Human anaphylatoxin C3a increases glycogenolysis in perfused rat liver. This action is inhibited by prostanoid synthesis inhibitors and prostanoid antagonists. Because prostanoids but not anaphylatoxin C3a can increase glycogenolysis in hepatocytes, it has been proposed that prostanoid formation in nonparenchymal cells represents an important step in the C3a-dependent increase in hepatic glycogenolysis. This study shows that (a) human anaphylatoxin C3a (0.1 to 10 pg/ml) dose-dependently increased prostaglandin D,, thromboxane B, and prostaglandin F,, formation in rat liver macrophages (Kupffer cells); (b) the C3amediated increase in prostanoid formation was maximal after 2 min and showed tachyphylaxis; and (c) the C3a-elicited prostanoid formation could be inhibited specifically by preincubation of C3a with carboxypeptidase B to remove the essential C-terminal arginine or by preincubation of C3a with Fab fragments of a neutralizing monoclonal antibody. These data support the hypothesis that the C3a-dependent activation of hepatic glycogenolysis is mediated by way of a C3a-induced prostanoid production in Kupffer cells. (HEPATOLOGY 1993; 18: 1516-1521.) The human anaphylatoxin C3a is generated by the proteolytic cleavage of the third complement component C3. C3a is under the control of serum carboxypeptidase N, which cleaves the C-terminal Arg-77 and thereby inactivates C3a. The classic anaphylatoxic effects of C3a such as smooth muscle contraction and enhanced vascular permeability are only in part due to direct activation of the effector cells by C3a receptors. Other proinflammatory mediators such as histamine and prostanoids may be involved in the signal chains. Thus the C3a-mediated contraction of guinea pig lung parenchymal strips were inhibited by indomethacin (11, and