title: Induction of cyclooxygenase-2 synthesis by ligation of the macrophage alpha(2)-macroglobulin signalling receptor.
abstract: We have studied the induction of cyclooxygenase-2 (COX-2) in macrophages consequent to ligating the alpha(2)-macroglobulin (alpha(2)M) signalling receptor (alpha(2)MSR) with receptor-recognized forms of alpha(2)M (alpha(2)M*). Macrophage stimulation with alpha(2)M* increased total cellular and nuclear COX-2 two- to threefold. The maximal increase in COX-2 occurred at a ligand concentration of 50-100 pM and after 2 h. Modulation of intracellular Ca(2+) levels or incubation of [35S] methionine-labelled macrophages with actinomycin D, prior to treatment with alpha(2)M*, markedly reduced the induction of total cellular and nuclear COX-2. Protein kinase C (PKC) or phospholipase A(2) (PLA(2)) inhibition in alpha(2)M*-stimulated macrophages or inhibition of the p21(ras)-dependent mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI 3-kinase) signalling pathways also significantly reduced alpha(2)M*-induced total cellular and nuclear COX-2 expression. Thus, COX-2 induction is dependent on cPLA(2) activity, Ca(2+) mobilization, and PKC activity and requires participation of both the p21(ras)-dependent MAPK and PI 3-kinase signalling pathways. COX-2 activation may mediate alpha(2)M*-induced mitogenesis, which we have previously observed in this and other cell types.
authors.affiliation: Department of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: U K
authors.initials: UK
authors.lastname: Misra
authors.forename: S V
authors.initials: SV
authors.lastname: Pizzo
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D000511:alpha-Macroglobulins / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D019384:Nucleic Acid Synthesis Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000511:alpha-Macroglobulins; D003609:Dactinomycin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D010741:Phospholipases A; D010738:Type C Phospholipases; D016283:Proto-Oncogene Proteins p21(ras); D043265:Phosphatidylinositol Diacylglycerol-Lyase; D002118:Calcium