Leukemia Inhibitory Factor Coordinates the Down-regulation of the Visual Cycle in the Retina and Retinal-pigmented Epithelium

Abstract

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.

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

“…However, because exogenous CNTF induces the release of a myriad of growth factors in the retina, it remains to be determined which signaling pathway contributes to the epigenetic changes observed in CNTF-treated retinas. Furthermore, intravitreal injection of LIF causes a downregulation of RPE65 protein, the key isomerase required in the RPE to restore the 11-cis-retinal chromophore, leading to a slower regeneration of rhodopsin (10). We also observed CNTFinduced STAT3 phosphorylation in RPE cells (Figs.…”

“…In addition, CNTF prolongs the survival of retinal ganglion cells (3)(4)(5) and promotes axonal growth in optic nerve crush or transection models (6)(7)(8). Furthermore, CNTF may affect the physiology and survival of RPE cells (9,10), which are critical in normal vision and retinal degenerative diseases. Based on its significant and broad neuroprotective effects in damaged retinas, a secreted form of human CNTF delivered from an encapsulated cell device has been tested in clinical trials and approved by the Food and Drug Administration (FDA) to treat retinitis pigmentosa (RP) and geographic atrophy (GA), a subset of age-related macular degeneration (AMD) (11)(12)(13)(14).…”

Retinal Pigmented Epithelial Cells Obtained from Human Induced Pluripotent Stem Cells Possess Functional Visual Cycle Enzymes in Vitro and in Vivo

“…Possible explanations are that aberrant post-translational modifications of RPE65 occurred because of the culture conditions, or unknown transcription factors to the AP-4, nuclear factor one, and octamerous elements could regulate the Rpe65 promoter activity (30,31). Other groups reported decreased expression of visual cycle enzymes after light exposure or under conditions of retinal detachment in vivo (24,32). Of note, leukemia inhibitory factor, an interleukin-6 family neurocytokine, could be up-regulated in response to different types of retinal stress and have neuroprotective activity through activation of the gp130 receptor/ STAT3 pathway in RPE in vivo (32).…”

“…Other groups reported decreased expression of visual cycle enzymes after light exposure or under conditions of retinal detachment in vivo (24,32). Of note, leukemia inhibitory factor, an interleukin-6 family neurocytokine, could be up-regulated in response to different types of retinal stress and have neuroprotective activity through activation of the gp130 receptor/ STAT3 pathway in RPE in vivo (32). In primary RPE cells, culture conditions may function as a stress inducer, but induced iPS-RPE cells could already have adjusted to culture conditions.…”

Transcription Factor SOX9 Plays a Key Role in the Regulation of Visual Cycle Gene Expression in the Retinal Pigment Epithelium

“…Down-regulation of visual cycle genes has been reported in various conditions, including light damage (8), retinal detachment (8), NaIO 3 -induced oxidative damage (9,10), subretinal injection of amyloid-␤ (1-42) (53), intravitreal injection of leukemia inhibitory factor (LIF) (54), and conditional inactivation of mitochondrial transcription factor A (Tfam) in mouse RPE (10). The gp130/STAT3 pathway is required for the effect of LIF (54).…”