Stimulation of glycogen phosphorylase in rat hepatocytes via prostanoid release from Kupffer cells by recombinant rat anaphylatoxin C5a but not by native human C5a in hepatocyte/Kupffer cell co‐cultures

Abstract

Stimulation of glycogen phosphorylase in rat hepatocytes via prostanoid release from Kupffer cells by recombinant rat anaphylatoxin C5a but not by native human C5a in hepatocyte/Kupffer cell co-cultures first published in: FEBS Letters 372 (1995), 1, p. 108-112, DOI 10.1016 . Surprisingly, human C5a, which in most systems elicits much stronger effects than C3a, did not increase glycogenolysis in perfused rat liver [3]. It was assumed that the lack of an effect of human C5a in perfused rat liver was due to a species incompatibility [3].The aim of the current study was to corroborate the apparent species specificity of anaphylatoxin. C5a and, moreover, to demonstrate the C5a-elicited intercellular communication via prostanoids in Kupffer cell/hepatocyte co-cultures. It was found that recombinant rat C5a but not native human C5a increased prostanoid formation in cultured rat Kupffer cells and stimulated glycogen phosphorylase activity in rat Kupffer cell/hepatocyte co-cultures via an aspirin-inhibitable mechanism.

Induction of Functional Anaphylatoxin C5a Receptors on Hepatocytes by In Vivo Treatment of Rats with IL-6

“…In contrast to these findings, C5aR mRNA (22) and protein (23) were expressed by Kupffer cells, hepatic stellate cells, and (weakly) sinusoidal endothelial cells but not by HC isolated from normal rat liver. This expression pattern was in line with functional studies demonstrating that recombinant rat C5a (rrC5a) activated glycogen phosphorylase (GPH) (24,25) and induced glucose output (26,27) in HC indirectly by stimulating PG and thromboxane release from Kupffer cells (24) and hepatic stellate cells (25). Analogously, C5a induced the synthesis of acute phase proteins in HC also indirectly by initiating proinflammatory cytokine formation by Kupffer cells (28).…”

“…In HC isolated from control animals, rrC5a failed to activate GPH at any time point after NaCl/ RSA injection. The lack of a direct rrC5a action on HC from normal rats has been shown previously using primary cultures (24,25). Direct induction of glucose output in perfused livers by rrC5a.…”

“…Thus, the C5a-dependent increase in glucose output from perfused livers of normal rats can be inhibited by the cyclooxygenase inhibitor indomethacin and the thromboxane receptor antagonist daltroban (27). Similarly, the C5a-dependent activation of GPH cannot be demonstrated in HC monocultures but only in cocultures of HC with prostanoid-secreting Kupffer cells (24) or hepatic stellate cells (25). Therefore, the findings of this study that C5a enhanced glucose output from perfused livers of IL-6-treated rats without impairment by indomethacin and daltroban (Fig.…”

“…X91892, ID: RNC5AARPT) (4) as described previously (4,24). RrC5a contained in addition to the original sequence of amino acids 1-77 the N-terminal sequence MRGSHHHHHHGS used for its purification from bacterial lysates by Ni 2ϩ -chelate chromatography and was depleted of endotoxins by affinity chromatography on polymyxin B agarose.…”

Anaphylatoxin C5a Induces Monocyte Recruitment and Differentiation into Dendritic Cells by TNF-α and Prostaglandin E2-Dependent Mechanisms

“…C5a, which is generated by activation-induced cleavage of the fifth component of complement, is a potent inducer of proinflammatory activities (20,21). Upon contact with C5a, mononuclear phagocytes release IL-1␤, IL-6, TNF-␣, and PGE 2 (22)(23)(24)(25)(26). A defined mixture of these stimuli has been shown to induce maturation of immature DC generated from monocytes in vitro in the presence of GM-CSF and IL-4 (27).…”