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

Binding of the zymogen serine protease Factor VII (FVII) to its cellular cofactor tissue factor (TF) triggers blood coagulation. Several recent reports have suggested that the formation of this complex may serve additional functions. We have used cDNA arrays to study differential gene expression in response to the interaction of activated FVII (FVIIa) with TF on a human keratinocyte cell line. Of 931 mRNA species observed up to 6 h after FVIIa (10 nM) addition, 24 were significantly up-regulated in what may resemble a wound-type response. Responders included mRNA species coding for transcription regulators (c-fos, egr-1, ETR101, BTEB2, c-myc, fra-1, and tristetraproline), growth factors (amphiregulin, hbEGF, CTGF, and FGF-5), proinflammatory cytokines (IL-1beta, IL-8, LIF, and MIP2alpha), proteins involved in cellular reorganization/migration (RhoE, uPAR, and collagenases 1 and 3), and others (PAI-2, cyclophilin, GADD45, Jagged1, and prostaglandin E(2) receptor). 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 expression.