Exogenous Interferon-γ Induces Endogenous Synthesis of Interferon-α and -β by Murine Macrophages for Induction of Nitric Oxide Synthase

Abstract

Murine macrophages (MФ) are activated either by interferon-γ (IFN-γ) or interferon-α/β (IFN-α/β) in combination with bacterial lipopolysaccharide (LPS) to induce synthesis of tumor necrosis factor α (TNF-α) and nitric oxide synthase (iNOS) mRNA synthesis for generation of tumor cytotoxic nitric oxide (NO). In the present study, the effect of exogenous IFN-γ on the induction of endogenous mRNA synthesis and secretion of IFN-α/β by murine MФ was investigated. Neutralizing antibodies to IFN-α/β reversed TNF-α and NOS mRNA synthesis, as well as nitric oxide (NO)-mediated tumor cytotoxicity. Quantitative reverse transcription polymerase chain reaction (RT-PCR) revealed that treatment of MФ with IFN-γ induced increases in both IFN-α and IFN-β mRNA synthesis by approximately 2-fold and 10-fold, respectively, which corresponded to a 2-fold increase in secretion of IFN-α/β by ELISA. These data indicate that exogenous IFN-γ induces endogenous synthesis and secretion of IFN-α/β by MФ, which appears to act in concert with endogenously synthesized TNF-α for the autocrine induction of NOS mRNA synthesis.