Genetic determinants of lipopolysaccharide and D-galactosamine-mediated hepatocellular apoptosis and lethality

Abstract

Lipopolysaccharide and D-galactosamine induced lethality and apoptotic liver injury is dependent upon endogenously produced TNF-α. Unlike the response to high dose lipopolysaccharide alone, death in this model is a direct result of hepatocyte apoptosis. In a series of recent studies, we have demonstrated that mortality and hepatic injury following lipopolysaccharide administration in D-galactosamine-sensitized mice is dependent upon secreted 17 kDa TNF-α acting primarily through the p55 TNF receptor. Transgenic mice expressing null forms of TNF-α, the p55 receptor, or expressing only a cell-associated form of TNF-α exhibited no mortality and only modest liver injury when challenged with 8 mg of D-galactosamine and 100 ng of lipopolysaccharide. Although Fas ligand expression is increased in the liver, it appeared to play no significant role in outcome, since mice expressing a mutant form of Fas ligand are still sensitive to LPS- and D-galactosamine-induced lethality. Finally, we have seen significant variation in LPS- and D-galactosamine-mediated lethality among different strains of mice. The non-obese diabetic or NOD mouse is highly resistant to LPSand D-galactosamine-induced lethality, and this appears to be secondary to a post-receptor defect in p55 TNF receptor signaling. The studies confirm an essential role for TNF-α and p55 TNF receptor signaling in the hepatocyte apoptosis and lethality associated with lipopolysaccharide and D-galactosamine administration.

References

Ksontini R. , Colagiovanni DB , Josephs MD et al. Disparate roles for TNF-alpha and Fas ligand in concanavalin A-induced hepatitis. J Immunol 1998; 160: 4082—4089.

Solorzano CC , Ksontini R. , Pruitt JH et al. Involvement of 26-kDa cell-associated TNF-alpha in experimental hepatitis and exacerbation of liver injury with a matrix metalloproteinase inhibitor. J Immunol 1997; 158: 414—419.

Galanos C. , Freudenberg MA , Reutter W. Galactosamine-induced sensitization to the lethal effects of endotoxin. Proc Natl Acad Sci USA 1979; 76: 5939—5943.

Mignon A. , Rouquet N. , Fabre M. et al. LPS challenge in D-galactosamine-sensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock. Am J Respir Crit Care Med 1999; 159: 1308—1315.

Leist M. , Gantner F. , Jilg S. , Wendel A. Activation of the 55 kDa TNF receptor is necessary and sufficient for TNF-induced liver failure, hepatocyte apoptosis, and nitrite release. J Immunol 1995; 154: 1307—1316.

Morikawa A. , Sugiyama T. , Kato Y. et al. Apoptotic cell death in the response of D-galactosamine-sensitized mice to lipopolysaccharide as an experimental endotoxic shock model. Infect Immun 1996; 64: 734—738.

Ksontini R. , MacKay SL , Moldawer LL Revisiting the role of tumor necrosis factor alpha and the response to surgical injury and inflammation. Arch Surg 1998; 133: 558—567.

Peschon JJ , Torrance DS , Stocking KL et al. TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation. J Immunol 1998; 160: 943—952.

Welborn III MB , Van Zee K. , Edwards PD et al. A human tumor necrosis factor p75 receptor agonist stimulates in vitro T cell proliferation but does not produce inflammation or shock in the baboon. J Exp Med 1996; 184: 165—171.

10.

Van Zee KJ , Stackpole SA , Montegut WJ et al. A human tumor necrosis factor (TNF) a mutant that binds exclusively to the p55 TNF receptor produces toxicity in the baboon. J Exp Med 1994; 179: 1185—1191.

11.

Alexopoulou L. , Pasparakis M. , Kollias G. A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling . Eur J Immunol 1997; 27:2588—2592.

12.

Kusters S. , Tiegs G. , Alexopoulou L. et al. In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis. Eur J Immunol 1997; 27: 2870—2875.

13.

Grell M. , Douni E. , Wajant H. et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 1995; 83: 793—802.

14.

Espevik T. , Nissen Meyer J. A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods 1986; 95: 99—105.

15.

Fukuzuka K. , Edwards III CK , Clare-Salzler M. , Copeland EM , Moldawer LL , Mozingo DW Glucocorticoid induced, caspase dependent organ apoptosis early after burn injury. Am J Physiol 2000; 278: R1005—R1018.

16.

Josephs MD , Bahjat FR , Fukuzuka K. et al. Lipopolysaccharide and D-galactosamine-induced hepatic injury is mediated by TNF-alpha and not by Fas ligand. Am J Physiol 2000; 278: R1196—R1201.

17.

Nowak M. , Gaines GC , Rosenberg J. et al. LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted TNF-alpha and the TNF-p55 receptor. Am J Physiol 2000; 278: R1202—R1209.

18.

Bahjat FR , Dharnidharka VR , Fukuzuka K. , Morel L. , Clare-Salzler M. , Moldawer LL Reduced susceptibility of NOD mice to tumor necrosis factor and D-galactosamine-mediated hepatocellular apoptosis and lethality. J Immunol 2000; 165: 6559—6567.

19.

Bohlinger I. , Leist M. , Gantner F. , Angermuller S. , Tiegs G. , Wendel A. DNA fragmentation in mouse organs during endotoxic shock. Am J Pathol 1996; 149: 1381—1393.

20.

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

21.

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

22.

Pfeffer K. , Matsuyama T. , Kundig TM et al. Mice deficient for the 55 kD tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection . Cell 1993; 73: 457—467.

23.

Rothe J. , Lesslauer W. , Lotscher H. et al. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes . Nature 1993; 364: 798—802.

24.

Marino MW , Dunn A. , Grail D. et al. Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci USA 1997; 94: 8093—8098.

25.

Tannahill CL , Fukuzuka K. , Marum T. et al. Discordant tumor necrosis factor-alpha superfamily gene expression in bacterial peritonitis and endotoxemic shock . Surgery 1999; 126: 349—357.

26.

Kondo T. , Suda T. , Fukuyama H. , Adachi M. , Nagata S. Essential roles of the Fas ligand in the development of hepatitis. Nat Med 1997; 3: 409—413.

27.

Mira JP , Cariou A. , Grall F. et al. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA 1999; 282: 561—568.