Transcriptional Control Mechanism of Fibrinogen Gene Expression

A bstract : Although fibrinogen genes are expressed constitutively in hepatocytes, their transcription can be greatly increased during inflammatory stress. Extensive studies have focused on the cytokine mediated transcriptional regulation of fibrinogen genes. It is clear that interleukin‐6 (IL‐6) and its family of cytokines are the major inducers of fibrinogen gene expression. Functional analyses of all three fibrinogen promoters for human and rat all demonstrate that the conserved CTGGGAA motifs within the proximal promoter of each fibrinogen gene are the IL‐6 responsive elements. Exploration of the rat γ fibrinogen gene demonstrated that the IL‐6 activated transcription factor, STAT3, binds to the CTGGGAA motif and is required for the IL‐6 mediated upregulation of this gene. IL‐6 mediated fibrinogen production can be significantly elevated by glucocorticoid treatment. The synergistic effect of glucocorticoids and IL‐6 relies on the functional interaction between STAT3 and glucocorticoid receptor. In addition to the upregulation signals for fibrinogen gene expression during inflammatory stress, other signaling also downregulates the expression of fibrinogen genes. For example, the proinflammatory cytokine IL‐1β exerts inhibitory function on IL‐6 mediated fibrinogen gene expression. Given the fact that elevated levels of fibrinogen in blood correlate with increased risk for cardiovascular disease, there is strong motivation to explore the molecular mechanisms that control fibrinogen expression, especially those signals that may downmodulate expression and thus provide novel approaches to controlling fibrinogen levels.