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Retinal-Cell–Conditioned Medium Prevents TNF--Induced Apoptosis of Purified Ganglion Cells

From the Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, Institut National de la Santé et de la Recherche Médicale (INSERM) U592, Hôpital Saint-Antoine, Paris, France.

PURPOSE. Retinal ischemic processes occurring in glaucoma or diabetic retinopathy induce the secretion of tumor necrosis factor (TNF)-. This cytokine was reported to be either toxic to or protective of retinal ganglion cells (RGCs). In the present study, its effect on RGCs was analyzed in different culture conditions.

METHODS. Adult rat RGCs were prepared in mixed retinal cell cultures and in purified cultures. They were incubated in normoxic or ischemic conditions, in the presence or absence of TNF and/or conditioned media isolated from rat retinal glial cell cultures and from adult mixed retinal cell cultures.

RESULTS. In mixed retinal cell culture, RGCs were insensitive to TNF-, whereas it induced their degeneration in purified adult RGC cultures. This TNF-elicited toxicity was suppressed by TNF-R1-neutralizing antibodies or caspase 8/10 inhibitors. Analyses of mRNA and protein content in purified RGCs revealed a time-dependent reduction in the expression of the inhibitor of caspase-8, c-FLIP. c-FLIP mRNA was also undetectable after 5 days of culture in the presence of TNF. The retinal cell-conditioned medium protected the RGCs from TNF-induced death and prevented the decrease in c-FLIP mRNA and protein in purified cultures. This medium promoted NF-B translocation in purified RGCs, whereas an NF-B inhibitor induced RGC death in mixed retinal cells.

CONCLUSIONS. The results confirm that TNF can induce RGC death by TNF-R1 activation. They indicate, however, that other retinal cells can release a molecule that promotes NF-B translocation in RGCs, the synthesis of the anti-caspase-8, c-FLIP, and thereby prevents TNF-mediated RGC death.

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