Search for mediators of the lipogenic effects of tumor necrosis factor: potential role for interleukin 6.

The significance of potential second messengers as mediators of the metabolic effects of tumor necrosis factor (TNF) was explored by studying their role in stimulating hepatic lipogenesis. Platelet-activating factor and prostaglandins have previously been suggested to mediate some of the toxic effects of TNF. An inhibitor of platelet-activating factor (WEB 2086) and two inhibitors of the synthesis of prostaglandins (ibuprofen and aspirin) had no effect on the ability of TNF to increase hepatic lipogenesis or serum triglyceride levels in the rat. Another inhibitor of the toxic effects of TNF, pentoxifylline, also had no effect on lipid metabolism in the rat. Catecholamines are increased after TNF administration, but alpha- and beta-adrenergic blockade did not prevent the lipogenic effects of TNF. However, interleukin 6, a cytokine whose synthesis and secretion are induced by TNF, is able to acutely stimulate hepatic lipogenesis in mice. Interleukin 6 stimulates hepatic lipogenesis by increasing hepatic citrate concentrations, the same mechanism by which TNF stimulates hepatic lipogenesis. These data suggest that interleukin 6, but not platelet-activating factor, prostaglandins, or catecholamines, could potentially mediate the lipogenic effects of TNF.