Suppressive effects of interleukin-18 on liver function in rat liver allografts

Shigeshi Ono, Hideaki Obara, Atsushi Takayanagi, Minoru Tanabe, Shigeyuki Kawachi, Osamu Itano, Masahiro Shinoda, Minoru Kitago, Taizo Hibi, Tomohiro Chiba, Wenlin Du, Kenji Matsumoto, Arno W. Tilles, Martin L. Yarmush, Sadakazu Aiso, Nobuyoshi Shimizu, Michiie Sakamoto, Yuko Kitagawa

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: Interleukin-18 (IL-18) is a potent proinflammatory cytokine that augments both innate and acquired immune responses. It is also a crucial regulator of lymphocyte production of interferon-γ (IFN-γ), which can promote acute cellular rejection of transplanted solid organs. Methods: To evaluate the role of IL-18 in liver transplantation, we constructed an adenoviral vector encoding IL-18 binding protein (Adex-IL18bp), which specifically suppressed the biologic activity of IL-18, and examined the effect of this suppression on liver allografts by using a high-responder rat model (ACI to Lewis) of orthotopic liver transplantation (OLTx). Donor rats were given one intravenous injection of Adex-IL18bp or Adex-LacZ (control vector) 2 d before OLTx. Results: Seven days after OLTx, overexpression of IL-18bp resulting from the adenovirus gene transfer was associated with significantly decreased serum alanine aminotransferase levels and less histologic hepatic injury in recipient rats with Adex-IL18bp-pretreated donors compared with Adex-LacZ controls. Adex-IL18bp pretreatment also significantly prolonged rat/allograft survival, inhibited expression of IFN-γ, and reduced levels (versus control values) of both CXCL10 and CX3CL1, which can be induced by IFN-γ. Conclusion: These results suggest that IL-18 has an important role in liver allograft rejection through IFN-γ and chemokines and that specific suppression of IL-18 may improve liver function early after transplantation.

Original languageEnglish
Pages (from-to)293-300
Number of pages8
JournalJournal of Surgical Research
Volume176
Issue number1
DOIs
Publication statusPublished - 2012 Jul 1
Externally publishedYes

Keywords

  • adenovirus vector
  • interferon-γ
  • interleukin-18
  • liver allograft

ASJC Scopus subject areas

  • Surgery

Cite this

Ono, S., Obara, H., Takayanagi, A., Tanabe, M., Kawachi, S., Itano, O., ... Kitagawa, Y. (2012). Suppressive effects of interleukin-18 on liver function in rat liver allografts. Journal of Surgical Research, 176(1), 293-300. https://doi.org/10.1016/j.jss.2011.07.053

Suppressive effects of interleukin-18 on liver function in rat liver allografts. / Ono, Shigeshi; Obara, Hideaki; Takayanagi, Atsushi; Tanabe, Minoru; Kawachi, Shigeyuki; Itano, Osamu; Shinoda, Masahiro; Kitago, Minoru; Hibi, Taizo; Chiba, Tomohiro; Du, Wenlin; Matsumoto, Kenji; Tilles, Arno W.; Yarmush, Martin L.; Aiso, Sadakazu; Shimizu, Nobuyoshi; Sakamoto, Michiie; Kitagawa, Yuko.

In: Journal of Surgical Research, Vol. 176, No. 1, 01.07.2012, p. 293-300.

Research output: Contribution to journalArticle

Ono, S, Obara, H, Takayanagi, A, Tanabe, M, Kawachi, S, Itano, O, Shinoda, M, Kitago, M, Hibi, T, Chiba, T, Du, W, Matsumoto, K, Tilles, AW, Yarmush, ML, Aiso, S, Shimizu, N, Sakamoto, M & Kitagawa, Y 2012, 'Suppressive effects of interleukin-18 on liver function in rat liver allografts', Journal of Surgical Research, vol. 176, no. 1, pp. 293-300. https://doi.org/10.1016/j.jss.2011.07.053
Ono, Shigeshi ; Obara, Hideaki ; Takayanagi, Atsushi ; Tanabe, Minoru ; Kawachi, Shigeyuki ; Itano, Osamu ; Shinoda, Masahiro ; Kitago, Minoru ; Hibi, Taizo ; Chiba, Tomohiro ; Du, Wenlin ; Matsumoto, Kenji ; Tilles, Arno W. ; Yarmush, Martin L. ; Aiso, Sadakazu ; Shimizu, Nobuyoshi ; Sakamoto, Michiie ; Kitagawa, Yuko. / Suppressive effects of interleukin-18 on liver function in rat liver allografts. In: Journal of Surgical Research. 2012 ; Vol. 176, No. 1. pp. 293-300.
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abstract = "Background: Interleukin-18 (IL-18) is a potent proinflammatory cytokine that augments both innate and acquired immune responses. It is also a crucial regulator of lymphocyte production of interferon-γ (IFN-γ), which can promote acute cellular rejection of transplanted solid organs. Methods: To evaluate the role of IL-18 in liver transplantation, we constructed an adenoviral vector encoding IL-18 binding protein (Adex-IL18bp), which specifically suppressed the biologic activity of IL-18, and examined the effect of this suppression on liver allografts by using a high-responder rat model (ACI to Lewis) of orthotopic liver transplantation (OLTx). Donor rats were given one intravenous injection of Adex-IL18bp or Adex-LacZ (control vector) 2 d before OLTx. Results: Seven days after OLTx, overexpression of IL-18bp resulting from the adenovirus gene transfer was associated with significantly decreased serum alanine aminotransferase levels and less histologic hepatic injury in recipient rats with Adex-IL18bp-pretreated donors compared with Adex-LacZ controls. Adex-IL18bp pretreatment also significantly prolonged rat/allograft survival, inhibited expression of IFN-γ, and reduced levels (versus control values) of both CXCL10 and CX3CL1, which can be induced by IFN-γ. Conclusion: These results suggest that IL-18 has an important role in liver allograft rejection through IFN-γ and chemokines and that specific suppression of IL-18 may improve liver function early after transplantation.",
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AU - Obara, Hideaki

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AU - Kawachi, Shigeyuki

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AU - Shinoda, Masahiro

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AU - Hibi, Taizo

AU - Chiba, Tomohiro

AU - Du, Wenlin

AU - Matsumoto, Kenji

AU - Tilles, Arno W.

AU - Yarmush, Martin L.

AU - Aiso, Sadakazu

AU - Shimizu, Nobuyoshi

AU - Sakamoto, Michiie

AU - Kitagawa, Yuko

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