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Abstract
One of the hallmarks of an acute inflammatory response is a change in the circulating levels of a subset of hepatic-derived plasma proteins, collectively named the acute phase reactants. Fibrinogen is one example of an acute phase reactant whose synthesis increases significantly during the early stages of an acute inflammatory response, primarily by the stimulatory actions of the cytokine interleukin-6 (IL-6) and glucocorticoids. In this study, a careful examination of the fate of each fibrinogen transcript in primary rat hepatocytes during and following stimulation with IL-6 was performed. Northern blot analysis demonstrated a coordinated increase in the levels of all three fibrinogen mRNAs following IL-6 addition. The decline in the levels of the fibrinogen transcripts also occurred in a tightly coordinated fashion, requiring both transcription and translation. To gain information on the mechanisms by which the hepatocyte responds to IL-6, we examined the expression of the IL-6 receptor (IL-6-R) and the signal transducing protein gp130 during in vivo and in vitro stimulation of inflammation. The results indicate that IL-6-R expression is dynamic, up-regulated by glucocorticoids, and subsequently down-regulated by IL-6 and interleukin-1. No detectable changes in gp130 expression were observed. Data are provided indicating that regulation of IL-6-R is substantially different from gp130, and that up-regulation of the receptor plays a critical role in increasing the sensitivity of hepatocytes to the incoming IL-6 signals. We also show that the IL-6/IL-6-R complex is stable and that IL-6 is rapidly internalized and degraded by hepatocytes by a receptor-mediated mechanism. These results have expanded the understanding of IL-6 control of fibrinogen expression during an acute inflammatory reaction. Information from these studies provides evidence that the return to homeostasis is stringently regulated. When taken in the context of the intact animal, one sees that elegant homeostatic controls exist at several sites in the inflammatory pathway, in which glucocorticoids and cytokines operate in a balanced way to control the defense system of the animal.
