Intracellular interleukin-32\u03b3 mediates antiviral activity of cytokines against hepatitis B virus

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

doi:10.1038/s41467-018-05782-5

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.

Highlights

Cytokines are involved in early host defense against pathogen infections
As the expression of liver-enriched transcription factors is regulated by the mitogenactivated protein kinases (MAPKs) signaling pathway[26,36], we investigated whether this pathway is involved in IL-32γ-mediated downregulation of HNF1α and HNF4α
As we showed that IL-32-mediated inhibition of hepatitis B virus (HBV) replication is an intracellular event, if there is no paracrine effect, the IL-32 and HBV plasmids transduced by hydrodynamic injection should be mostly co-localized in same hepatocytes

Summary

Introduction

Tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) have critical functions in non-cytopathic elimination of hepatitis B virus (HBV) in hepatocytes. 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. IL-32 was discovered as a proinflammatory cytokine that is secreted from natural killer (NK) cells and activates mitogenactivated protein kinases (MAPKs) and NF-κB signaling pathways[12,13]. It is produced by various epithelial and immune cells such as T lymphocytes, NK cells, and monocytes. The direct antiviral action of IL-32 in hepatocytes has not been demonstrated

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Conclusion