Regulation of C1-inhibitor synthesis by interferons and other agents.
C1-inhibitor (C1-inh) is synthesised and secreted by at least four cell types: hepatocytes, mononuclear phagocytes, fibroblasts and umbilical vein endothelial cells. The production of this protein by monocytes/macrophages and Hep G2 cells has been studied in great detail. Environmental factors alter C1-inh synthesis by these cells. A number of agents which inhibit monocyte C1-inh production (such as histamine, PGE2 C5a des arg and serum treated immune complexes) bind to membrane receptors, activate adenylate cyclase, elevate intracellular cAMP and activate cAMP-dependent protein kinase. Elevation of monocyte cAMP levels is associated with decreased C1-inh secretion by these cells and reduced C1-inh mRNA levels. These changes can be seen within 8 hours of exposure. Stimulation of monocyte C1-inh synthesis occurs after the addition of agents which induce the formation of sodium ion and calcium ion channels, activate the phosphatidyl inositol cycle and activate protein kinase C (immune-complexes, carbamylcholine and phenylephrine). Agents which act directly on protein kinase C (phorbol myristate acetate) also stimulate C1-inh synthesis. Amongst the most potent stimulators of monocyte and Hep G2 C1-inh synthesis are the interferons (Ifns) Ifn alpha, Ifn beta and Ifn gamma. These are known to bind to specific receptors on cells (Ifn alpha and beta binding to Type I Ifn receptors and Ifn-gamma binding to type II Ifn receptors). At least two mechanisms by which Ifn receptor-ligand interaction elicit their effects exist. These are: 1) binding of an activated receptor transducer/regulatory component to specific DNA sequences on Ifn sensitive genes; 2) the activation of protein kinase C and binding of its regulatory components to specific DNA sequences. Ifn alpha, beta and gamma cause a dose related increase in monocyte and Hep G2 cell C1-inh mRNA abundance and protein synthesis. Ifn-gamma is the most potent of the interferons on monocyte C1-inh synthesis. Ifn alpha and beta being less effective but equipotent. These cytokines elicit their maximum effect on monocyte C1-inh synthesis after 1-2 hours treatment. This rapid stimulation of monocyte C1-inh synthesis suggests that this increases the transcription of the C1-inh gene. After removal of Ifns from monocytes the elevated C1-inh mRNA levels subside towards control levels of expression in Ifn alpha and beta-treated cells but remain elevated in Ifn-gamma-treated monocytes. This binding suggests that Ifn-gamma alters the stability of C1-inh mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
Lappin
D
D
University Department of Pathology, Western Infirmary, Glasgow, U.K.
Whaley
K
K
D006528:Carcinoma, Hepatocellular / Q000473:pathology; D003174:Complement C1 Inactivator Proteins / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007372:Interferons / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology; D008113:Liver Neoplasms / Q000473:pathology; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000378:metabolism
D003174:Complement C1 Inactivator Proteins; D005938:Glucocorticoids; D012333:RNA, Messenger; D007372:Interferons