Endogenous interferon-γ induced by bacterial lipopolysaccbaride ; its production mechanism and roles as a mediator

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Host responses to bacterial lipopolysaccharide (LPS) are mediated by production of various mediators such as tumor necrosis factor (TNF), interleukin (IL)-6 and nitric oxide (NO). Interferon (IFN)-γ, which plays important roles in immune system, is detectable in vivo in the sera of LPS-injected animals but its induction mechanisms by LPS in vitro and its roles as an LPS mediator have not been well understood.Mouse peritoneal exudate cells (PEC) were cultured and stimulated with LPS for induction of mediators. In the presence of anti-IFN-γ, NO production in the PEC culture was remarkably suppressed but production of TNF and IL-6 was scarcely suppressed. Besides anti-IFN-γ, various antibodies against LPS mediators were examined and found that anti-IL-12 and anti-IL-18 showed suppressivc effect on LPS-induced production of NO and IFN-γ, and that these antibodies in synergy showed strong suppression. These cytokines, known as IFN-γ-inducing cytokines, stimulated in synergy the PEC for production of IFN-γ and NO. Macrophage population in the PEC prepared as adherent cells responded well to LPS for IL-12 production but weakly for production of IFN-γ and NO. The macrophages also responded well to IFN-γ for NO production. For production of IFN-γ by stimulation with LPS or IL12+IL18, non-adherent cells in the PEC culture were required. Considering these results all together, a pathway trough the production of intermediates such as IL-12 and IL-18 by macrophages that stimulate non-adherent cells for production of IFN-γ was revealed to play a main role in the LPS-induced IFN-γ production and the IFN-γ contributed largely to production of NO by macrophages but scarcely to production of TNF and IL-6.