Varma Tushar K, Lin Cheng Y, Toliver-Kinsky Tracy E, Sherwood Edward R
Department of Anesthesiology, The University of Texas Medical Branch, Galveston 77555-0591, USA.
Clin Diagn Lab Immunol. 2002 May;9(3):530-43. doi: 10.1128/cdli.9.3.530-543.2002.
Gamma interferon (IFN-gamma) is an important mediator of endotoxin (lipopolysaccharide [LPS])-induced immune responses. However, the specific cell types that produce IFN-gamma in response to LPS and the cellular factors that regulate LPS-induced IFN-gamma production have not been fully determined. The present studies were undertaken to characterize the cell populations that produce IFN-gamma after LPS challenge in the spleens of mice and to determine the regulatory factors that modulate LPS-induced production of IFN-gamma. Our studies show that the levels of splenic IFN-gamma mRNA and protein production peak at 6 and 8 h, respectively, after systemic LPS challenge. Approximately 60% of IFN-gamma-producing cells are natural killer (NK) cells (CD3(-)DX5(+)) and 25% are NKT cells (CD3(+)DX5(+)). Most of the remaining IFN-gamma-producing cells are T cells (CD3(+)DX5(-)), macrophages, and dendritic cells. Functionally, interleukin-12 (IL-12) is the major IFN-gamma-stimulating factor after LPS challenge, with costimulation provided by IL-15, IL-18, and B7 proteins. IL-10 is a major inhibitor of LPS-induced IFN-gamma production. Unlike intact heat-killed gram-negative and gram-positive bacteria, the class II major histocompatibility complex did not play a functional role in LPS-induced IFN-gamma production. LPS is a potent stimulus for splenic IL-10, IL-12 p40, and IL-15 mRNA expression, whereas IL-12 p35 and IL-18 mRNAs, as well as B7 proteins, are constitutively expressed in the mouse spleen. Of the factors studied, IL-18 serves as the most potent costimulus with IL-12 for IFN-gamma production, followed by IL-15 and B7 proteins. These data demonstrate that NK cells and NKT cells are the most abundant IFN-gamma-producing cells in the mouse spleen after LPS challenge and that IL-10 and IL-12 are key functional regulators of LPS-induced IFN-gamma production.
γ干扰素（IFN-γ）是内毒素（脂多糖[LPS]）诱导的免疫反应的重要介质。然而，响应LPS产生IFN-γ的特定细胞类型以及调节LPS诱导的IFN-γ产生的细胞因子尚未完全确定。本研究旨在表征小鼠脾脏中LPS刺激后产生IFN-γ的细胞群体，并确定调节LPS诱导的IFN-γ产生的调节因子。我们的研究表明，全身LPS刺激后，脾脏IFN-γ mRNA水平和蛋白质产生分别在6小时和8小时达到峰值。约60%产生IFN-γ的细胞是自然杀伤（NK）细胞（CD3(-)DX5(+)），25%是NKT细胞（CD3(+)DX5(+)）。其余产生IFN-γ的细胞大多是T细胞（CD3(+)DX5(-)）、巨噬细胞和树突状细胞。在功能上，白细胞介素-12（IL-12）是LPS刺激后主要的IFN-γ刺激因子，IL-15、IL-18和B7蛋白提供共刺激。IL-10是LPS诱导的IFN-γ产生的主要抑制剂。与完整的热灭活革兰氏阴性菌和革兰氏阳性菌不同，II类主要组织相容性复合体在LPS诱导的IFN-γ产生中不发挥功能作用。LPS是脾脏IL-10、IL-12 p40和IL-15 mRNA表达的有效刺激物，而IL-12 p35和IL-18 mRNA以及B7蛋白在小鼠脾脏中组成性表达。在所研究的因子中，IL-18是与IL-12共同刺激产生IFN-γ最有效的因子，其次是IL-15和B7蛋白。这些数据表明，NK细胞和NKT细胞是LPS刺激后小鼠脾脏中产生IFN-γ最丰富的细胞，并且IL-10和IL-12是LPS诱导的IFN-γ产生的关键功能调节因子。
