INDUCTION OF CERULOPLASMIN SYNTHESIS BY IFN-GAMMA IN HUMAN MONOCYTIC CELLS

Ceruloplasmin is a 132-kDa glycoprotein abundant in human plasma, It h as multiple in vitro activities, including copper transport, lipid pro - and antioxidant activity, and oxidation of ferrous ion and aromatic amines; however, its physiologic role is uncertain, Although cerulopla smin is synthesized primarily by the liver in adult humans, production by cells of monocytic origin has been reported, We here show that IFN -gamma is a potent inducer of ceruloplasmin synthesis by monocytic cel ls, Activation of human monoblastic leukemia U937 cells with IFN-gamma increased the production of ceruloplasmin by at least 20-fold, The id entity of the protein was confirmed by plasmin fingerprinting, IFN-gam ma also increased ceruloplasmin mRNA, Induction followed a 2- to 4-h l ag and was partially blocked by cycloheximide, indicating a requiremen t for newly synthesized factors, Ceruloplasmin induction in monocytic cells was agonist specific, as IL-1, IL-3, IL-6, IFN-alpha, IFN-beta, TNF-alpha, and LPS were completely ineffective, The induction was also cell type specific, as IFN-gamma did not induce ceruloplasmin synthes is in endothelial or smooth muscle cells, In contrast, IFN-gamma was s timulatory in other monocytic cells, including THP-1 cells and human p eripheral blood monocytes, and also in HepG2 cells, Ceruloplasmin secr eted by IFN-gamma-stimulated U937 cells had ferroxidase activity and w as, in fact, the only secreted protein with this activity, Monocytic c ell-derived ceruloplasmin may contribute to defense responses via its ferroxidase activity, which may drive iron homeostasis in a direction unfavorable to invasive organisms.