Interleukin-6 as a Photoreceptor Neuroprotectant in an Experimental Model of Retinal Detachment

Retinal detachment (RD), defined as the separation of the neurosensory retina from subjacent retinal pigment epithelium (RPE), results in the apoptotic death of photoreceptor cells.1-4 Rodent and feline models of RD have demonstrated the activation of proapoptotic pathways nearly immediately after the retina becomes separated from the RPE.1-4 Histologic markers of apoptosis, such as terminal deoxynucleotidyl transferase nick-end label (TUNEL) staining, reach a peak at approximately 3 days after RD, with apoptotic activity and progressive cell death persisting for the duration of the detachment period. Clinical experience in the repair of retinal detachments, however, has demonstrated that there is a window of opportunity for repair with preservation of good visual acuity. Retrospective case series have demonstrated that significant numbers of patients with macula-off RDs repaired within 5 to 10 days after onset of detachment can retain relatively good visual function but that visual acuity drops significantly as the time between detachment and repair extends.5-7 The delayed time between the activation of proapoptosis pathways and the clinical onset of visual loss suggests that intrinsic neuroprotective factors may become activated within the neural retina and may serve to counterbalance the effects of the proapoptotic pathways activated by retinal–RPE separation. Previous work in our laboratory using gene microarray analysis of experimental detachment in rats revealed the increased expression of genes involved in stress–response pathways.8 Of particular interest was the increased transcription and translation of interleukin (IL)-6 and downstream components of its associated signal transduction pathway. IL-6 is a pleiotropic cytokine with a role in inflammation, hematopoiesis, angiogenesis, cell differentiation, and neuronal survival.9-11 In the central nervous system, IL-6 is synthesized by microglia, astrocytes, and neurons.12,13 In the retina, IL-6 is synthesized by Muller cells and the RPE.14,15 A neuroprotective role for IL-6 has been previously suggested in different models of ocular injury. In rat models of retinal ischemia–reperfusion injury, IL-6 protein levels are upregulated within 8 hours after injury.16 Furthermore, intravitreal injection of exogenous IL-6 immediately after ischemia–reperfusion injury or before N-methyl-d-aspartate (NMDA)-induced toxicity increases survival of retinal ganglion cells.16,17 In vitro studies have shown that IL-6 increases the duration of rat retinal ganglion cell survival in primary tissue culture.18,19 Collectively, these data suggest that IL-6 upregulation after injury may serve to function as a neuronal survival factor. The goal of this study is to test the hypothesis that IL-6 functions as an inhibitor of photoreceptor apoptosis after RD. Understanding the effect of IL-6 on photoreceptor survival may provide insight into potential therapeutic strategies for protecting photoreceptors during periods of photoreceptor–RPE separation.