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. 1997 May;65(5):1892–1898. doi: 10.1128/iai.65.5.1892-1898.1997

Tumor necrosis factor receptor p55 is essential for intrahepatic granuloma formation and hepatocellular apoptosis in a murine model of bacterium-induced fulminant hepatitis.

H Tsuji 1, A Harada 1, N Mukaida 1, Y Nakanuma 1, H Bluethmann 1, S Kaneko 1, K Yamakawa 1, S I Nakamura 1, K I Kobayashi 1, K Matsushima 1
PMCID: PMC175237  PMID: 9125577

Abstract

Accumulating evidence implicates tumor necrosis factor (TNF) and Fas systems in liver injury, although the interaction between these two systems remains to be investigated. In this study, we examined Propionibacterium acnes-primed TNF receptor p55-deficient (TNFRp55-/-) or Fas-deficient MRL/MpJ Lpr/Lpr mice challenged with lipopolysaccharide (LPS). Priming with P. acnes caused mononuclear cell infiltration into the hepatic lobules and granuloma formation in the livers of TNFRp55 wild-type mice. Subsequent LPS challenge caused massive liver injury and a marked increase in transaminase levels, leading to acute lethality in control wild-type mice. In contrast, the same treatment caused few pathological changes in livers of TNFRp55-/- mice, and all animals survived. P. acnes and subsequent LPS challenge induced granuloma formation and apoptotic changes, respectively, in livers of MRL/MpJ Lpr/Lpr mice. However, liver injury was 50% of that in control MRL/MpJ +/+ mice, suggesting some role of the Fas-Fas ligand system in this liver injury model. On the other hand, an agonistic anti-Fas antibody caused massive apoptosis and hemorrhagic changes of the liver without any priming with P. acnes, leading to death in both TNFRp55-/- and control wild-type mice. These results suggest that TNFRp55 but not Fas was involved in P. acnes-induced granuloma formation as well as subsequent LPS-induced liver injury and that TNFRp55 and Fas independently induced apoptosis of hepatocytes in vivo.

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Selected References

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  1. Adachi M., Suematsu S., Kondo T., Ogasawara J., Tanaka T., Yoshida N., Nagata S. Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver. Nat Genet. 1995 Nov;11(3):294–300. doi: 10.1038/ng1195-294. [DOI] [PubMed] [Google Scholar]
  2. Amiri P., Locksley R. M., Parslow T. G., Sadick M., Rector E., Ritter D., McKerrow J. H. Tumour necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice. Nature. 1992 Apr 16;356(6370):604–607. doi: 10.1038/356604a0. [DOI] [PubMed] [Google Scholar]
  3. Arthur M. J., Bentley I. S., Tanner A. R., Saunders P. K., Millward-Sadler G. H., Wright R. Oxygen-derived free radicals promote hepatic injury in the rat. Gastroenterology. 1985 Nov;89(5):1114–1122. doi: 10.1016/0016-5085(85)90218-5. [DOI] [PubMed] [Google Scholar]
  4. Chensue S. W., Ruth J. H., Warmington K., Lincoln P., Kunkel S. L. In vivo regulation of macrophage IL-12 production during type 1 and type 2 cytokine-mediated granuloma formation. J Immunol. 1995 Oct 1;155(7):3546–3551. [PubMed] [Google Scholar]
  5. Cleveland J. L., Ihle J. N. Contenders in FasL/TNF death signaling. Cell. 1995 May 19;81(4):479–482. doi: 10.1016/0092-8674(95)90068-3. [DOI] [PubMed] [Google Scholar]
  6. Cooper A. M., Dalton D. K., Stewart T. A., Griffin J. P., Russell D. G., Orme I. M. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med. 1993 Dec 1;178(6):2243–2247. doi: 10.1084/jem.178.6.2243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Erickson S. L., de Sauvage F. J., Kikly K., Carver-Moore K., Pitts-Meek S., Gillett N., Sheehan K. C., Schreiber R. D., Goeddel D. V., Moore M. W. Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature. 1994 Dec 8;372(6506):560–563. doi: 10.1038/372560a0. [DOI] [PubMed] [Google Scholar]
  8. Ferluga J., Allison A. C. Role of mononuclear infiltrating cells in pathogenesis of hepatitis. Lancet. 1978 Sep 16;2(8090):610–611. doi: 10.1016/s0140-6736(78)92828-3. [DOI] [PubMed] [Google Scholar]
  9. Flynn J. L., Chan J., Triebold K. J., Dalton D. K., Stewart T. A., Bloom B. R. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993 Dec 1;178(6):2249–2254. doi: 10.1084/jem.178.6.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Flynn J. L., Goldstein M. M., Chan J., Triebold K. J., Pfeffer K., Lowenstein C. J., Schreiber R., Mak T. W., Bloom B. R. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity. 1995 Jun;2(6):561–572. doi: 10.1016/1074-7613(95)90001-2. [DOI] [PubMed] [Google Scholar]
  11. Fraser A., Evan G. A license to kill. Cell. 1996 Jun 14;85(6):781–784. doi: 10.1016/s0092-8674(00)81005-3. [DOI] [PubMed] [Google Scholar]
  12. Fujioka N., Mukaida N., Harada A., Akiyama M., Kasahara T., Kuno K., Ooi A., Mai M., Matsushima K. Preparation of specific antibodies against murine IL-1ra and the establishment of IL-1ra as an endogenous regulator of bacteria-induced fulminant hepatitis in mice. J Leukoc Biol. 1995 Jul;58(1):90–98. doi: 10.1002/jlb.58.1.90. [DOI] [PubMed] [Google Scholar]
  13. Galle P. R., Hofmann W. J., Walczak H., Schaller H., Otto G., Stremmel W., Krammer P. H., Runkel L. Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med. 1995 Nov 1;182(5):1223–1230. doi: 10.1084/jem.182.5.1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grell M., Douni E., Wajant H., Löhden M., Clauss M., Maxeiner B., Georgopoulos S., Lesslauer W., Kollias G., Pfizenmaier K. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell. 1995 Dec 1;83(5):793–802. doi: 10.1016/0092-8674(95)90192-2. [DOI] [PubMed] [Google Scholar]
  15. Grell M., Krammer P. H., Scheurich P. Segregation of APO-1/Fas antigen- and tumor necrosis factor receptor-mediated apoptosis. Eur J Immunol. 1994 Oct;24(10):2563–2566. doi: 10.1002/eji.1830241045. [DOI] [PubMed] [Google Scholar]
  16. Hiramatsu N., Hayashi N., Katayama K., Mochizuki K., Kawanishi Y., Kasahara A., Fusamoto H., Kamada T. Immunohistochemical detection of Fas antigen in liver tissue of patients with chronic hepatitis C. Hepatology. 1994 Jun;19(6):1354–1359. [PubMed] [Google Scholar]
  17. Hsu H., Xiong J., Goeddel D. V. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995 May 19;81(4):495–504. doi: 10.1016/0092-8674(95)90070-5. [DOI] [PubMed] [Google Scholar]
  18. Ikeda N., Mukaida N., Kaneko S., Fujioka N., Su S., Nariuchi H., Unoura M., Harada K., Nakanuma Y., Kobayashi K. Prevention of endotoxin-induced acute lethality in Propionibacterium acnes-primed rabbits by an antibody to leukocyte integrin beta 2 with concomitant reduction of cytokine production. Infect Immun. 1995 Dec;63(12):4812–4817. doi: 10.1128/iai.63.12.4812-4817.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kindler V., Sappino A. P., Grau G. E., Piguet P. F., Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989 Mar 10;56(5):731–740. doi: 10.1016/0092-8674(89)90676-4. [DOI] [PubMed] [Google Scholar]
  20. Leist M., Gantner F., Bohlinger I., Germann P. G., Tiegs G., Wendel A. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest. J Immunol. 1994 Aug 15;153(4):1778–1788. [PubMed] [Google Scholar]
  21. Leist M., Gantner F., Bohlinger I., Tiegs G., Germann P. G., Wendel A. Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models. Am J Pathol. 1995 May;146(5):1220–1234. [PMC free article] [PubMed] [Google Scholar]
  22. 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 Feb 1;154(3):1307–1316. [PubMed] [Google Scholar]
  23. Leist M., Gantner F., Künstle G., Bohlinger I., Tiegs G., Bluethmann H., Wendel A. The 55-kD tumor necrosis factor receptor and CD95 independently signal murine hepatocyte apoptosis and subsequent liver failure. Mol Med. 1996 Jan;2(1):109–124. [PMC free article] [PubMed] [Google Scholar]
  24. Mizoguchi Y., Sakagami Y., Kuboi H., Kobayashi K., Yano I. Effects of the polysaccharide chain of lipopolysaccharide in an experimental massive hepatic cell necrosis model. Biochem Biophys Res Commun. 1988 Sep 30;155(3):1305–1310. doi: 10.1016/s0006-291x(88)81283-x. [DOI] [PubMed] [Google Scholar]
  25. Nagakawa J., Hishinuma I., Hirota K., Miyamoto K., Yamanaka T., Tsukidate K., Katayama K., Yamatsu I. Involvement of tumor necrosis factor-alpha in the pathogenesis of activated macrophage-mediated hepatitis in mice. Gastroenterology. 1990 Sep;99(3):758–765. doi: 10.1016/0016-5085(90)90965-4. [DOI] [PubMed] [Google Scholar]
  26. Nagata S., Suda T. Fas and Fas ligand: lpr and gld mutations. Immunol Today. 1995 Jan;16(1):39–43. doi: 10.1016/0167-5699(95)80069-7. [DOI] [PubMed] [Google Scholar]
  27. Neumann B., Machleidt T., Lifka A., Pfeffer K., Vestweber D., Mak T. W., Holzmann B., Krönke M. Crucial role of 55-kilodalton TNF receptor in TNF-induced adhesion molecule expression and leukocyte organ infiltration. J Immunol. 1996 Feb 15;156(4):1587–1593. [PubMed] [Google Scholar]
  28. Ogasawara J., Watanabe-Fukunaga R., Adachi M., Matsuzawa A., Kasugai T., Kitamura Y., Itoh N., Suda T., Nagata S. Lethal effect of the anti-Fas antibody in mice. Nature. 1993 Aug 26;364(6440):806–809. doi: 10.1038/364806a0. [DOI] [PubMed] [Google Scholar]
  29. Orme I. M. Immunity to mycobacteria. Curr Opin Immunol. 1993 Aug;5(4):497–502. doi: 10.1016/0952-7915(93)90029-r. [DOI] [PubMed] [Google Scholar]
  30. Pfeffer K., Matsuyama T., Kündig T. M., Wakeham A., Kishihara K., Shahinian A., Wiegmann K., Ohashi P. S., Krönke M., Mak T. W. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell. 1993 May 7;73(3):457–467. doi: 10.1016/0092-8674(93)90134-c. [DOI] [PubMed] [Google Scholar]
  31. Rothe J., Lesslauer W., Lötscher H., Lang Y., Koebel P., Köntgen F., Althage A., Zinkernagel R., Steinmetz M., Bluethmann H. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature. 1993 Aug 26;364(6440):798–802. doi: 10.1038/364798a0. [DOI] [PubMed] [Google Scholar]
  32. Rothe M., Pan M. G., Henzel W. J., Ayres T. M., Goeddel D. V. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell. 1995 Dec 29;83(7):1243–1252. doi: 10.1016/0092-8674(95)90149-3. [DOI] [PubMed] [Google Scholar]
  33. Schulze-Osthoff K., Krammer P. H., Dröge W. Divergent signalling via APO-1/Fas and the TNF receptor, two homologous molecules involved in physiological cell death. EMBO J. 1994 Oct 3;13(19):4587–4596. doi: 10.1002/j.1460-2075.1994.tb06780.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Smith C. A., Farrah T., Goodwin R. G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell. 1994 Mar 25;76(6):959–962. doi: 10.1016/0092-8674(94)90372-7. [DOI] [PubMed] [Google Scholar]
  35. Tanaka Y., Kobayashi K., Takahashi A., Arai I., Higuchi S., Otomo S., Habu S., Nishimura T. Inhibition of inflammatory liver injury by a monoclonal antibody against lymphocyte function-associated antigen-1. J Immunol. 1993 Nov 1;151(9):5088–5095. [PubMed] [Google Scholar]
  36. Tanner A. R., Keyhani A. H., Wright R. The influence of endotoxin in vitro on hepatic macrophage lysosomal enzyme release in different rat models of hepatic injury. Liver. 1983 Jun;3(3):151–160. doi: 10.1111/j.1600-0676.1983.tb00864.x. [DOI] [PubMed] [Google Scholar]
  37. Ulich T. R., Guo K. Z., Irwin B., Remick D. G., Davatelis G. N. Endotoxin-induced cytokine gene expression in vivo. II. Regulation of tumor necrosis factor and interleukin-1 alpha/beta expression and suppression. Am J Pathol. 1990 Nov;137(5):1173–1185. [PMC free article] [PubMed] [Google Scholar]
  38. Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10:411–452. doi: 10.1146/annurev.iy.10.040192.002211. [DOI] [PubMed] [Google Scholar]
  39. Wong G. H., Goeddel D. V. Fas antigen and p55 TNF receptor signal apoptosis through distinct pathways. J Immunol. 1994 Feb 15;152(4):1751–1755. [PubMed] [Google Scholar]
  40. Wyke R. J., Canalese J. C., Gimson A. E., Williams R. Bacteraemia in patients with fulminant hepatic failure. Liver. 1982 Mar;2(1):45–52. doi: 10.1111/j.1600-0676.1982.tb00177.x. [DOI] [PubMed] [Google Scholar]

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