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

宿主对细菌脂多糖(LPS)的反应是通过产生多种介质如肿瘤坏死因子(TNF)、白介素6(IL)和一氧化氮(NO)来实现的。干扰素-γ在免疫系统中起重要作用，在体内可在注射内毒素的动物血清中检测到，但其体外诱导机制及其作为内毒素介质的作用尚不清楚。在干扰素-γ抗体存在下，培养的人脐静脉内皮细胞中NO的产生受到明显抑制，但对肿瘤坏死因子和IL-6的产生几乎没有抑制作用。除抗干扰素-γ外，还检测了多种抗脂多糖介体的抗体，发现抗IL-12和抗IL-18对脂多糖诱导的NO和干扰素-γ的产生有抑制作用，且这些抗体协同作用表现出很强的抑制作用。这些细胞因子被称为干扰素-γ诱导细胞因子，它们协同刺激肺内皮细胞产生干扰素-γ和一氧化氮。黏附细胞的巨噬细胞群对内毒素刺激产生IL-12反应良好，但对干扰素-γ和NO的产生反应较弱。巨噬细胞对干扰素-γ产生NO的反应也很好。若要在脂多糖或IL12+IL18刺激下产生干扰素-γ，则需要在培养上清中加入非贴壁细胞。综上所述，巨噬细胞产生IL-12和IL-18等中间产物刺激非黏附细胞产生干扰素-γ的途径在脂多糖诱导的干扰素-γ的产生中起主要作用，而干扰素-γ对巨噬细胞产生NO起主要作用，但对肿瘤坏死因子和IL-6的产生几乎没有贡献。

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.