Leukemia inhibitory factor coordinates the down-regulation of the visual cycle in the retina and retinal-pigmented epithelium.
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.
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
Ana J
AJ
Chucair-Elliott
Michael H
MH
Elliott
Jiangang
J
Wang
Gennadiy P
GP
Moiseyev
Jian-Xing
JX
Ma
Luis E
LE
Politi
Nora P
NP
Rotstein
Shizuo
S
Akira
Satoshi
S
Uematsu
John D
JD
Ash
D000818:Animals; D015153:Blotting, Western; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004596:Electroretinography; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D019745:cis-trans-Isomerases / Q000235:genetics / Q000378:metabolism; D000099178:Retinoid Isomerohydrolase
D050822:Cytokine Receptor gp130; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C494200:Il6st protein, mouse