Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice

Won Il Jeong, Ogyi Park, Yang Gun Suh, Jin Seok Byun, So Young Park, Earl Choi, Ja Kyung Kim, Hyojin Ko, Hua Wang, Andrew M. Miller, Bin Gao

Research output: Contribution to journalArticle

Abstract

Activation of innate immunity (natural killer [NK] cell/interferon-γ [IFN-γ]) has been shown to play an important role in antiviral and antitumor defenses as well as antifibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2-week or a 10-week carbon tetrachloride (CCl 4) challenge, respectively. Injection of polyinosinic-polycytidylic acid (poly I:C) or IFN-γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2-week CCl 4 model. Such activation was diminished in the 10-week CCl 4 model. Consistent with these findings, the inhibitory effect of poly I:C and IFN-γ on liver fibrosis was markedly reduced in the 10-week versus the 2-week CCl 4 model. In vitro coculture experiments demonstrated that 4-day cultured (early activated) HSCs induce NK cell activation via an NK group 2 member D/retinoic acid-induced early gene 1-dependent mechanism. Such activation was reduced when cocultured with 8-day cultured (intermediately activated) HSCs due to the production of transforming growth factor-β (TGF-β) by HSCs. Moreover, early activated HSCs were sensitive, whereas intermediately activated HSCs were resistant to IFN-γ-mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN-γ inhibition of cell proliferation in intermediately activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN-γ signaling and functioning, whereas production of TGF-β by HSCs inhibited NK cell function and cytotoxicity against HSCs. Conclusion: The antifibrogenic effects of NK cell/IFN-γ are suppressed during advanced liver injury, which is likely due to increased production of TGF-β and expression of SOCS1 in intermediately activated HSCs.

Original languageEnglish (US)
Pages (from-to)1373-1382
Number of pages10
JournalHepatology
Volume53
Issue number4
DOIs
StatePublished - Apr 2011
Externally publishedYes

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Hepatic Stellate Cells
Innate Immunity
Natural Killer Cells
Liver Cirrhosis
Interferons
Transforming Growth Factors
Cytokines
Cell Proliferation
Poly C
Poly I-C
Carbon Tetrachloride
Liver
Wounds and Injuries
Coculture Techniques
Tretinoin
Vitamin A
Genes
Antiviral Agents

ASJC Scopus subject areas

  • Hepatology

Cite this

Jeong, W. I., Park, O., Suh, Y. G., Byun, J. S., Park, S. Y., Choi, E., ... Gao, B. (2011). Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice. Hepatology, 53(4), 1373-1382. https://doi.org/10.1002/hep.24190

Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice. / Jeong, Won Il; Park, Ogyi; Suh, Yang Gun; Byun, Jin Seok; Park, So Young; Choi, Earl; Kim, Ja Kyung; Ko, Hyojin; Wang, Hua; Miller, Andrew M.; Gao, Bin.

In: Hepatology, Vol. 53, No. 4, 04.2011, p. 1373-1382.

Research output: Contribution to journalArticle

Jeong, WI, Park, O, Suh, YG, Byun, JS, Park, SY, Choi, E, Kim, JK, Ko, H, Wang, H, Miller, AM & Gao, B 2011, 'Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice', Hepatology, vol. 53, no. 4, pp. 1373-1382. https://doi.org/10.1002/hep.24190
Jeong, Won Il ; Park, Ogyi ; Suh, Yang Gun ; Byun, Jin Seok ; Park, So Young ; Choi, Earl ; Kim, Ja Kyung ; Ko, Hyojin ; Wang, Hua ; Miller, Andrew M. ; Gao, Bin. / Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice. In: Hepatology. 2011 ; Vol. 53, No. 4. pp. 1373-1382.
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AU - Park, Ogyi

AU - Suh, Yang Gun

AU - Byun, Jin Seok

AU - Park, So Young

AU - Choi, Earl

AU - Kim, Ja Kyung

AU - Ko, Hyojin

AU - Wang, Hua

AU - Miller, Andrew M.

AU - Gao, Bin

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N2 - Activation of innate immunity (natural killer [NK] cell/interferon-γ [IFN-γ]) has been shown to play an important role in antiviral and antitumor defenses as well as antifibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2-week or a 10-week carbon tetrachloride (CCl 4) challenge, respectively. Injection of polyinosinic-polycytidylic acid (poly I:C) or IFN-γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2-week CCl 4 model. Such activation was diminished in the 10-week CCl 4 model. Consistent with these findings, the inhibitory effect of poly I:C and IFN-γ on liver fibrosis was markedly reduced in the 10-week versus the 2-week CCl 4 model. In vitro coculture experiments demonstrated that 4-day cultured (early activated) HSCs induce NK cell activation via an NK group 2 member D/retinoic acid-induced early gene 1-dependent mechanism. Such activation was reduced when cocultured with 8-day cultured (intermediately activated) HSCs due to the production of transforming growth factor-β (TGF-β) by HSCs. Moreover, early activated HSCs were sensitive, whereas intermediately activated HSCs were resistant to IFN-γ-mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN-γ inhibition of cell proliferation in intermediately activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN-γ signaling and functioning, whereas production of TGF-β by HSCs inhibited NK cell function and cytotoxicity against HSCs. Conclusion: The antifibrogenic effects of NK cell/IFN-γ are suppressed during advanced liver injury, which is likely due to increased production of TGF-β and expression of SOCS1 in intermediately activated HSCs.

AB - Activation of innate immunity (natural killer [NK] cell/interferon-γ [IFN-γ]) has been shown to play an important role in antiviral and antitumor defenses as well as antifibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2-week or a 10-week carbon tetrachloride (CCl 4) challenge, respectively. Injection of polyinosinic-polycytidylic acid (poly I:C) or IFN-γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2-week CCl 4 model. Such activation was diminished in the 10-week CCl 4 model. Consistent with these findings, the inhibitory effect of poly I:C and IFN-γ on liver fibrosis was markedly reduced in the 10-week versus the 2-week CCl 4 model. In vitro coculture experiments demonstrated that 4-day cultured (early activated) HSCs induce NK cell activation via an NK group 2 member D/retinoic acid-induced early gene 1-dependent mechanism. Such activation was reduced when cocultured with 8-day cultured (intermediately activated) HSCs due to the production of transforming growth factor-β (TGF-β) by HSCs. Moreover, early activated HSCs were sensitive, whereas intermediately activated HSCs were resistant to IFN-γ-mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN-γ inhibition of cell proliferation in intermediately activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN-γ signaling and functioning, whereas production of TGF-β by HSCs inhibited NK cell function and cytotoxicity against HSCs. Conclusion: The antifibrogenic effects of NK cell/IFN-γ are suppressed during advanced liver injury, which is likely due to increased production of TGF-β and expression of SOCS1 in intermediately activated HSCs.

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