Fetuin, a negative acute phase protein, attenuates TNF synthesis and the innate inflammatory response to carrageenan

Activation of the innate immune system, even by relatively innocuous stimul i, stimulates the release of cytokines (e.g. TNF) that can injure or kill t he host. To maintain homeostasis, mammals have evolved a counter-regulatory response that suppresses the development of excessively robust inflammatio n. Fetuin, a 66-kD negative acute phase glycoprotein, was first identified in 1944. We recently discovered an anti-inflammatory role for fetuin, becau se it suppressed the release of TNF from lipopolysaccharide- (LPS) stimulat ed macrophages. Here the anti-inflammatory effects of fetuin were studied i n vivo in an LPS-independent model of acute inflammation caused by administ ration of carrageenan. Administration of fetuin (5-500 mg/kg intraperitonea lly) dose-dependently attenuated the development of paw edema as compared t o either asialofetuin (500 mg/kg) or bovine albumin 1500 mg/kg). TNF produc tion in the carrageenan-injected paws was significantly inhibited by admini stration of fetuin (586 +/- 98 pg TNF/paw) as compared to either asialofetu in (1018 +/- 186 pg TNF/paw) or saline (1,005 +/- 172 pg TNF/paw). When spe cific anti-fetuin IgG was administered into the paw prior to the applicatio n of carrageenan, the development of edema formation was significantly incr eased as compared to irrelevant IgG, indicating that endogenous fetuin norm ally attenuates the inflammatory response. These results now reveal a previ ously unrecognized anti-inflammatory role of fetuin in counter-regulating t he innate immune response, and suggest that it may be possible to use fetui n as an experimental anti-inflammatory agent.