Natural killer cells mediate severe liver injury in a murine model of halothane hepatitis.
Severe halothane (HAL)-induced hepatotoxicity occurs in one in 6000-30,000 patients by an unknown mechanism. Female sex is a risk factor in humans and rodents. We tested the hypothesis that a sex difference in natural killer (NK) cell activity contributes to HAL-induced liver injury. HAL (15 mmol/kg, ip) treatment resulted in severe liver injury by 12 h in female, wild-type BALB/cJ mice, and the magnitude of liver injury varied with stage of the estrous cycle. Ovariectomized (OVX) mice developed only mild liver injury. Plasma interferon-gamma (IFN-γ) was elevated 10-fold in HAL-treated females compared with similarly treated male mice or with OVX female mice. IFN-γ knockout mice were resistant to severe HAL-induced liver injury. The deactivation of NK cells with anti-asialo GM1 treatment attenuated liver injury and the increase in plasma IFN-γ compared with immunoglobulin G-treated control mice. Mice with a mutated form of perforin, a protein involved in granule-mediated cytotoxicity, were protected from severe liver injury. Furthermore, HAL increased the activity of NK cells in vivo, as indicated by increased surface expression of CD69, an early activation marker. In response to HAL, NK cell receptor ligands on the surface of hepatocytes were expressed in a manner that can activate NK cells. These results confirm the sexual dimorphic hepatotoxic response to HAL in mice and suggest that IFN-γ and NK cells have essential roles in the development of severe HAL-induced hepatotoxicity.
Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan 48824-1302, USA.
Christine M
CM
Dugan
Aaron M
AM
Fullerton
Robert A
RA
Roth
Patricia E
PE
Ganey
D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology* / Q000276:immunology; D030762:Estrous Cycle; D005260:Female; D005434:Flow Cytometry; D006221:Halothane / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010052:Ovariectomy; D012720:Severity of Illness Index; D012727:Sex Characteristics; D051197:Toll-Like Receptor 4 / Q000276:immunology; D000099192:CD69 Antigens
D018685:Anesthetics, Inhalation; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D006221:Halothane; D007371:Interferon-gamma; D037181:Lectins, C-Type; D051197:Toll-Like Receptor 4; D000099192:CD69 Antigens; C493487:Tlr4 protein, mouse
Lancet. 1989 May 20;1(8647):1143
2566087
Biochem Biophys Res Commun. 2010 Jul 2;397(3):453-8
20510877
Xenobiotica. 1980 Apr;10(4):243-6
7415204
Immunity. 2002 Jul;17(1):19-29
12150888
Int Immunopharmacol. 2007 Dec 15;7(13):1765-75
17996687
Gastroenterology. 2010 Jun;138(7):2246-59
20394749
Br Med J. 1971 Jul 3;3(5765):18-22
5091889
Semin Liver Dis. 2008 May;28(2):142-52
18452114
J Exp Med. 1989 Jan 1;169(1):59-72
2521244
Lancet. 1975 Apr 12;1(7911):821-4
48054
J Immunol. 2000 Jun 15;164(12):6480-6
10843705
Cytometry. 2001 Sep 1;45(1):47-55
11598946
Biochem Pharmacol. 2010 Jul 15;80(2):255-61
20359463
Transplant Proc. 1989 Feb;21(1 Pt 1):881-4
2650288
Cell Mol Immunol. 2005 Apr;2(2):92-100
16191414
Semin Immunopathol. 2009 Sep;31(3):333-43
19639317
Annu Rev Pharmacol Toxicol. 1988;28:367-87
3289490
Shock. 2009 Mar;31(3):280-4
19218854
Mol Pharmacol. 1978 Jul;14(4):672-81
683177
Birth Defects Res B Dev Reprod Toxicol. 2007 Apr;80(2):84-97
17342777
Transplantation. 1969 Feb;7(2):105-11
4884914
J Gastroenterol Hepatol. 1996 Jun;11(6):594-601
8792316
J Pharmacol Exp Ther. 1988 Jun;245(3):1103-9
3385639
J Immunol. 1997 Aug 1;159(3):1418-28
9233639
FASEB J. 2002 Aug;16(10):1227-36
12153990
Immunol Rev. 2000 Feb;173:89-97
10719670
J Immunogenet. 1986 Apr-Jun;13(2-3):141-51
3493296
J Pharmacol Exp Ther. 1985 Jun;233(3):857-62
3891968
Cell. 1995 Apr 7;81(1):9-12
7536631
Hepatology. 2006 Dec;44(6):1421-31
17133481
Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):614-8
8290572
Chem Res Toxicol. 2001 Apr;14(4):362-70
11304124
J Immunol. 1981 Jul;127(1):34-8
7240748
Liver Int. 2009 Mar;29(3):349-55
18662276
Ann Intern Med. 2002 Dec 17;137(12):947-54
12484709
Clin Liver Dis. 2005 May;9(2):191-211, v
15831268
Immunity. 2000 Jun;12(6):721-7
10894171
Int J Cancer. 2003 Apr 10;104(3):354-61
12569559
Eur J Immunol. 1980 Mar;10(3):175-80
6966574
Hepatology. 2008 Sep;48(3):889-97
18712839
J Pharmacol Exp Ther. 1985 Mar;232(3):802-9
3973829
Nature. 2002 Jul 11;418(6894):191-5
12110890
Cell Tissue Res. 1976 Oct 19;173(4):423-35
991252
J Pharmacol Exp Ther. 2010 May;333(2):364-72
20124411
Immunity. 2003 Oct;19(4):469-77
14563312
Immunol Rev. 2007 Dec;220:169-82
17979846
World J Gastroenterol. 2008 Sep 14;14(34):5322-6
18785286
Cell Immunol. 2001 Nov 25;214(1):12-20
11902825
Cytometry. 2001 Sep 1;45(1):56-64
11598947
Expert Opin Drug Metab Toxicol. 2006 Aug;2(4):493-503
16859400
Annu Rev Immunol. 1993;11:571-611
8476573
Hepatology. 2009 Jan;49(1):215-26
19111017
J Steroid Biochem Mol Biol. 2010 May 31;120(2-3):105-15
20045727
J Exp Med. 2001 Mar 19;193(6):661-70
11257133