Grunfeld C, Soued M, Adi S, Moser A H, Fiers W, Dinarello C A, Feingold K R
Department of Medicine, University of California, San Francisco.
Cancer Res. 1991 Jun 1;51(11):2803-7.
Multiple cytokines stimulate hepatic lipogenesis in rodents. We have previously shown that lipogenic cytokines can be divided into 2 classes by their mechanism of action and their synergistic interactions. We now report the effects of interleukin 4, a cytokine known to inhibit the synthesis and action of other cytokines. Interleukin 4 by itself did not alter hepatic lipogenesis. However, interleukin 4 inhibited the characteristic stimulation of hepatic lipogenesis that is seen with tumor necrosis factor, interleukin 1, and interleukin 6. These 3 cytokines stimulate hepatic lipogenesis by the same mechanism, increasing hepatic levels of citrate, a key allosteric activator of acetyl CoA carboxylase, the rate-limiting enzyme of fatty acid synthesis. Interleukin 4 blocks the ability of tumor necrosis factor to increase hepatic citrate. In contrast, interleukin 4 does not block the stimulation of hepatic lipogenesis by interferon-alpha, a cytokine that increases hepatic lipogenesis by a mechanism other than increasing hepatic citrate levels. These results demonstrate that interleukin 4 can inhibit the metabolic action of selected cytokines, which provides strong support for our proposal that lipogenic cytokines operate through 2 distinct mechanisms of action and can therefore be divided into 2 separate classes based on their interactions. These results also emphasize the multiple relationships between the immune response and lipid metabolism.
多种细胞因子可刺激啮齿动物的肝脏脂肪生成。我们之前已经表明，脂肪生成细胞因子可根据其作用机制和协同相互作用分为两类。我们现在报告白细胞介素4的作用，白细胞介素4是一种已知可抑制其他细胞因子合成和作用的细胞因子。白细胞介素4本身不会改变肝脏脂肪生成。然而，白细胞介素4可抑制肿瘤坏死因子、白细胞介素1和白细胞介素6所引起的肝脏脂肪生成的特征性刺激。这三种细胞因子通过相同的机制刺激肝脏脂肪生成，即增加柠檬酸在肝脏中的水平，柠檬酸是乙酰辅酶A羧化酶的关键变构激活剂，而乙酰辅酶A羧化酶是脂肪酸合成的限速酶。白细胞介素4可阻断肿瘤坏死因子增加肝脏柠檬酸的能力。相比之下，白细胞介素4不会阻断干扰素-α对肝脏脂肪生成的刺激，干扰素-α通过增加肝脏柠檬酸水平以外的机制增加肝脏脂肪生成。这些结果表明，白细胞介素4可抑制特定细胞因子的代谢作用，这为我们提出的脂肪生成细胞因子通过两种不同作用机制发挥作用并因此可根据其相互作用分为两类的提议提供了有力支持。这些结果还强调了免疫反应与脂质代谢之间的多种关系。
