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

doi:10.1016/j.jss.2011.07.053

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 journal › Article › peer-review

19 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 language	English
Pages (from-to)	293-300
Number of pages	8
Journal	Journal of Surgical Research
Volume	176
Issue number	1
DOIs	https://doi.org/10.1016/j.jss.2011.07.053
Publication status	Published - 2012 Jul

Keywords

adenovirus vector
interferon-γ
interleukin-18
liver allograft

ASJC Scopus subject areas

Surgery

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10.1016/j.jss.2011.07.053

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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, A. W., Yarmush, M. L., 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, 176(1), 293-300. https://doi.org/10.1016/j.jss.2011.07.053

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

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title = "Suppressive effects of interleukin-18 on liver function in rat liver allografts",

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.",

keywords = "adenovirus vector, interferon-γ, interleukin-18, liver allograft",

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

year = "2012",

month = jul,

doi = "10.1016/j.jss.2011.07.053",

language = "English",

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T1 - Suppressive effects of interleukin-18 on liver function in rat liver allografts

AU - Ono, Shigeshi

AU - Obara, Hideaki

AU - Takayanagi, Atsushi

AU - Tanabe, Minoru

AU - Kawachi, Shigeyuki

AU - Itano, Osamu

AU - Shinoda, Masahiro

AU - Kitago, Minoru

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

PY - 2012/7

Y1 - 2012/7

N2 - 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.

AB - 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.

KW - adenovirus vector

KW - interferon-γ

KW - interleukin-18

KW - liver allograft

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

Abstract

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