Vascular endothelial growth factor (
VEGF) and
tumor necrosis factor-alpha (
TNF-alpha) show significant overlap with regard to their effects in the eye. It has been postulated that
VEGF-induced
leukostasis, breakdown of the blood-retinal barrier, and
ischemia-induced
retinal neovascularization may be mediated, at least in part, through
TNF-alpha. In this study, we used mice deficient in
TNF-alpha to test our hypothesis. Compared to wild type mice,
TNF-alpha-deficient mice showed an 80% reduction in leukocyte accumulation in retinal vessels after intravitreous injection of
VEGF, and 100% reductions after intravitreous
injections of
interleukin-1beta (IL-1beta) or
platelet-activating factor (PAF). The increase in
retinal vascular permeability induced by injection of PAF was significantly reduced in mice lacking
TNF-alpha, but
VEGF- and IL-1beta-induced leakage was unaffected. Compared to wild type mice with
oxygen-induced ischemic retinopathy,
TNF-alpha-deficient mice with ischemic retinopathy showed significantly reduced
leukostasis and mild reduction in vascular leakage, but no significant difference in
retinal neovascularization. These data suggest that
TNF-alpha mediates
VEGF-, IL-1beta-, and PAF-induced
leukostasis and vascular leakage mediated by PAF, but not leakage caused by
VEGF or IL-1beta.
Ischemia-induced
retinal neovascularization, which has previously been shown to require
VEGF, does not require
TNF-alpha and is unaffected by attenuation of
leukostasis.