Inhibition by prostaglandin E2 of anaphylatoxin C5a-but not zymosan-induced prostanoid release from rat Kupffer cells

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Abstract

The proinflammatory anaphylatoxin C5a induces the release of prostanoids, ie, prostaglandins (PG) and thromboxane (TX), from the resident liver macrophages (Kupffer cells [KC]). Because KC themselves express prostanoid receptors, prostanoids - besides having paracrine functions - might regulate their own release in an autocrine loop. So far, such a possible feedback regulation has not been investigated systematically, probably because of methodological difficulties to measure newly synthesized prostanoids in the presence of added prostanoids. Here, after prelabeling of phospholipids with [14C]arachidonate, cellularly formed [14C]prostanoids were determined in the presence of added unlabelled prostanoids by thin layer chromatography. In cultured KC, recombinant rat C5a (rrC5a) rapidly increased PGD2, PGE2, and TXA2 release, which was strongly reduced by PGE2, but neither by PGD2 nor by the TXA2 analog U46619. The inhibitory effect of PGE2 was mimicked by cAMP, indicating that the Gs-coupled PGE2 receptors type 2 or 4 were involved. Zymosan also enhanced prostanoid release from KC, but with slightly slower kinetics; this action was neither inhibited by PGE2 nor by cAMP. Also in perfused rat livers, rrC5a enhanced prostanoid release from KC as shown by prostanoid overflow and thereby indirectly increased glucose output from hepatocytes. Again, PGE2, but not PGD2, inhibited rrC5a-elicited prostanoid overflow. This resulted in a complete inhibition of rrC5a-induced, prostanoid -mediated glucose output. Thus, PGE2 can inhibit specifically the C5a-induced prostanoid release from KC via a feedback mechanism and thereby limit prostanoid-mediated hepatocellular defense reactions, eg, glucose release.

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Pestel, S., Jungermann, K., Götze, O., & Schieferdecker, H. L. (2002). Inhibition by prostaglandin E2 of anaphylatoxin C5a-but not zymosan-induced prostanoid release from rat Kupffer cells. Laboratory Investigation, 82(4), 463–471. https://doi.org/10.1038/labinvest.3780439

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