TNF-alpha is critical for ischemia-induced leukostasis, but not retinal neovascularization nor VEGF-induced leakage

J Neuroimmunol. 2007 Jan;182(1-2):73-9. doi: 10.1016/j.jneuroim.2006.09.015. Epub 2006 Nov 14.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Retinal Barrier* / drug effects
  • Capillary Permeability / drug effects
  • Interleukin-1beta / pharmacology
  • Ischemia / chemically induced
  • Ischemia / complications*
  • Ischemia / metabolism*
  • Leukostasis / chemically induced
  • Leukostasis / etiology*
  • Mice
  • Mice, Knockout
  • Oxygen
  • Platelet Activating Factor / pharmacology
  • Retinal Neovascularization / metabolism*
  • Retinal Vessels*
  • Tumor Necrosis Factor-alpha / deficiency
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor A / pharmacology

Substances

  • Interleukin-1beta
  • Platelet Activating Factor
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Oxygen