Induction of fibrinogen and a subset of acute phase response genes involves a novel monokine which is mimicked by phorbol esters.

We have investigated the requirements for the induction of the acute phase response to inflammation using the FAZA rat hepatocyte cell line which can be induced to activate the acute phase response genes with supernatants from human or rat monocytes. Using ribonuclease mapping of fibrinogen transcripts, we find that the tumor promoter 12-O-tetradecanoylphorbol-13-acetate can induce a 10-20-fold increase in properly initiated and spliced fibrinogen mRNA. This response is likely to be mediated by protein kinase C (Ca2+/phospholipid-dependent enzyme) since the synthetic diacylglycerol, 1-oleoyl-2-acetylglycerol, can also induce fibrinogen mRNA. In addition to the alpha, beta, and gamma chains of fibrinogen, other acute phase response mRNAs are induced by 12-O-tetradecanoylphorbol-13-acetate including alpha 2-macroglobulin. The active agent capable of inducing the fibrinogen mRNAs in the monocyte supernatants is clearly not interleukin 1 (IL-1) or tumor necrosis factor. The FAZA cell line does not have detectable IL-1 receptors and does not respond to either murine or human IL-1 or the 30-kDa precursor for IL-1. In addition, fibrinogen cannot be induced by tumor necrosis factor alpha in this cell line, and the active agent in monocytes supernatants cannot be neutralized with polyclonal or monoclonal antibodies to tumor necrosis factor alpha. We conclude that a third as yet uncharacterized agent is responsible for the induction of fibrinogen during the acute phase response and that this agent transduces its signal to the fibrinogen genes by a mechanism involving protein kinase C.