073841 PubMedCentralPubMedGoogle Scholar
  64. Kleinherenbrink-Stins MF, van de Boom JH, Schouten D, Roholl PJ, Niels van der Heyde M, Brouwer A et al (1991) Visualization of the interaction of native and modified lipoproteins with parenchymal, endothelial and Kupffer cells from human liver. Hepatology 14(1):79–90PubMedGoogle Scholar
  65. Knittel T, Mehde M, Kobold D, Saile B, Dinter C, Ramadori G (1999) Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta1. J Hepatol 30(1):48–60PubMedGoogle Scholar
  66. Knolle PA, Gerken G (2000) Local control of the immune response in the liver. Immunol Rev 174:21–34PubMedGoogle Scholar
  67. Knolle P, Schlaak J, Uhrig A, Kempf P, Meyer zum Buschenfelde KH, Gerken G (1995) Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol 22(2):226–229PubMedGoogle Scholar
  68. Koblish HK, Hunter CA, Wysocka M, Trinchieri G, Lee WM (1998) Immune suppression by recombinant interleukin (rIL)-12 involves interferon gamma induction of nitric oxide synthase 2 (iNOS) activity: inhibitors of NO generation reveal the extent of rIL-12 vaccine adjuvant effect. J Exp Med 188(9):1603–1610PubMedCentralPubMedGoogle Scholar
  69. Kolios G, Valatas V, Kouroumalis E (2006) Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol 12(46):7413–7420PubMedCentralPubMedGoogle Scholar
  70. Kono H, Fujii H, Asakawa M, Yamamoto M, Maki A, Matsuda M et al (2002) Functional heterogeneity of the Kupffer cell population is involved in the mechanism of gadolinium chloride in rats administered endotoxin. J Surg Res 106(1):179–187PubMedGoogle Scholar
  71. Kruse J, von Bernstorff W, Evert K, Albers N, Hadlich S, Hagemann S et al (2013) Macrophages promote tumour growth and liver metastasis in an orthotopic syngeneic mouse model of colon cancer. Int J Colorectal Dis 28(10):1337–1349. doi: 10.1007/s00384-013-1703-z PubMedGoogle Scholar
  72. Lang PA, Recher M, Honke N, Scheu S, Borkens S, Gailus N et al (2010) Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice. Hepatology 52(1):25–32. doi: 10.1002/hep.23640 PubMedGoogle Scholar
  73. Lang T, Lo C, Skinner N, Locarnini S, Visvanathan K, Mansell A (2011) The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway. J Hepatol 55(4):762–769. doi: 10.1016/j.jhep.2010.12.042 PubMedGoogle Scholar
  74. Laskin DL, Weinberger B, Laskin JD (2001) Functional heterogeneity in liver and lung macrophages. J Leukoc Biol 70(2):163–170PubMedGoogle Scholar
  75. Lau WY, Chen GG, Lai PB, Chun YS, Leung BC, Chak EC et al (2001) Induction of Fas and Fas ligand expression on malignant glioma cells by Kupffer cells, a potential pathway of antiliver metastases. J Surg Res 101(1):44–51. doi: 10.1006/jsre.2001.6253 PubMedGoogle Scholar
  76. Lau DT, Negash A, Chen J, Crochet N, Sinha M, Zhang Y et al (2013) Innate immune tolerance and the role of Kupffer cells in differential responses to interferon therapy among patients with HCV genotype 1 infection. Gastroenterology 144(2):402–413.e12. doi:10.1053/j.gastro.2012.10.044PubMedGoogle Scholar
  77. Lee TS, Chau LY (2002) Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med 8(3):240–246. doi: 10.1038/nm0302-240 PubMedGoogle Scholar
  78. Lehner MD, Ittner J, Bundschuh DS, van Rooijen N, Wendel A, Hartung T (2001) Improved innate immunity of endotoxin-tolerant mice increases resistance to Salmonella enterica serovar typhimurium infection despite attenuated cytokine response. Infect Immun 69(1):463–471. doi: 10.1128/IAI.69.1.463-471.2001 PubMedCentralPubMedGoogle Scholar
  79. Leroux A, Ferrere G, Godie V, Cailleux F, Renoud ML, Gaudin F et al (2012) Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol 57(1):141–149. doi: 10.1016/j.jhep.2012.02.028 PubMedGoogle Scholar
  80. Li H, Zheng HW, Chen H, Xing ZZ, You H, Cong M et al (2012) Hepatitis B virus particles preferably induce Kupffer cells to produce TGF-beta1 over pro-inflammatory cytokines. Dig Liver Dis 44(4):328–333. doi: 10.1016/j.dld.2011.11.005 PubMedGoogle Scholar
  81. Lieber A, He CY, Meuse L, Schowalter D, Kirillova I, Winther B et al (1997) The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors. J Virol 71(11):8798–8807PubMedCentralPubMedGoogle Scholar
  82. Liu Q, Zaiss AK, Colarusso P, Patel K, Haljan G, Wickham TJ et al (2003) The role of capsid-endothelial interactions in the innate immune response to adenovirus vectors. Hum Gene Ther 14(7):627–643. doi: 10.1089/104303403321618146 PubMedGoogle Scholar
  83. Liu ZJ, Yan LN, Li XH, Xu FL, Chen XF, You HB et al (2008) Up-regulation of IRAK-M is essential for endotoxin tolerance induced by a low dose of lipopolysaccharide in Kupffer cells. J Surg Res 150(1):34–39. doi: 10.1016/j.jss.2007.12.759 PubMedGoogle Scholar
  84. Lloyd CM, Phillips AR, Cooper GJ, Dunbar PR (2008) Three-colour fluorescence immunohistochemistry reveals the diversity of cells staining for macrophage markers in murine spleen and liver. J Immunol Methods 334(1–2):70–81. doi: 10.1016/j.jim.2008.02.005 PubMedGoogle Scholar
  85. Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117(1):175–184. doi: 10.1172/JCI29881 PubMedCentralPubMedGoogle Scholar
  86. Maeda S, Kamata H, Luo JL, Leffert H, Karin M (2005) IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121(7):977–990. doi: 10.1016/j.cell.2005.04.014 PubMedGoogle Scholar
  87. Marra F, Romanelli RG, Giannini C, Failli P, Pastacaldi S, Arrighi MC et al (1999) Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells. Hepatology 29(1):140–148. doi: 10.1002/hep.510290107 PubMedGoogle Scholar
  88. Matsuoka M, Pham NT, Tsukamoto H (1989) Differential effects of interleukin-1 alpha, tumor necrosis factor alpha, and transforming growth factor beta 1 on cell proliferation and collagen formation by cultured fat-storing cells. Liver 9(2):71–78PubMedGoogle Scholar
  89. Mengshol JA, Golden-Mason L, Arikawa T, Smith M, Niki T, McWilliams R et al (2010) A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS One 5(3):e9504. doi: 10.1371/journal.pone.0009504 PubMedCentralPubMedGoogle Scholar
  90. Meyer DH, Bachem MG, Gressner AM (1990) Modulation of hepatic lipocyte proteoglycan synthesis and proliferation by Kupffer cell-derived transforming growth factors type beta 1 and type alpha. Biochem Biophys Res Commun 171(3):1122–1129PubMedGoogle Scholar
  91. Moriyama H, Yamamoto T, Takatsuka H, Umezu H, Tokunaga K, Nagano T et al (1997) Expression of macrophage colony-stimulating factor and its receptor in hepatic granulomas of Kupffer-cell-depleted mice. Am J Pathol 150(6):2047–2060PubMedCentralPubMedGoogle Scholar
  92. Mota MM, Hafalla JCR, Rodriguez A (2002) Migration through host cells activates Plasmodium sporozoites for infection. Nat Med 8(11):1318–1322. doi: 10.1038/Nm785 PubMedGoogle Scholar
  93. Movita D, Kreefft K, Biesta P, van Oudenaren A, Leenen PJ, Janssen HL et al (2012) Kupffer cells express a unique combination of phenotypic and functional characteristics compared with splenic and peritoneal macrophages. J Leukoc Biol 92(4):723–733. doi: 10.1189/jlb.1111566 PubMedGoogle Scholar
  94. Naito M, Hasegawa G, Ebe Y, Yamamoto T (2004) Differentiation and function of Kupffer cells. Med Electron Microsc 37(1):16–28. doi: 10.1007/s00795-003-0228-x PubMedGoogle Scholar
  95. Nath B, Szabo G (2009) Alcohol-induced modulation of signaling pathways in liver parenchymal and nonparenchymal cells: implications for immunity. Semin Liver Dis 29(2):166–177. doi:10.1055/s-0029-1214372PubMedGoogle Scholar
  96. Nebbia G, Peppa D, Schurich A, Khanna P, Singh HD, Cheng Y et al (2012) Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLoS One 7(10):e47648. doi: 10.1371/journal.pone.0047648 PubMedCentralPubMedGoogle Scholar
  97. Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH et al (2008) Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab 7(6):496–507. doi: 10.1016/j.cmet.2008.04.003 PubMedCentralPubMedGoogle Scholar
  98. Ofek I, Sharon N (1988) Lectinophagocytosis: a molecular mechanism of recognition between cell surface sugars and lectins in the phagocytosis of bacteria. Infect Immun 56(3):539–547PubMedCentralPubMedGoogle Scholar
  99. Papackova Z, Palenickova E, Dankova H, Zdychova J, Skop V, Kazdova L et al (2012) Kupffer cells ameliorate hepatic insulin resistance induced by high-fat diet rich in monounsaturated fatty acids: the evidence for the involvement of alternatively activated macrophages. Nutr Metab (Lond) 9:22. doi: 10.1186/1743-7075-9-22
  100. Park JW, Jeong G, Kim SJ, Kim MK, Park SM (2007) Predictors reflecting the pathological severity of non-alcoholic fatty liver disease: comprehensive study of clinical and immunohistochemical findings in younger Asian patients. J Gastroenterol Hepatol 22(4):491–497. doi: 10.1111/j.1440-1746.2006.04758.x PubMedGoogle Scholar
  101. Paschos KA, Majeed AW, Bird NC (2010) Role of Kupffer cells in the outgrowth of colorectal cancer liver metastases. Hepatol Res 40(1):83–94. doi: 10.1111/j.1872-034X.2009.00578.x PubMedGoogle Scholar
  102. Pereira CA, Steffan AM, Kirn A (1984) Kupffer and endothelial liver cell damage renders A/J mice susceptible to mouse hepatitis virus type 3. Virus Res 1(7):557–563PubMedGoogle Scholar
  103. Petracca R, Falugi F, Galli G, Norais N, Rosa D, Campagnoli S et al (2000) Structure-function analysis of hepatitis C virus envelope-CD81 binding. J Virol 74(10):4824–4830PubMedCentralPubMedGoogle Scholar
  104. Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V et al (2012) IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest 122(10):3476–3489. doi: 10.1172/JCI60777 PubMedCentralPubMedGoogle Scholar
  105. Pinto AJ, Stewart D, van Rooijen N, Morahan PS (1991) Selective depletion of liver and splenic macrophages using liposomes encapsulating the drug dichloromethylene diphosphonate: effects on antimicrobial resistance. J Leukoc Biol 49(6):579–586PubMedGoogle Scholar
  106. Ploss A, Evans MJ (2012) Hepatitis C virus host cell entry. Curr Opin Virol 2(1):14–19. doi: 10.1016/j.coviro.2011.12.007 PubMedCentralPubMedGoogle Scholar
  107. Pohlmann S, Zhang J, Baribaud F, Chen Z, Leslie GJ, Lin G et al (2003) Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. J Virol 77(7):4070–4080PubMedCentralPubMedGoogle Scholar
  108. Polakos NK, Cornejo JC, Murray DA, Wright KO, Treanor JJ, Crispe IN et al (2006) Kupffer cell-dependent hepatitis occurs during influenza infection. Am J Pathol 168(4):1169–1178. doi: 10.2353/ajpath.2006.050875 PubMedCentralPubMedGoogle Scholar
  109. Pradel G, Frevert U (2001) Malaria sporozoites actively enter and pass through rat Kupffer cells prior to hepatocyte invasion. Hepatology 33(5):1154–1165. doi: 10.1053/jhep.2001.24237 PubMedGoogle Scholar
  110. Pradel G, Garapaty S, Frevert U (2002) Proteoglycans mediate malaria sporozoite targeting to the liver. Mol Microbiol 45(3):637–651PubMedGoogle Scholar
  111. Pradere JP, Kluwe J, De Minicis S, Jiao JJ, Gwak GY, Dapito DH et al (2013) Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58(4):1461–1473. doi: 10.1002/hep.26429 PubMedGoogle Scholar
  112. Rivera CA, Bradford BU, Hunt KJ, Adachi Y, Schrum LW, Koop DR et al (2001) Attenuation of CCl(4)-induced hepatic fibrosis by GdCl(3) treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol 281(1):G200–G207PubMedGoogle Scholar
  113. Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M (2007) Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 47(4):571–579. doi: 10.1016/j.jhep.2007.04.019 PubMedCentralPubMedGoogle Scholar
  114. Roh MS, Wang L, Oyedeji C, LeRoux ME, Curley SA, Pollock RE et al (1990) Human Kupffer cells are cytotoxic against human colon adenocarcinoma. Surgery 108(2):400–404, discussion 4–5PubMedGoogle Scholar
  115. Roudkenar MH, Li L, Baba T, Kuwahara Y, Nakagawa H, Wang L et al (2008) Gene expression profiles in mouse liver cells after exposure to different types of radiation. J Radiat Res 49(1):29–40. doi: 10.1269/jrr.07078 PubMedGoogle Scholar
  116. Salazar-Mather TP, Hokeness KL (2006) Cytokine and chemokine networks: pathways to antiviral defense. Curr Top Microbiol Immunol 303:29–46. doi: 10.1007/978-3-540-33397-5_2 PubMedGoogle Scholar
  117. Salkowski CA, Detore G, Franks A, Falk MC, Vogel SN (1998) Pulmonary and hepatic gene expression following cecal ligation and puncture: monophosphoryl lipid A prophylaxis attenuates sepsis-induced cytokine and chemokine expression and neutrophil infiltration. Infect Immun 66(8):3569–3578PubMedCentralPubMedGoogle Scholar
  118. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K et al (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336(6077):86–90. doi: 10.1126/science.1219179 PubMedGoogle Scholar
  119. Shi J, Fujieda H, Kokubo Y, Wake K (1996) Apoptosis of neutrophils and their elimination by Kupffer cells in rat liver. Hepatology 24(5):1256–1263. doi: 10.1053/jhep.1996.v24.pm0008903407 PubMedGoogle Scholar
  120. Shi J, Gilbert GE, Kokubo Y, Ohashi T (2001) Role of the liver in regulating numbers of circulating neutrophils. Blood 98(4):1226–1230PubMedGoogle Scholar
  121. Smith JS, Xu Z, Tian J, Stevenson SC, Byrnes AP (2008) Interaction of systemically delivered adenovirus vectors with Kupffer cells in mouse liver. Hum Gene Ther 19(5):547–554. doi: 10.1089/hum.2008.004 PubMedGoogle Scholar
  122. Song E, Chen J, Ouyang N, Wang M, Exton MS, Heemann U (2001) Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis. Br J Cancer 84(9):1265–1271. doi: 10.1054/bjoc.2000.1737 PubMedCentralPubMedGoogle Scholar
  123. Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N et al (2010) Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology 51(2):511–522. doi: 10.1002/hep.23337 PubMedGoogle Scholar
  124. Sturm A, Amino R, van de Sand C, Regen T, Retzlaff S, Rennenberg A et al (2006) Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids. Science 313(5791):1287–1290. doi: 10.1126/science.1129720 PubMedGoogle Scholar
  125. Takii Y, Nakamura M, Ito M, Yokoyama T, Komori A, Shimizu-Yoshida Y et al (2005) Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis. Lab Invest 85(7):908–920. doi: 10.1038/labinvest.3700285 PubMedGoogle Scholar
  126. Tavares J, Formaglio P, Thiberge S, Mordelet E, Van Rooijen N, Medvinsky A et al (2013) Role of host cell traversal by the malaria sporozoite during liver infection. J Exp Med. doi: 10.1084/jem.20121130 PubMedCentralPubMedGoogle Scholar
  127. ten Hagen TL, van Vianen W, Heremans H, Bakker-Woudenberg IA (1998) Differential nitric oxide and TNF-alpha production of murine Kupffer cell subfractions upon priming with IFN-gamma and TNF-alpha. Liver 18(5):299–305PubMedGoogle Scholar
  128. Terpstra V, van Berkel TJ (2000) Scavenger receptors on liver Kupffer cells mediate the in vivo uptake of oxidatively damaged red blood cells in mice. Blood 95(6):2157–2163PubMedGoogle Scholar
  129. Thurman RG, Bradford BU, Iimuro Y, Knecht KT, Arteel GE, Yin M et al (1998) The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury. J Gastroenterol Hepatol 13(Suppl):S39–S50PubMedGoogle Scholar
  130. Tilg H (2010) Obesity, metabolic syndrome, and microbiota: multiple interactions. J Clin Gastroenterol 44(Suppl 1):S16–S18. doi: 10.1097/MCG.0b013e3181dd8b64 PubMedGoogle Scholar
  131. Tomioka M, Iinuma H, Okinaga K (2000) Impaired Kupffer cell function and effect of immunotherapy in obstructive jaundice. J Surg Res 92(2):276–282. doi: 10.1006/jsre.2000.5868 PubMedGoogle Scholar
  132. Tosello-Trampont AC, Landes SG, Nguyen V, Novobrantseva TI, Hahn YS (2012) Kupffer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-alpha production. J Biol Chem 287(48):40161–40172. doi: 10.1074/jbc.M112.417014 PubMedCentralPubMedGoogle Scholar
  133. Triger DR, Wright R (1973) Hyperglobulinaemia in liver disease. Lancet 1(7818):1494–1496PubMedGoogle Scholar
  134. Trinchieri G (2012) Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol 30:677–706. doi: 10.1146/annurev-immunol-020711-075008 PubMedGoogle Scholar
  135. Tu Z, Bozorgzadeh A, Pierce RH, Kurtis J, Crispe IN, Orloff MS (2008) TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med 205(1):233–244. doi: 10.1084/jem.20072195 PubMedCentralPubMedGoogle Scholar
  136. Tu Z, Pierce RH, Kurtis J, Kuroki Y, Crispe IN, Orloff MS (2010) Hepatitis C virus core protein subverts the antiviral activities of human Kupffer cells. Gastroenterology 138(1):305–314. doi: 10.1053/j.gastro.2009.09.009 PubMedGoogle Scholar
  137. Valatas V, Kolios G, Manousou P, Xidakis C, Notas G, Ljumovic D et al (2004) Secretion of inflammatory mediators by isolated rat Kupffer cells: the effect of octreotide. Regul Pept 120(1–3):215–225. doi: 10.1016/j.regpep.2004.03.009 PubMedGoogle Scholar
  138. Van den Eynden GG, Majeed AW, Illemann M, Vermeulen PB, Bird NC, Hoyer-Hansen G et al (2013) The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. Cancer Res 73(7):2031–2043. doi: 10.1158/0008-5472.CAN-12-3931 PubMedGoogle Scholar
  139. van Egmond M, van Garderen E, van Spriel AB, Damen CA, van Amersfoort ES, van Zandbergen G et al (2000) FcalphaRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity. Nat Med 6(6):680–685. doi: 10.1038/76261 PubMedGoogle Scholar
  140. Visvanathan K, Skinner NA, Thompson AJ, Riordan SM, Sozzi V, Edwards R et al (2007) Regulation of toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology 45(1):102–110. doi: 10.1002/hep.21482 PubMedGoogle Scholar
  141. Vollmar B, Menger MD (2009) The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 89(4):1269–1339. doi: 10.1152/physrev.00027.2008 PubMedGoogle Scholar
  142. Wallace K, Burt AD, Wright MC (2008) Liver fibrosis. Biochem J 411(1):1–18. doi: 10.1042/BJ20071570 PubMedGoogle Scholar
  143. Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F et al (2014) M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59(1):130–142. doi: 10.1002/hep.26607 PubMedGoogle Scholar
  144. Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M et al (2012) IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 13(8):753–760. doi: 10.1038/ni.2360 PubMedCentralPubMedGoogle Scholar
  145. Wen SW, Ager EI, Christophi C (2013) Bimodal role of Kupffer cells during colorectal cancer liver metastasis. Cancer Biol Ther 14(7):606–613. doi: 10.4161/cbt.24593 PubMedCentralPubMedGoogle Scholar
  146. Widmann JJ, Fahimi HD (1975) Proliferation of mononuclear phagocytes (Kupffer cells) and endothelial cells in regenerating rat liver. A light and electron microscopic cytochemical study. Am J Pathol 80(3):349–366PubMedCentralPubMedGoogle Scholar
  147. Wiktor-Jedrzejczak W, Gordon S (1996) Cytokine regulation of the macrophage (M phi) system studied using the colony stimulating factor-1-deficient op/op mouse. Physiol Rev 76(4): 927–947PubMedGoogle Scholar
  148. Willekens FL, Werre JM, Kruijt JK, Roerdinkholder-Stoelwinder B, Groenen-Dopp YA, van den Bos AG et al (2005) Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors. Blood 105(5):2141–2145. doi: 10.1182/blood-2004-04-1578 PubMedGoogle Scholar
  149. Wisse E (1972) An ultrastructural characterization of the endothelial cell in the rat liver sinusoid under normal and various experimental conditions, as a contribution to the distinction between endothelial and Kupffer cells. J Ultrastruct Res 38(5):528–562PubMedGoogle Scholar
  150. Wright TL, Roll FJ, Jones AL, Weisiger RA (1988) Uptake and metabolism of polymerized albumin by rat liver. Role of the scavenger receptor. Gastroenterology 94(2):443–452PubMedGoogle Scholar
  151. Wu J, Meng Z, Jiang M, Pei R, Trippler M, Broering R et al (2009) Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology 49(4):1132–1140. doi: 10.1002/hep.22751 PubMedGoogle Scholar
  152. Wu J, Li J, Salcedo R, Mivechi NF, Trinchieri G, Horuzsko A (2012) The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res 72(16):3977–3986. doi: 10.1158/0008-5472.CAN-12-0938 PubMedCentralPubMedGoogle Scholar
  153. Wyke RJ (1987) Problems of bacterial infection in patients with liver disease. Gut 28(5):623–641PubMedCentralPubMedGoogle Scholar
  154. Wynn TA, Barron L (2010) Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 30(3):245–257. doi: 10.1055/s-0030-1255354 PubMedCentralPubMedGoogle Scholar
  155. Xidakis C, Ljumovic D, Manousou P, Notas G, Valatas V, Kolios G et al (2005) Production of pro- and anti-fibrotic agents by rat Kupffer cells; the effect of octreotide. Dig Dis Sci 50(5): 935–941PubMedGoogle Scholar
  156. Xu C, Chen X, Chang C, Wang G, Wang W, Zhang L et al (2012) Characterization of transcriptional profiling of Kupffer cells during liver regeneration in rats. Cell Biol Int 36(8):721–732. doi: 10.1042/CBI20110104 PubMedGoogle Scholar
  157. Yamada M, Naito M, Takahashi K (1990) Kupffer cell proliferation and glucan-induced granuloma formation in mice depleted of blood monocytes by strontium-89. J Leukoc Biol 47(3):195–205PubMedGoogle Scholar
  158. Yamamoto T, Kaizu C, Kawasaki T, Hasegawa G, Umezu H, Ohashi R et al (2008) Macrophage colony-stimulating factor is indispensable for repopulation and differentiation of Kupffer cells but not for splenic red pulp macrophages in osteopetrotic (op/op) mice after macrophage depletion. Cell Tissue Res 332(2):245–256. doi: 10.1007/s00441-008-0586-8 PubMedGoogle Scholar
  159. Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI et al (1999) Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 117(4):942–952PubMedGoogle Scholar
  160. Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M et al (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38(1):79–91. doi: 10.1016/j.immuni.2012.12.001 PubMedCentralPubMedGoogle Scholar
  161. You Q, Cheng L, Kedl RM, Ju C (2008) Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 48(3):978–990. doi: 10.1002/hep.22395 PubMedCentralPubMedGoogle Scholar
  162. You Q, Holt M, Yin H, Li G, Hu CJ, Ju C (2013) Role of hepatic resident and infiltrating macrophages in liver repair after acute injury. Biochem Pharmacol 86(6):836–843. doi: 10.1016/j.bcp.2013.07.006 PubMedGoogle Scholar
  163. Zaiss AK, Liu Q, Bowen GP, Wong NC, Bartlett JS, Muruve DA (2002) Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors. J Virol 76(9):4580–4590PubMedCentralPubMedGoogle Scholar
  164. Zocco MA, Carloni E, Pescatori M, Saulnier N, Lupascu A, Nista EC et al (2006) Characterization of gene expression profile in rat Kupffer cells stimulated with IFN-alpha or IFN-gamma. Dig Liver Dis 38(8):563–577. doi: 10.1016/j.dld.2006.04.015 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Andrea M. Woltman
    • 1
  • Andre Boonstra
    • 1
  • Makoto Naito
    • 2
  • Pieter J. M. Leenen
    • 3
  1. 1.Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
  2. 2.Division of Cellular and Molecular PathologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
  3. 3.Department of ImmunologyErasmus MC University Medical CenterRotterdamThe Netherlands

Personalised recommendations