REGULATION OF ENERGY-METABOLISM BY INTERLEUKIN-1-BETA, BUT NOT BY INTERLEUKIN-6, IS MEDIATED BY NITRIC-OXIDE IN PRIMARY CULTURED RAT HEPATOCYTES

The effects of inflammatory cytokines (interleukin-1 beta, interleukin -6, and tumor necrosis factor-alpha) on energy metabolism were studied in primary cultured rat hepatocytes, Adenine nucleotide (ATP, ADP, an d AMP) content, lactate production, the ketone body ratio (acetoacetat e/beta-hydroxybutyrate) reflecting the liver mitochondrial redox state (NAD(+)/NADH), and nitric oxide formation were measured. Insulin incr eased ATP content in hepatocytes and had a maximal effect after 8-12 h of culture. Both interleukin-1 beta and interleukin-6, but not tumor necrosis factor-alpha, significantly inhibited the ATP increase time- and dose-dependently, Interleukin-1 beta and interleukin-6 also stimul ated lactate production. During the same period, interleukin-1 beta bu t not interleukin-6 decreased the ketone body ratio. Furthermore, inte deukin-1 beta markedly stimulated nitric oxide formation in hepatocyte s, and this increase was blocked by N-G-monomethyl-L-arginine (a nitri c oxide synthase inhibitor) and by interleukin-l receptor antagonist. N-G-monomethyl-L-arginine reversed inhibition of the ATP increase, dec rease in the ketone body ratio, and increase in lactate production, wh ich were induced by interleukin-1 beta. Interleukin-1 receptor antagon ist completely abolished all of the effects induced by interleukin-1 b eta. These results demonstrated that interleukin-1 beta beta and inter leukin-6 affect the insulin-induced energy metabolism in rat hepatocyt es by different mechanisms. Specifically, interleukin-1 beta inhibits ATP synthesis by causing the mitochondrial dysfunction, a process whic h may be mediated by nitric oxide.