FEEDBACK-INHIBITION OF GLUCAGON-STIMULATED GLYCOGENOLYSIS IN HEPATOCYTE KUPFFER CELL COCULTURES BY GLUCAGON-ELICITED PROSTAGLANDIN PRODUCTION IN KUPFFER CELLS

Prostaglandins, released from Kupffer cells, have been shown to mediat e the increase in hepatic glycogenolysis by various stimuli such as zy mosan, endotoxin, immune complexes, and anaphylotoxin C3a involving pr ostaglandin (PG) receptors coupled to phospholipase C via a G(0) prote in. PGs also decreased glucagon-stimulated glycogenolysis in hepatocyt es by a different signal chain involving PGE(2) receptors coupled to a denylate cyclase via a G(i) protein (EP(3) receptors). The source of t he prostaglandins for this latter glucagon-antagonistic action is so f ar unknown. This study provides evidence that Kupffer cells may be one source: in Kupffer cells, maintained in primary culture for 72 hours, glucagon (0.1 to 10 nmol/ L) increased PGE(2), PGF(2 alpha), and PGD( 2) synthesis rapidly and transiently. Maximal prostaglandin concentrat ions were reached after 5 minutes. Glucagon (1 nmol/L) elevated the cy clic adenosine monophosphate (cAMP) and inositol triphosphate (InsP(3) ) levels in Kupffer cells about fivefold and twofold, respectively. Th e increase in glyco gen phosphorylase activity elicited by 1 nmol/L gl ucagon was about twice as large in monocultures of hepatocytes than in cocultures of hepatocytes and Kupffer cells with the same hepatocyte density. Treatment of cocultures with 500 mu mol/L acetylsalicylic aci d (ASA) to irreversibly inhibit cyclooxygenase (PGH-synthase) 30 minut es before addition of glucagon abolished this difference. These data s upport the hypothesis that PGs produced by Kupffer cells in response t o glucagon might participate in a feedback loop inhibiting glucagon-st imulated glycogenolysis in hepatocytes.