Increased fibrinogen synthesis in mice during the acute phase response: co-operative interaction of interleukin 1, interleukin 6, and interleukin 1 receptor antagonist.

Interleukin 6 (IL-6) stimulates fibrinogen (Fg) gene expression both in vivo and in vitro; while interleukin 1 (IL-1) paradoxically stimulates in vivo, yet inhibits in vitro, Fg synthesis. The naturally occurring interleukin 1 receptor antagonist (IL-1ra) and passive immunization with anti-IL-6 antiserum were used to study the in vivo mechanism of action of IL-1 on Fg gene expression. Changes in plasma Fg and hepatic Fg mRNA concentrations were measured following administration of exogenous IL-1ra together with IL-6 or IL-1 to CD2F1 mice. Our results suggest that in vivo, IL-1 per se inhibits Fg production since when IL-1ra was co-administered with IL-6, greater concentrations of Fg were observed than when IL-6 was administered alone. The data suggest that IL-1 stimulates Fg production through intermediate production of IL-6, since stimulation was abrogated when either IL-1ra or anti-IL-6 antiserum was co-administered with IL-1. An in vivo role for IL-1ra in the stimulation of Fg by IL-1 was supported by the observation that within 1 h of IL-1 administration to mice, IL-1ra mRNA was detectable in liver. It appears that IL-1, an early mediator of inflammation, inhibits constitutive expression of Fg genes and stimulates the IL-1ra and IL-6 genes. The inhibitory effect of IL-1 is reversed by endogenous IL-1ra and by the direct stimulation of Fg gene expression by IL-6.