Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon gamma.
C1 inhibitor (C1INH), the major plasma inhibitor of activated C1, kallikrein, and activated Hageman factor, may be an important factor in limiting inflammatory injury mediated by the complement and contact systems. C1INH is thought to be synthesized primarily in the liver; however, the regulators of hepatic C1 inhibitor synthesis are completely unknown. In this report, we analyze the regulation of C1INH synthesis by hepatocyte stimulating factors in human hepatoma cell lines and primary hepatocytes. Interleukin-6 and interferon gamma increase C1INH production in both hepatoma cells and hepatocytes. These cytokines stimulate de novo synthesis of functional C1INH, acting at a pretranslational level as assessed by Northern blotting. The stimulatory effects of interleukin-6 and interferon gamma on C1INH synthesis are separate and are differentially modulated by interleukin-1. These results establish that hepatic C1INH synthesis is regulated by hepatocyte stimulating factors and reveal novel interactions between these factors.
Zuraw
B L
BL
Department of Molecular and Experimental Medicine, Research Institute of Scripps Clinic, La Jolla, California 92037.
Lotz
M
M
D000209:Acute-Phase Proteins / Q000378:metabolism; D000210:Acute-Phase Reaction; D015152:Blotting, Northern; D002478:Cells, Cultured; D003174:Complement C1 Inactivator Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003173:Complement C1s / Q000378:metabolism; D003175:Complement C2 / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D015291:Transforming Growth Factors / Q000494:pharmacology
D000209:Acute-Phase Proteins; D003174:Complement C1 Inactivator Proteins; D003175:Complement C2; D003176:Complement C3; D003181:Complement C4; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015847:Interleukin-4; D015291:Transforming Growth Factors; D003907:Dexamethasone; D007371:Interferon-gamma; D003173:Complement C1s