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Virus Res. 2003 Nov;97(2):117-26.

Active and inactive influenza virus induction of tumor necrosis factor-alpha and nitric oxide in J774.1 murine macrophages: modulation by interferon-gamma and failure to induce apoptosis.

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  • 1Radiation Pathophysiology and Toxicology Department, Armed Forces Radiobiology Research Institute, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.

Abstract

Infection of J774.1 murine macrophages by influenza A virus (IAV) induces two major responses, production of host defense molecules and death by apoptosis. We investigated whether induction of two cytotoxic compounds, tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), directly caused IAV-induced apoptosis, and whether induction could be modulated by interferon-gamma (IFN-gamma) or the replication competence of the virus. Live IAV potently induced production of both TNF-alpha and NO, but UV inactivated virus was a poor inducer of both molecules. When cells were pre-treated with IFN-gamma, inactive IAV became as effective an inducer of NO, but not TNF-alpha, as live IAV. Amantadine, which antagonizes viral entry and replication, partly inhibited TNF-alpha and NO production in unprimed cells, but did not inhibit NO in IFN-gamma primed cells. IAV-induced cytotoxicity was not due to the induction of TNF-alpha or NO. Cells were insensitive to either TNF-alpha-containing supernatants or to recombinant TNF-alpha. Anti-TNF-alpha antibody did not protect cells from IAV-induced cell death, and anti-oxidants that inhibited TNF-alpha production also failed to increase cell survival. Inhibitors of NO production did not protect from IAV-induced cell death, either alone or in combination with superoxide dismutase (SOD). We conclude that, even though IAV was a potent inducer of TNF-alpha and NO in macrophages, IAV-induced apoptosis was not mediated directly by them. Importantly, viral replication was not required for the induction of TNF-alpha or NO, and the action of inactive IAV could be potentiated by IFN-gamma.

PMID:
14602203
[PubMed - indexed for MEDLINE]
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