Binding of Factor VIIa to tissue factor on keratinocytes induces gene expression

Binding of the zymogen serine protease Factor VII (FVII) to its cellular co factor tissue factor (TF) triggers blood coagulation. Several recent report s have suggested that the formation of this complex may serve additional fu nctions. We have used cDNA arrays to study differential gene expression in response to the interaction of activated FVII (FVIIa) with TF on a human ke ratinocyte cell line, Of 931 mRNA species observed up to 6 h after FVIIa (1 0 nM) addition, 24 were significantly up-regulated in what may resemble a w ound-type response. Responders included mRNA species coding for transcripti on regulators (c-fos, egr-1, ETR101, BTEB2, c-myc, fra-1, and tristetraprol ine), growth factors (amphiregulin, hbEGF, CTGF, and FGF-5), proinflammator y cytokines (IL-1 beta, IL-8, LIF, and MIP2 alpha), proteins involved in ce llular reorganization/migration (RhoE, uPAR, and collagenases 1 and 3), and others (PAI-2, cyclophilin, GADD45, Jagged1, and prostaglandin E-2 recepto r). The transcriptional response to FVIIa was abrogated by antibodies to TF and left unaffected by hirudin, The pattern of genes induced suggests that the FVIIa.TF complex may play an active role in early wound repair as well as hemostasis. The former is a novel function ascribed to the complex that may also be contributing to the pathophysiology of unwarranted TF expressi on.