title: Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells.
abstract: 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).
authors.affiliation: Laboratory of Immunology, INSERM U519, IFRMP23, University of Rouen, France. gasque@cardiff.ac.uk
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Monsinjon
authors.forename: Philippe
authors.initials: P
authors.lastname: Gasque
authors.forename: Philippe
authors.initials: P
authors.lastname: Chan
authors.forename: Alexander
authors.initials: A
authors.lastname: Ischenko
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Brady
authors.forename: Marc C
authors.initials: MC
authors.lastname: Fontaine
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D015926:Complement C3a / Q000378:metabolism / Q000494:pharmacology*; D015936:Complement C5a / Q000378:metabolism / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D020014:K562 Cells; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D018925:Chemokines; D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D008565:Membrane Proteins; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a; D015936:Complement C5a