Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 29, Pages 20927-20941Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.440115
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Funding
- Major State Basic Research Development Program of China [2009CB522506, 2013CB911102]
- National Natural Science Foundation of China [81271821]
- National Mega Project on Major Infectious Diseases Prevention [2012ZX10004503-004]
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Interleukin (IL)-32 has been recognized as a proinflammatory cytokine that participates in responses to viral infection. However, little is known about how IL-32 is induced in response to viral infection and the mechanisms of IL-32-mediated antiviral activities. We discovered that IL-32 is elevated by hepatitis B virus (HBV) infection both in vitro and in vivo and that HBV induced IL-32 expression at the level of both transcription and post-transcription. Furthermore, microRNA-29b was found to be a key factor in HBV-regulated IL-32 expression by directly targeting the mRNA 3'-untranslated region of IL-32. Antiviral analysis showed that IL-32 was not sufficient to alter HBV replication in HepG2.2.15 cells. To mimic the viremic phase of viral infection, freshly isolated peripheral blood mononuclear cells were treated with IL-32 gamma, the secretory isoform, and the supernatants were used for antiviral assays. Surprisingly, these supernatants exhibited extensive antiviral activity against multiplex viruses besides HBV. Thus, we speculated that the IL-32 gamma-treated peripheral blood mononuclear cells produced and secreted an unknown antiviral factor. Using antibody neutralization assays, we identified the factor as interferon (IFN)-lambda 1 and not IFN-alpha. Further studies indicated that IL-32 gamma effectively inhibited HBV replication in a hydrodynamic injection mouse model. Clinical data showed that elevated levels of IFN-lambda 1 both in serum and liver tissue of HBV patients were positively correlated to the increased levels of IL-32. Our results demonstrate that elevated IL-32 levels during viral infection mediate antiviral effects by stimulating the expression of IFN-lambda 1.
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