Interleukin 4 inhibits stimulation of hepatic lipogenesis by tumor necrosis factor, interleukin 1, and interleukin 6 but not by interferon-alpha.
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.
Grunfeld
C
C
Department of Medicine, University of California, San Francisco.
Soued
M
M
Adi
S
S
Moser
A H
AH
Fiers
W
W
Dinarello
C A
CA
Feingold
K R
KR
D000818:Animals; D007370:Interferon Type I / Q000037:antagonists & inhibitors; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D015847:Interleukin-4 / Q000494:pharmacology*; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D000093242:Interleukin-6 Inhibitors
D007370:Interferon Type I; D007375:Interleukin-1; D015847:Interleukin-4; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors