IL-4 and interferon-γ differentially modulate vascular endothelial growth factor release from normal human keratinocytes and fibroblasts

IL-4 and interferon-gamma (IFN-gamma) are crucial modulators of the immune system and are reported as active antitumor agents and potent inhibitors of angiogenesis. We investigated the effects of these two cytokines on the expression of vascular endothelial growth factor (VEGF), a mediator of major importance in the angiogenesis associated with inflammation, wound healing and tumor invasion and expressed by activated keratinocytes and dermal fibroblasts. Human keratinocytes (HK) and fibroblasts (HF) derived from foreskins, were further cultured during 24 h in defined medium, supplemented or not with the selected growth factors, EGF and TGF-beta1, respectively, before receiving the addition of either IL-4 or IFN-gamma during 24 and 48 h. In basal conditions, fibroblasts produced smaller amounts of VEGF than keratinocytes; the addition of growth factors to the skin cells induced a drastic increase of VEGF secretion. In HF, the basal level of VEGF secretion was reduced by IFN-gamma and slightly increased by IL-4 whereas in HK, IFN-gamma enhanced the secretion of VEGF after 48 h and IL-4 either tended to reduce VEGF secretion or did not exert any effect. Similar but more significant results were observed in skin cells activated by growth-stimulating factors. The association of IL-4 and IFN-gamma mimicked the effects of IFN-gamma alone both in HF and HK. Taken together, these results indicate opposite effects of IFN-gamma and IL-4 on VEGF expression from normal and activated HF and HK. IL-4 may be considered as a poor modulator of VEGF secretion by dermal and epidermal cells. Conversely, IFN-gamma appears as a prominent and versatile mediator in the desregulated angiogenesis associated with inflammatory skin reactions characterized by a T-helper type 1 cell-mediated response.