Cyclosporine inhibits basic fibroblast growth factor-driven proliferation of human endothelial cells and keratinocytes.
Keratinocytes and endothelial cells produce basic fibroblast growth factor (b-FGF), and this cytokine is mitogenic for both cell types. Additionally, b-FGF is stored in the vicinity of keratinocytes and endothelial cells in basement membrane and extracellular matrix, and can be displaced from these "buffers" by various stimuli. Displacement of b-FGF by physical stimuli, such as scratching or rubbing, could explain koebnerization in diseases such as psoriasis. It has been shown that the fungal metabolite cyclosporine A will inhibit the proliferation of keratinocytes in vitro when their proliferation is driven by epidermal growth factor (EGF) and/or bovine pituitary extract. Since b-FGF may be both a positive autocrine and paracrine signal involved in the proliferation of both keratinocytes and endothelial cells, we evaluated the effects of cyclosporine on the b-FGF-driven proliferation of these cell types in vitro. We have shown that normal human keratinocyte and endothelial cell proliferation driven by b-FGF alone can be inhibited by cyclosporine A. Concentrations of cyclosporine A achievable in skin after oral administration can significantly inhibit the b-FGF-driven proliferation of both of these cell types. Basic fibroblast growth factor may be an important signal driving both keratinocyte proliferation and angiogenesis in certain disease states, such as psoriasis, as well as aberrant endothelial cell proliferation as is seen in Kaposi's sarcoma. The efficacy of cyclosporine A in treating these disease states may be due, at least in part, to the ability of cyclosporine A to interrupt b-FGF-mediated autocrine and paracrine feedback loops acting on and between endothelial cells and keratinocytes.
Sharpe
R J
RJ
Department of Dermatology, Beth Israel Hospital, Boston, Mass 02215.
Arndt
K A
KA
Bauer
S I
SI
Maione
T E
TE
D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival; D003524:Cyclosporins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D013936:Thymidine; D014316:Tritium
D003524:Cyclosporins; D014316:Tritium; D005346:Fibroblast Growth Factors; D013936:Thymidine