Differential regulation of fibrinogen γ chain splice isoforms by interleukin-6

Introduction: Fibrinogen is a major structural protein in blood clots, and is also a well-known acute phase reactant. The γ chain gene of fibrinogen has two alternative splice variants, γA and γ' chains. γ' fibrinogen constitutes about 7% of total fibrinogen. Total fibrinogen levels and γ' fibrinogen levels have been associated with cardiovascular disease, but the mechanisms regulating the production of the two isoforms are unknown. Several inflammatory cytokines are known to influence the production of total fibrinogen, but the role of cytokines in the production of γ' fibrinogen has not been examined. However, epidemiologic studies have shown an association between γ' fibrinogen levels and inflammatory markers in humans. Materials and methods: The expression of γ' fibrinogen and total fibrinogen by HepG2 liver cells was quantitated after treatment with interleukin-1β, transforming growth factor-β, tumor necrosis factor-α, and interleukin-6. Results: Interleukin-1β, transforming growth factor-β, and tumor necrosis factor-α, known down-regulators of total fibrinogen synthesis, also downregulate γ' fibrinogen synthesis in HepG2 cells. However, interleukin-6 differentially up-regulates the production of total and γ' fibrinogen, leading to a 3.6-fold increase in γA mRNA, but an 8.3-fold increase in γ' mRNA. Conclusions: These findings indicate that γ' fibrinogen is disproportionately up-regulated by inflammatory responses induced by interleukin-6.