Intracellular interleukin-32γ mediates antiviral activity of cytokines against hepatitis B virus

Doo Hyun Kim; Eun Sook Park; Ah Ram Lee; Soree Park; Yong Kwang Park; Sung Hyun Ahn; Hong Seok Kang; Ju Hee Won; Yea Na Ha; Byeong June Jae; Dong Sik Kim; Woo Chang Chung; Moon Jung Song; Kee Hwan Kim; Seung Hwa Park; Soo Hyun Kim; Kyun Hwan Kim

doi:10.1038/s41467-018-05782-5

Intracellular interleukin-32γ mediates antiviral activity of cytokines against hepatitis B virus

Doo Hyun Kim, Eun Sook Park, Ah Ram Lee, Soree Park, Yong Kwang Park, Sung Hyun Ahn, Hong Seok Kang, Ju Hee Won, Yea Na Ha, Byeong June Jae, Dong Sik Kim, Woo Chang Chung, Moon Jung Song, Kee Hwan Kim, Seung Hwa Park, Soo Hyun Kim, Kyun Hwan Kim

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39 Scopus citations

Abstract

Cytokines are involved in early host defense against pathogen infections. In particular, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) have critical functions in non-cytopathic elimination of hepatitis B virus (HBV) in hepatocytes. However, the molecular mechanisms and mediator molecules are largely unknown. Here we show that interleukin-32 (IL-32) is induced by TNF and IFN-γ in hepatocytes, and inhibits the replication of HBV by acting intracellularly to suppress HBV transcription and replication. The gamma isoform of IL-32 (IL-32γ) inhibits viral enhancer activities by downregulating liver-enriched transcription factors. Our data are validated in both an in vivo HBV mouse model and primary human hepatocytes. This study thus suggests that IL-32γ functions as intracellular effector in hepatocytes for suppressing HBV replication to implicate a possible mechanism of non-cytopathic viral clearance.

Original language	English
Article number	3284
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05782-5
State	Published - 1 Dec 2018

Bibliographical note

Funding Information:
This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (NRF-2017R1A2B3006335 and NRF-2016R1A5A2012284), and by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (No. HI17C0874).

Publisher Copyright:
© 2018, The Author(s).

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10.1038/s41467-018-05782-5

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Kim, D. H., Park, E. S., Lee, A. R., Park, S., Park, Y. K., Ahn, S. H., Kang, H. S., Won, J. H., Ha, Y. N., Jae, B. J., Kim, D. S., Chung, W. C., Song, M. J., Kim, K. H., Park, S. H., Kim, S. H., & Kim, K. H. (2018). Intracellular interleukin-32γ mediates antiviral activity of cytokines against hepatitis B virus. Nature Communications, 9(1), Article 3284. https://doi.org/10.1038/s41467-018-05782-5

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abstract = "Cytokines are involved in early host defense against pathogen infections. In particular, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) have critical functions in non-cytopathic elimination of hepatitis B virus (HBV) in hepatocytes. However, the molecular mechanisms and mediator molecules are largely unknown. Here we show that interleukin-32 (IL-32) is induced by TNF and IFN-γ in hepatocytes, and inhibits the replication of HBV by acting intracellularly to suppress HBV transcription and replication. The gamma isoform of IL-32 (IL-32γ) inhibits viral enhancer activities by downregulating liver-enriched transcription factors. Our data are validated in both an in vivo HBV mouse model and primary human hepatocytes. This study thus suggests that IL-32γ functions as intracellular effector in hepatocytes for suppressing HBV replication to implicate a possible mechanism of non-cytopathic viral clearance.",

author = "Kim, {Doo Hyun} and Park, {Eun Sook} and Lee, {Ah Ram} and Soree Park and Park, {Yong Kwang} and Ahn, {Sung Hyun} and Kang, {Hong Seok} and Won, {Ju Hee} and Ha, {Yea Na} and Jae, {Byeong June} and Kim, {Dong Sik} and Chung, {Woo Chang} and Song, {Moon Jung} and Kim, {Kee Hwan} and Park, {Seung Hwa} and Kim, {Soo Hyun} and Kim, {Kyun Hwan}",

note = "Funding Information: This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (NRF-2017R1A2B3006335 and NRF-2016R1A5A2012284), and by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (No. HI17C0874). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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AU - Park, Yong Kwang

AU - Ahn, Sung Hyun

AU - Kang, Hong Seok

AU - Won, Ju Hee

AU - Ha, Yea Na

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AU - Kim, Dong Sik

AU - Chung, Woo Chang

AU - Song, Moon Jung

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AU - Park, Seung Hwa

AU - Kim, Soo Hyun

AU - Kim, Kyun Hwan

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N2 - Cytokines are involved in early host defense against pathogen infections. In particular, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) have critical functions in non-cytopathic elimination of hepatitis B virus (HBV) in hepatocytes. However, the molecular mechanisms and mediator molecules are largely unknown. Here we show that interleukin-32 (IL-32) is induced by TNF and IFN-γ in hepatocytes, and inhibits the replication of HBV by acting intracellularly to suppress HBV transcription and replication. The gamma isoform of IL-32 (IL-32γ) inhibits viral enhancer activities by downregulating liver-enriched transcription factors. Our data are validated in both an in vivo HBV mouse model and primary human hepatocytes. This study thus suggests that IL-32γ functions as intracellular effector in hepatocytes for suppressing HBV replication to implicate a possible mechanism of non-cytopathic viral clearance.

AB - Cytokines are involved in early host defense against pathogen infections. In particular, tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) have critical functions in non-cytopathic elimination of hepatitis B virus (HBV) in hepatocytes. However, the molecular mechanisms and mediator molecules are largely unknown. Here we show that interleukin-32 (IL-32) is induced by TNF and IFN-γ in hepatocytes, and inhibits the replication of HBV by acting intracellularly to suppress HBV transcription and replication. The gamma isoform of IL-32 (IL-32γ) inhibits viral enhancer activities by downregulating liver-enriched transcription factors. Our data are validated in both an in vivo HBV mouse model and primary human hepatocytes. This study thus suggests that IL-32γ functions as intracellular effector in hepatocytes for suppressing HBV replication to implicate a possible mechanism of non-cytopathic viral clearance.

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Intracellular interleukin-32γ mediates antiviral activity of cytokines against hepatitis B virus

Abstract

Bibliographical note

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