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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3087-3094
CHEMOKINES
Platelet factor 4 inhibits FGF2-induced endothelial cell
proliferation via the extracellular signal-regulated kinase
pathway but not by the phosphatidylinositol 3-kinase
pathway
Eric Sulpice,
Marijke Bryckaert,
Julie Lacour,
Jean-Olivier Contreres, and
Gerard Tobelem
From the Institut des Vaisseaux et du Sang
(IVS) and Institut National de la Santé et de la
Recherche Médicale (INSERM) U348, Paris, France.
Platelet factor 4 (PF-4) is a member of the chemokine family with
powerful antiangiogenic properties. The mechanism by which PF-4
inhibits endothelial cell proliferation is unclear. We investigated the
effects of PF-4 on the intracellular signal transduction induced by
basic fibroblast growth factor (FGF2). We found that PF-4 (10 µg/mL)
inhibited the FGF2-induced proliferation of adrenal cortex capillary
endothelial (ACE) cells. The inhibition of MEK1/2 (mitogen-activated protein kinase kinase) by PD98059 or of PI3K
(phosphatidylinositol 3-kinase) by Ly294002 abolished the proliferation
induced by FGF2, suggesting that ACE cell proliferation required dual
signaling through both the extracellular signal-regulated kinase (ERK)
and PI3K pathways. Ly294002 had no significant effect on ERK
phosphorylation, whereas PD98059 had a weak effect on the
phosphorylation of Akt, suggesting that 2 separate cascades are
required for ACE cell proliferation. The addition of PF-4 (10 µg/mL)
significantly inhibited ERK phosphorylation (95%), showing that PF-4
acted directly on or upstream from this kinase. Surprisingly, PF-4 did
not affect FGF2-induced Akt phosphorylation. This suggests that PF-4
disrupts FGF2 signaling via an intracellular mechanism of inhibition.
To exclude the possibility that PF-4 inhibited the binding of FGF2 to
only one FGF receptor, preferentially activating the ERK pathway, we
investigated the effect of PF-4 on FGF2-induced ERK and Akt phosphorylation, using mutant heparan sulfate-deficient Chinese hamster ovary cells transfected with the FGF-R1 cDNA. The addition of
PF-4 (1 µg/mL) significantly inhibited ERK phosphorylation (90%), with no effect on Akt phosphorylation, suggesting that PF-4
acts downstream from the FGF-R1 receptor. In conclusion, this is the
first report showing that PF-4 inhibits FGF2 activity downstream from
its receptor.
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