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Differentiated Human Alveolar Type II Cells Secrete Antiviral IL-29 (IFN-1) in Response to Influenza A Infection¹

Jieru Wang^*, Rebecca Oberley-Deegan^*, Shuanglin Wang^*, Mrinalini Nikrad^*, C. Joel Funk^*, Kevan L. Hartshorn and Robert J. Mason^2,*

^* Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206; and Department of Hematology/Oncology, Boston University School of Medicine, Boston, MA 02118

Alveolar type II epithelial cells (ATIIs) are one of the primary targets for influenza A pneumonia. The lack of a culture system for maintaining differentiated ATIIs hinders our understanding of pulmonary innate immunity during viral infection. We studied influenza A virus (IAV)-induced innate immune responses in differentiated primary human ATIIs and alveolar macrophages (AMs). Our results indicate that ATIIs, but not AMs, support productive IAV infection. Viral infection elicited strong inflammatory chemokine and cytokine responses in ATIIs, including secretion of IL-8, IL-6, MCP-1, RANTES, and MIP-1β, but not TNF-, whereas AMs secreted TNF- as well as other cytokines in response to infection. Wild-type virus A/PR/8/34 induced a greater cytokine response than reassortant PR/8 virus, A/Phil/82, despite similar levels of replication. IAV infection increased mRNA expression of IFN genes IFN-β, IL-29 (IFN-1), and IL-28A (IFN-2). The major IFN protein secreted by type II cells was IL-29 and ATIIs appear to be a major resource for production of IL-29. Administration of IL-29 and IFN-β before infection significantly reduced the release of infectious viral particles and CXC and CC chemokines. IL-29 treatment of type II cells induced mRNA expression of antiviral genes MX1, OAS, and ISG56 but not IFN-β. IL-29 induced a dose-dependent decrease of viral nucleoprotein and an increase of antiviral genes but not IFN-β. These results suggest that IL-29 exerts IFN-β-independent protection in type II cells through direct activation of antiviral genes during IAV infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant HL-029891, the Parker B. Francis Fellowship Foundation, U.S. Army Medical Research and Material Command Grant W81XWH-07-1-550; and the ExxonMobil Foundation.

² Address correspondence and reprint requests to Dr. Robert J. Mason, Department of Medicine, Smith Building, A459, National Jewish Medical and Research Center, Denver, CO 80206. E-mail address: masonb{at}NSHealth.org

³ Abbreviations used in this paper: IAV, influenza A virus; HA, hemagglutinin; N, neuraminidase; ATII, alveolar type II cell; AM, alveolar macrophage; MOI, multiplicity of infection; hpi, hour postinoculation; MDCK, Madin-Darby canine kidney cell; NP, nucleoprotein; IP-10, IFN-induced protein 10.

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