Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells.

C3a and C5a anaphylatoxins are cytokine-like polypeptides generated during complement (C) system activation and released at the inflammatory site. They exert several biological activities through binding to the G-protein-coupled receptors C3aR and C5aR, respectively. Cloning and Northern blot experiments have indicated that both receptors are expressed by myeloid as well as nonmyeloid cells (e.g., endothelial and epithelial cells). To better understand the roles of C anaphylatoxins during inflammation, we investigated their effects on the expression of cytokine and chemokine genes by cultured human umbilical cord endothelial cells (HUVEC). HUVEC constitutively expressed both anaphylatoxin receptors, and addition of physiological concentrations of C3a or C5a (nM range) caused a strong up-regulation of IL-8, IL-1beta, and RANTES mRNA in a time- and dose-dependent manner. Conversely, a decrease in IL-6 mRNA was observed, but only with C5a stimulation. These variations in mRNA levels were inhibited by pretreatment with anti-C5aR and anti-C3aR antibodies as well as pertussis toxin, indicating that G-proteins are involved in anaphylatoxin-activated signal transduction pathways. Finally, we showed that C3a and C5a both strongly activate downstream MAP kinase signaling pathways (p44 and p42 Erk kinases).