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Interleukin 4 Inhibits Stimulation of Hepatic Lipogenesis by Tumor Necrosis Factor, Interleukin 1, and Interleukin 6 but not by Interferon-¹

Department of Medicine, University of California—San Francisco, Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, California 94121 [C. G., M. S., S. A., A. H. M., K. R. F.]; Laboratory of Molecular Biology, State University of Gent, Belgium [W. F.]; and Department of Medicine, Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts 02111 [C. A. D.]

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-, 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.

¹ This work was supported by grants from the Department of Veterans Affairs and the NIH (DK-40990 and AI-15614). C. G. is a recipient of a Clinical Investigator Award from the Department of Veterans Affairs.

² To whom requests for reprints should be addressed at Metabolism Section (111F), Department of Veterans Affairs, Medical Center, 4150 Clement Street, San Francisco, CA 94121.

Received 12/19/90. Accepted 3/13/91.

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