Leukemia inhibitory factor (LIF), an interleukin-6 family neurocytokine, is up-regulated in response to different types of retinal stress and has neuroprotective activity through activation of the gp130 receptor/STAT3 pathway. We observed that LIF induces rapid, robust, and sustained activation of STAT3 in both the retina and retinal pigmented epithelium (RPE). Here, we tested whether LIF-induced STAT3 activation within the RPE can down-regulate RPE65, the central enzyme in the visual cycle that provides the 11-cis-retinal chromophore to photoreceptors in vivo. We generated conditional knock-out mice to specifically delete STAT3 or gp130 in RPE, retina, or both RPE and retina. After intravitreal injection of LIF, we analyzed the expression levels of visual cycle genes and proteins, isomerase activity of RPE65, levels of rhodopsin protein, and the rates of dark adaptation and rhodopsin regeneration. We found that RPE65 protein levels and isomerase activity were reduced and recovery of bleachable rhodopsin was delayed in LIF-injected eyes. In mice with functional gp130/STAT3 signaling in the retina, rhodopsin protein was also reduced by LIF. However, the LIF-induced down-regulation of RPE65 required a functional gp130/STAT3 cascade intrinsic to RPE. Our data demonstrate that a single cytokine, LIF, can simultaneously and independently affect both RPE and photoreceptors through the same signaling cascade to reduce the generation and utilization of 11-cis-retinal.
Background: Neurocytokines (LIF and CNTF) mediate photoreceptor protection and down-regulation of phototransduction.
Results: LIF down-regulates the visual cycle decreasing RPE65 expression and activity through activation of STAT3 in RPE.
Conclusion: The gp130/STAT3 pathway is independently modulated in RPE and retina for coordinated control of visual cycle activity.
Significance: A single, endogenous paracrine factor (LIF) can stimulate RPE cells to reduce production of 11-cis-retinal.
This work was supported, in whole or in part, by National Institutes of Health Grants R01EY16459 (to J. D. A.), R01EY012231 (to J. X. M.), R01EY018659 (to J. X. M.), R01EY019309 (to J. X. M.), R01EY019494 (to M. H. E.), EY012190 (NEI core grant), and Grants RR024215 and RR017703 (Center of Biomedical Research Excellence). This work was also supported by Foundation Fighting Blindness and an unrestricted grant from Research to Prevent Blindness, Inc.
