The effect of TNF-alpha and IL-6 on the permeability of the rat blood-retinal barrier in vivo.

Abstract

The blood-retinal barrier (BRB), which is formed by the retinal vascular endothelium and the retinal pigment epithelium, is responsible for controlling the passage of cells and molecules into the neuroretina. During ocular inflammatory diseases, however, this selective control is altered due to changes in BRB function such as increased permeability and leucocyte recruitment. The causative factors leading to barrier breakdown are not entirely understood although cytokines have recently been implicated. We have investigated the effect of the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) upon the integrity of the rat BRB. Lewis rats received a dose of each cytokine by intravitreal injection and the permeability of the BRB was assessed using the smaller molecular weight vascular tracer 14C mannitol. A significant opening of the barrier to mannitol was detected following an intravitreal injection of 2 x 10(4) U of TNF-alpha which persisted from day 1 to day 5 post-injection (PI). The permeability of the BRB returned to normal values by day 7 PI. Only occasional mononuclear inflammatory cells were seen in the retina and vitreous of the TNF-alpha-treated eyes although they remained in evidence up to day 5 PI. In the TNF-alpha-infected eye there was immunohistological evidence of activation of tissue-resident cells, particularly in the inner plexiform layer. Of particular interest was the observation that the BRB of the non-injected contralateral eye also exhibited increased permeability over a similar time-course but without any evidence of cellular infiltration or activation of tissue-resident cells. Unlike TNF-alpha, the administration of 1 x 10(3) U of IL-6 into the vitreous caused no measurable increase in BRB permeability despite inducing a small infiltration of inflammatory cells.