FEEDBACK-INHIBITION OF GLUCAGON-STIMULATED GLYCOGENOLYSIS IN HEPATOCYTE KUPFFER CELL COCULTURES BY GLUCAGON-ELICITED PROSTAGLANDIN PRODUCTION IN KUPFFER CELLS
U. Hespeling et al., FEEDBACK-INHIBITION OF GLUCAGON-STIMULATED GLYCOGENOLYSIS IN HEPATOCYTE KUPFFER CELL COCULTURES BY GLUCAGON-ELICITED PROSTAGLANDIN PRODUCTION IN KUPFFER CELLS, Hepatology, 22(5), 1995, pp. 1577-1583
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.