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01-06-2005 | Original Article

A murine model of NKT cell-mediated liver injury induced by alpha-galactosylceramide/d-galactosamine

Authors: Hideki Fujii, Shuichi Seki, Sawako Kobayashi, Takuya Kitada, Nobuyoshi Kawakita, Keishi Adachi, Hiroko Tsutsui, Kenji Nakanishi, Hiromi Fujiwara, Yoshinori Ikarashi, Masaru Taniguchi, Kronenberg Mitchell, Masaru Ikemoto, Yuji Nakajima, Tetsuo Arakawa, Kenji Kaneda

Published in: Virchows Archiv | Issue 6/2005

Abstract

Natural killer-T (NKT) cells are rich in the liver. However, their involvement in liver injury is not fully understood. We developed here a new murine model of NKT-cell-activation-associated liver injury, and investigated a role of tumor necrosis factor alpha (TNF-α) and Fas in pathogenesis. We injected intraperitoneally alpha-galactosylceramide (α-GalCer), an NKT-cell stimulant, into d-galactosamine (GalN)-sensitized mice. Survival rate, pathological changes of the liver, and plasma concentrations of cytokines were studied. Alpha-GalCer/GalN administration gave a lethal effect within 7 h, making pathological changes such as massive parenchymal hemorrhage, hepatocyte apoptosis, sinusoidal endothelial cell injury, and close apposition of lymphocytes to apoptotic hepatocytes. Anti-NK1.1 mAb-pretreated mice and Vα14NKT knock out (KO) mice did not develop liver injury. Tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were elevated at 4 h in the plasma. These cytokines were produced by hepatic lymphocytes as demonstrated by in vitro stimulation with α-GalCer. The lethal effect was suppressed in TNF-α KO mice, TNF receptor-1 KO mice, and lpr/lpr (Fas deficient) mice, whereas it was not in IFN-γ KO mice. These results indicate that the present liver injury is characterized by parenchymal hemorrhage and hepatocyte apoptosis, and mediated by TNF-α secretion and direct cytotoxicity of α-GalCer-activated NKT cells.

Angermuller S, Kunstle G, Tiegs G (1998) Pre-apoptotic alterations in hepatocytes of TNFα-treated galactosamine-sensitized mice. J Histochem Cytochem 46:1175–1183PubMed

Bendelac A, Rivera MN, Park SH, Roark JH (1997) Mouse CD1-specific NK1 T cells: development, specificity, and function. Annu Rev Immunol 15:535–562CrossRefPubMed

Bursch W, Taper HS, Lauer B, Schulte-Hermann R (1985) Quantitative histological and histochemical studies on the occurrence and stages of controlled cell death (apoptosis) during regression of rat liver hyperplasia. Virchows Arch B Cell Pathol Incl Mol Pathol 50:153–166PubMed

Cardier JE, Schulte T, Kammer H, Kwak J, Cardier M (1999) Fas (CD95, APO-1) antigen expression and function in murine liver endothelial cells: implications for the regulation of apoptosis in liver endothelial cells. FASEB J 13:1950–1960PubMed

Cauwels A, Janssen B, Waeytens A, Cuvelier C, Brouckaert P (2003) Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. Nat Immunol 4:387–393CrossRefPubMed

Crispe IN (2003) Hepatic T cells and liver tolerance. Nat Rev Immunol 3:51–62CrossRefPubMed

Cui J, Shin T, Kawano T, Sato H, Kondo E, Toura I, Kaneko Y, Koseki H, Kannno M, Taniguchi M (1997) Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors. Science 278:1623–1626CrossRefPubMed

Deaciuc IV, Bagby GJ, Lang CH, Spitzer JJ (1993) Hyaluronic acid uptake by the isolated, perfused rat liver: an index of hepatic sinusoidal endothelial cell function. Hepatology 17:266–272CrossRefPubMed

Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D, Vidal JM, van de Vorstenbosch C; European Federation of Pharmaceutical Industries Association and European Centre for the Validation of Alternative Methods (2001) A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appl Toxicol 21:15–23CrossRefPubMed

10.

Dienes HP (1989) Viral and autoimmune hepatitis. Morphologic and pathogenetic aspects of cell damage in hepatitis with potential chronicity. Verroff Pathol 132:1–107

11.

Dini L, Pagliara P, Carla EC (2002) Phagocytosis of apoptotic cells by liver: a morphological study. Microsc Res Tech 57:530–540CrossRefPubMed

12.

Emoto M, Kaufmann SH (2003) Liver NKT cells: an account of heterogeneity. Trends Immunol 24:364–369CrossRefPubMed

13.

Galanos C, Freundenberg MA, Reutter W (1979) Galactosamine-induced sensitization to the lethal effects of endotoxin. Proc Natl Acad Sci USA 76:5939–5943PubMed

14.

Gantner F, Leist M, Jilg S, Germann PG, Freudenberg MA, Tiegs G (1995) Tumor necrosis factor-induced hepatic DNA fragmentation as an early marker of T cell-dependent liver injury in mice. Gastroenterology 109:166–176PubMed

15.

Godfrey DI, Hammond KJ, Poulton LD, Smyth MJ, Baxter AG (2000) NKT cells: facts, functions and fallacies. Immunol Today 21:573–583CrossRefPubMed

16.

Hashimoto W, Takeda K, Anzai R, Ogasawara K, Sakihara H, Sugiura K, Seki S, Kumagai K (1995) Cytotoxic NK1.1 Ag+ αβ T cells with intermediate TCR induced in the liver of mice by IL-12. J Immunol 154:4333–4340PubMed

17.

Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776CrossRefPubMed

18.

Illes Z, Kondo T, Newcombe J, Oka N, Tabira T, Yamamura T (2000) Differential expression of NK T cell V alpha24Jalpha Q invariant TCR chain in the lesionsof multiple sclerosis and chronic inflammatory demyelinating polyneuropathy. J Immunol 164:4375–4381PubMed

19.

Jaeschke H, Fisher MA, Lawson JA, Simmons CA, Farhood A, Jones DA (1998) Activation of caspase 3 (CPP32)-like proteases is essential for TNF-α-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model. J Immunol 160:3480–3486PubMed

20.

Kasahara I, Saitoh K, Nakamura K (2000) Apoptosis in acute hepatic failure: histopathological study of human liver tissue using the tunel method and immunohistochemistry. J Med Dent Sci 47:167–175PubMed

21.

Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Sato H, Kondo E, Harada M, Koseki H, Nakayama T et al (1998) Natural killer- like nonspecific tumor cell lysis mediated by specific ligand-activated Vα14 NKT cells. Proc Natl Acad Sci USA 95:5690–5693CrossRefPubMed

22.

Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E et al (1997) CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278:1626–1629CrossRefPubMed

23.

Kita H, Naidenko OV, Kronenberg M, Ansari AA, Rogers P, He XS, Koning F, Mikayama T et al. (2002) Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology 123:1031–1043CrossRefPubMed

24.

Künsters S, Tiegs L, Alexopoulou M, Pasparakis E, Douni G, Künstle H, Bluchmann A, Wendel K, Pfitzenmaier G, Kollias G, Grell M (1997) In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis. Eur J Immunol 27:2870–2875PubMed

25.

Künstle G, Leist M, Uhlig S, Revesz L, Feifel R, MacKenzie A, Wendel A (1997) ICE- protease inhibitors block murine liver injury and apoptosis caused by CD95 or by TNF-α. Immunol Lett 55:5–10CrossRefPubMed

26.

Künstle G, Hentze H, Germann P-G, Tiegs G, Meergans T, Wendel A (1999) Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation. Hepatology 30:1241–1251CrossRefPubMed

27.

Leist M, Jäattelä M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2:589–598CrossRefPubMed

28.

Leist M, Gantner F, Bohlinger I, Germann PG, Tiegs G, Wendel A (1994) Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-α requires transcriptional arrest. J Immunol 153:1778–1788PubMed

29.

Leist M, Gantner F, Bohlinger I, Tiegs G, Germann PG, Wendel A (1995) Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models. Am J Pathol 146:1220–1234PubMed

30.

Matsuda JL, Naidenko OV, Gapin L, Nakayama T, Taniguchi M, Wang CR, Koezuka Y, Kronenberg M (2000) Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J Exp Med 192:741–754CrossRefPubMed

31.

Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G (2004) Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcoholic consumption. Gastroenterology 126:1387–1399CrossRefPubMed

32.

Miyazawa Y, Tsutsui H, Mizuhara H, Fujiwara H, Kaneda K (1998) Involvement of intrasinusoidal hemostasis in the development of concanavalin A-induced hepatic injury in mice. Hepatology 27:497–506CrossRefPubMed

33.

Mohammed FF, Smookler DS, Taylot SE, Fingleton B, Kassiri Z, Sanchez OH, English JL, Matrisian LM, Au B, Yeh WC et al. (2004) Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver generation. Nat Genet 36:969–977CrossRefPubMed

34.

Morikawa A, Sugiyama T, Kato Y, Koide N, Jiang GZ, Takahashi K, Tamada Y, Yokochi T (1996) Apoptotic cell death in the response of D-galactosamine-sensitized mice to lipopolysaccharide as an experimental endotoxic shock model. Infect Immun 64:734–738PubMed

35.

Muschen M, Warskulat U, Douillard P, Gilbert E, Haussinger D (1998) Regulation of CD95(APO-1/Fas) receptor and ligand expression by lipopolysaccharide and dexamethasone in parenchymal and nonparenchymal rat liver cells. Hepatology 27:200–208CrossRefPubMed

36.

Nagaki M, Naiki T, Brenner DA, Osawa Y, Imose M, Hayashi H, Banno Y, Nakashima S, Moriwaki H (2000) Tumor necrosis factor α prevents tumor necrosis factor receptor-mediated mouse hepatocyte apoptosis, but not Fas-mediated apoptosis: role of nuclear factor-κB. Hepatology 32:1272–1279CrossRefPubMed

37.

Nakagawa R, Nagafune I, Tazunoki Y, Ehara H, Tomura H, Iijima R, Motoki K, Kamishohara M, Seki S (2001) Mechanism of the antimetastatic effect in the liver and of the hepatocyte injury induced by α-galactosylceramide in mice. J Immunol 166:6578–6584PubMed

38.

Nakatani K, Kaneda K, Seki S, Nakajima Y (2004) Pit cells as liver-associated natural killer cells: morphology and function. Med Electron Microsc 37:29–36CrossRefPubMed

39.

Nowak M, Gaines GC, Rosenberg J, Minter R, Bahjat FR, Rectenwald J, Mackay SL, Edwards CK III, Moldawer LL (2000) LPS-induced liver injury in D-galactosamine- sensitized mice requires secreted TNF-α and the TNF-p55 receptor. Am J Physiol Regul Integr Comp Physiol 278:R1202–R1209PubMed

40.

Osman Y, Kawamura T, Naito T, Takeda K, Van Kaer L, Okumura K, Abo T (2000) Activation of hepatic NKT cells and subsequent liver injury following administration of α-galactosylceramide. Eur J Immunol 30:1919–1928CrossRefPubMed

41.

Pretet JL, Pelletier L, Bernard B, Coumes-Marquet S, Kantelip B, Mougin C (2000) Apoptosis participates to liver damage in HSV-induced fulminant hepatitis. Apoptosis 8:655–663CrossRef

42.

Sass G, Heinlein S, Agli A, Bang R, Schümann J, Tiegs G (2002) Cytokine expression in three mouse models of experimental hepatitis. Cytokine 19:115–120CrossRefPubMed

43.

Seki S, Hashimoto W, Ogasawara K, Satoh M, Watanabe H, Habu Y, Hiraide H, Takeda K (1997) Antimetastatic effect of NK1+ T cells on experimental haematogenous tumor metastases in the liver and lungs of mice. Immunology 92:561–566CrossRefPubMed

44.

Shimizu Y, Margenthaler JA, Landeros K, Otomo N, Doherty G, Flye MW (2002) The resistance of P. acnes-primed interferon γ-deficient mice to low-dose lipopolysaccharide- induced acute liver injury. Hepatology 35:805–814CrossRefPubMed

45.

Sumida T, Sakamoto A, Murata H, Makino Y, Takahashi H, Yoshida S, Nishioka K, Iwamoto I, Taniguchi M (1995) Selective reduction of T cells bearing invariant Vα24 JαQ antigen receptor in patients with systemic sclerosis. J Exp Med 182:1163–1168CrossRefPubMed

46.

Sumida T, Maeda T, Taniguchi M, Nishioka K, Stohl W (1998) TCRαV24 gene expression in double negative T cells in systemic lupus erythematosus. Lupus 7:565–568CrossRefPubMed

47.

Tagawa Y, Sekikawa K, Iwakura Y (1997) Suppression of concanavalin A-induced hepatitis in IFN-γ-/- mice, but not in TNF-α-/- mice: role for IFN-γ in activating apoptosis of hepatocytes. J Immunol 159:1418–1428PubMed

48.

Tokushige K, Yamaguchi N, Ikeda I, Hashimoto E, Yamauchi K, Hayashi N (2000) Significance of soluble TNF receptor-I in acute-type fulminant hepatitis. Am J Gastroenterol 95:2040–2046CrossRefPubMed

49.

Trobonjaca Z, Leithäuser F, Möller P, Schirmbeck, Reimann J (2001) Activating immunity in the liver. I. Liver dendritic cells (but not hepatocytes) are potent activators of IFN-γ release by liver NKT cells. J Immunol 167:1413–1422PubMed

50.

Tsuji H, Mukaida N, Harada A, Kaneko S, Matsushita E, Nakanuma Y, Tsutsui H, Okamura H, Nakanishi K, Tagawa Y et al. (1999) Alleviation of lipopolysaccharide-induced acute liver injury in Propionibacterium acnes-primed IFN-γ-deficient mice by a concomitant reduction of TNF-α, IL-12, and IL-18 production. J Immunol 162:1049–1055PubMed

51.

Wanner GA, Mica L, Wanner-Schmid E, Kolb SA, Hentze H, Trentz O, Ertel W (1999) Inhibition of caspase activity prevents CD95-mediated hepatic microvascular perfusion failure and restores Kupffer cell clearance capacity. FASEB J 13:1239–1248PubMed

52.

Watanabe H, Miyaji C, Kawachi Y, Iiai T, Ohtsuka K, Iwanaga T, Takahashi-Iwanaga H, Abo T (1995) Relationships between intermediate TCR cells and NK1.1+T cells in various immune organs. NK1.1+T cells are present within a populations of intermediate TCR cells. J Immunol 155:2972–2983PubMed

53.

Wilson SB, Kent SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Schatz DA, Atkinson MA, Balk SP (1998) Extreme Th1 bias of invaiant Valpha24 JalphaQ T cells in type 1 diabetes. Nature 391:177–181CrossRefPubMed

54.

Wolf D, Hallmann R, Sass G, Sixt M, Kusters S, Fregien B, Trauwein C, Tiegs G (2001) TNF- alpha-induced expression of adhesion molecules in the liver is under the control of TNFR1— relevance for concanavalin A-induced hepatitis. J Immunol 166:1300–1307PubMed

55.

Yachida S, Kokudo Y, Wakabayashi H, Maeba T, Kaneda K, Maeta H (1998) Morphological and functional alterations to sinusoidal endothelial cells in the early phase of endotoxin-induced liver failure after partial hepatectomy in rats. Virchows Arch 433:173–181CrossRefPubMed

56.

Yasuda S, Nagaki M, Moriwaki H (2002) Staphylococcal enterotoxin B induces hepatic injury and lethal shock in endotoxin-resistant C3H/HeJ mice despite a deficient macrophage response. J Endotoxin Res 8:253–261CrossRefPubMed

57.

Zafrani ES, Cazier A, Baudelot AM, Feldmann G (1984) Ultrastructural lesions of the liver in human peliosis. A report of 12 cases. Am J Pathol 114:349–359PubMed

58.

Zhou BR, Gumenscheimer M, Freudenberg M, Galanos C (2003) A striking correlation between lethal activity and apoptotic DNA fragmentation of liver in response of D-galactosamine-sensitized mice to a non-lethal amount of lipopolysaccharide. Acta Pharmacol Sin 24:193–198PubMed

Title: A murine model of NKT cell-mediated liver injury induced by alpha-galactosylceramide/d-galactosamine
Authors: Hideki Fujii
Shuichi Seki
Sawako Kobayashi
Takuya Kitada
Nobuyoshi Kawakita
Keishi Adachi
Hiroko Tsutsui
Kenji Nakanishi
Hiromi Fujiwara
Yoshinori Ikarashi
Masaru Taniguchi
Kronenberg Mitchell
Masaru Ikemoto
Yuji Nakajima
Tetsuo Arakawa
Kenji Kaneda
Publication date: 01-06-2005
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 6/2005
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-005-1265-8

At a glance: The STEP trials

Springer Medicine

A murine model of NKT cell-mediated liver injury induced by alpha-galactosylceramide/d-galactosamine

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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