Gamma Interferon Augments Macrophage Activation by Lipopolysaccharide by Two Distinct Mechanisms, at the Signal Transduction Level and via an Autocrine Mechanism Involving Tumor Necrosis Factor Alpha and Interleukin-1

AUTOR(ES)

Held, Thomas K.

FONTE

American Society for Microbiology

RESUMO

When given in the presence of gamma interferon (IFN-γ), otherwise nontoxic doses of lipopolysaccharide (LPS or endotoxin) become highly lethal for mice. The mechanisms of this synergistic toxicity are not known. We considered the possibility that an interaction between the LPS-induced NF-κB and IFN-γ-induced JAK-STAT pathways at the pretranscriptional level may enhance the LPS-induced signals. To test this hypothesis, we incubated murine macrophage RAW 264.7 cells with IFN-γ for 2 h before addition of different doses of LPS. Consistent with the synergistic induction of inducible nitric oxide synthase mRNA and nitric oxide production by a combination of LPS and IFN-γ, IFN-γ strongly augmented LPS-induced NF-κB activation and accelerated the binding of NF-κB to DNA to as early as 5 min. In agreement with this, IFN-γ pretreatment promoted rapid degradation of IκB-α but not that of IκB-β. Inhibition of protein synthesis during IFN-γ treatment suppressed LPS-initiated NF-κB binding. A rapidly induced protein appeared to be involved in IFN-γ priming. Preincubation of cells with antibodies to tumor necrosis factor alpha or the interleukin-1 receptor partially reduced the priming effect of IFN-γ. In a complementary manner, LPS enhanced the activation of signal-transducing activator of transcription 1 by IFN-γ. These data suggest novel mechanisms for the synergy between IFN-γ and LPS by which they cross-regulate the signal-transducing molecules. Through this mechanism, IFN-γ may transform a given dose of LPS into a lethal stimulus capable of causing sepsis. It may also serve a beneficial purpose by enabling the host to respond quickly to relatively low doses of LPS and thereby activating antibacterial defenses.

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