Hunter C A, Chizzonite R, Remington J S
Department of Immunology and Infectious Disease, Palo Alto Medical Foundation, CA 94301, USA.
J Immunol. 1995 Nov 1;155(9):4347-54.
Mice with the severe combined immunodeficiency (SCID) possess an IFN-gamma-dependent mechanism of resistance to the intracellular pathogens Toxoplasma gondii and Listeria monocytogenes that is dependent on IL-12-induced production of IFN-gamma by NK cells. In this report we demonstrate that IL-1 beta is required for IL-12 to stimulate production of IFN-gamma by NK cells, and that IL-1 is important in IL-12-mediated resistance to T. gondii in vivo. Stimulation of SCID mouse splenocytes with tachyzoites of T. gondii resulted in production of IFN-gamma. Addition of neutralizing Ab specific for IL-1 beta to these cultures inhibited completely the production of IFN-gamma. Similar results were obtained when LPS or L. monocytogenes were used to stimulate production of IFN-gamma by SCID mouse splenocytes. Addition of a neutralizing Ab to IL-1 alpha did not affect production of IFN-gamma by SCID mouse splenocytes stimulated with T. gondii, L. monocytogenes, or LPS. Stimulation of SCID mouse splenocytes with IL-1 beta or IL-1 alpha did not result in production of IFN-gamma but enhanced remarkably the ability of T. gondii or IL-12 to stimulate production of IFN-gamma. Furthermore, production of IFN-gamma by SCID mouse splenocytes stimulated with IL-12 plus TNF-alpha was completely ablated by anti-IL-1 beta, but not by anti-IL-1 alpha. Analysis of the culture supernatants of spleen cells from SCID mice stimulated with T. gondii or IL-12 plus TNF-alpha detected low levels of IL-1 beta; addition of a neutralizing Ab to IFN-gamma resulted in a 5- to 10-fold increase in levels of IL-1 beta. Furthermore, stimulation of SCID mouse splenocytes with IL-12, in the presence of anti-IFN-gamma, resulted in an increase in detectable levels of IL-1 beta. To determine the in vivo relevance of our in vitro data, SCID mice were infected with T. gondii and treated with IL-12 alone or IL-12 in combination with an Ab specific for the type I IL-1 receptor. This Ab reduced production of IFN-gamma by SCID mouse splenocytes stimulated with either T. gondii, LPS, L. monocytogenes, or IL-12 plus IL-1 beta. In vivo administration of this Ab antagonized significantly the ability of exogenous IL-12 to delay the time to death of SCID mice infected with T. gondii.(ABSTRACT TRUNCATED AT 400 WORDS)
患有严重联合免疫缺陷（SCID）的小鼠具有一种依赖干扰素-γ的机制来抵抗细胞内病原体刚地弓形虫和单核细胞增生李斯特菌，该机制依赖于白细胞介素-12诱导自然杀伤（NK）细胞产生干扰素-γ。在本报告中，我们证明白细胞介素-1β是白细胞介素-12刺激NK细胞产生干扰素-γ所必需的，并且白细胞介素-1在白细胞介素-12介导的体内抗刚地弓形虫感染中起重要作用。用刚地弓形虫速殖子刺激SCID小鼠脾细胞可导致干扰素-γ的产生。向这些培养物中加入针对白细胞介素-1β的中和抗体可完全抑制干扰素-γ的产生。当使用脂多糖或单核细胞增生李斯特菌刺激SCID小鼠脾细胞产生干扰素-γ时，也获得了类似结果。向白细胞介素-1α中加入中和抗体并不影响用刚地弓形虫、单核细胞增生李斯特菌或脂多糖刺激的SCID小鼠脾细胞产生干扰素-γ。用白细胞介素-1β或白细胞介素-1α刺激SCID小鼠脾细胞不会导致干扰素-γ的产生，但能显著增强刚地弓形虫或白细胞介素-12刺激产生干扰素-γ的能力。此外，用白细胞介素-12加肿瘤坏死因子-α刺激的SCID小鼠脾细胞产生的干扰素-γ被抗白细胞介素-1β完全消除，但抗白细胞介素-1α则无此作用。分析用刚地弓形虫或白细胞介素-12加肿瘤坏死因子-α刺激的SCID小鼠脾细胞培养上清液，检测到低水平的白细胞介素-1β；向干扰素-γ中加入中和抗体可使白细胞介素-1β水平增加5至10倍。此外，在存在抗干扰素-γ的情况下，用白细胞介素-12刺激SCID小鼠脾细胞会导致可检测到的白细胞介素-1β水平增加。为了确定我们体外数据在体内的相关性，用刚地弓形虫感染SCID小鼠，并单独用白细胞介素-12或白细胞介素-12与I型白细胞介素-1受体特异性抗体联合治疗。该抗体可降低用刚地弓形虫、脂多糖、单核细胞增生李斯特菌或白细胞介素-12加白细胞介素-1β刺激的SCID小鼠脾细胞产生的干扰素-γ。在体内给予该抗体可显著拮抗外源性白细胞介素-12延迟感染刚地弓形虫的SCID小鼠死亡时间的能力。（摘要截短至400字）
