Regulation of hepatic synthesis of C3 and C4 during the acute-phase response in the rat.

Following the i.p. injection of casein, rats showed increased serum levels of C4 and C3. C4 levels peaked on day 2 and returned to normal by day 4, while C3 levels peaked on day 3 before returning to normal on day 4. These changes were paralleled by changes in the hepatocyte synthesis rates of these two proteins. Macrophages, isolated from the peritoneal cavities of rats on days 1 to 7 (day-1 to day-7 macrophages) following i.p. injection of casein, were cultured in vitro, and the peritoneal macrophage-conditioned media (PMCM) assayed for their abilities to stimulate synthesis of C4 and C3 by hepatocytes from control rats. Day-2 PMCM selectively stimulated synthesis of C4, while day-3 and day-4 PMCM selectively stimulated C3 synthesis. These activities were called C4-hepatocyte stimulating factor (C4-HSF) and C3-HSF, respectively. The addition of anti-interleukin (IL) 1, tumor necrosis factor (TNF)-alpha, TNF-beta, IL 6 or interferon (IFN)-gamma antibodies to day-2 PMCM did not affect C4-HSF activity, and none had any effect on C3-HSF activity in day-4 PMCM. However, the addition of anti-IL 1 to day-4 PMCM resulted in the re-expression of C4-HSF activity as well as loss of thymocyte proliferative activity. C4-HSF activity could also be detected in day-4 PMCM by separating it from IL 1 activity using gel filtration chromatography. Furthermore the addition of recombinant IL 1 beta to day-2 PMCM prevented the expression of C4-HSF activity. Thus IL 1 appears to play a regulatory role in the acute-phase response in the rat, by preventing the expression of C4-HSF activity. The identities of C4-HSF activity and C3-HSF are still unknown but we believe that C3-HSF activity could be IL 6 as it has a similar molecular weight (30 kDa) and purified human IL 6 was more effective than IL 1, TNF-alpha or TNF-beta in stimulating C3 synthesis by rat hepatocytes. C4-HSF activity appears to be a property of a previously undescribed cytokine. It is not IL 1 alpha or beta, TNF-alpha or -beta, IL 6 or IFN-gamma.