Inhibition of Glucagon-Signaling and Downstream Actions by Interleukin 1β and Tumor Necrosis Factor α in Cultured Primary Rat Hepatocytes

Abstract

In cultured rat hepatocytes, glucagon increased the phosphoenolpyruvate carboxykinase (PCK1) mRNA by increasing cellular cAMP concentrations. The proinflammatory cytokines rhIL1β and rhTNFα impaired the increase both in cAMP and PCK1 mRNA. Glucose formation from glycogen stimulated by glucagon was also attenuated by the cytokines, very likely due to the attenuation of the cAMP increase. Treatment of hepatocytes with the phosphodiesterase inhibitor IBMX or the inhibitory G-protein (G_i) inactivating compound pertussis toxin did not abolish the inhibition of the glucagon-stimulated increase in cAMP by the cytokines indicating that phosphodiesterase and G_i were not involved. The activation of adenylate cyclase by forskolin enhanced cAMP and PCK1 mRNA. Again, rhIL1β and rhTNFα attenuated the increase in PCK1 mRNA, however, not that in cAMP. The stimulation of PCK1 mRNA increase with the nonhydrolyzable cAMP analogue CPT-cAMP was inhibited by rhIL1β and rhTNFα indicating interference independent of changes in cAMP levels. It is concluded that rhIL1β and rhTNFα inhibited glucagon-stimulated signal transduction at the site of cAMP formation. In addition, glucagon-stimulated PCK1 mRNA was attenuated independent of cAMP formation very likely on the transcriptional and/or post-transcriptional level.

phosphoenolpyruvate carboxykinase - glucokinase - glycogenolysis - gluconeogenesis - glucagon - proinflammatory cytokines

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