Leukemia Inhibitory Factor (LIF) Downregulates the Synthesis of 11-cis Retinaldehyde by RPE and its Utilization in Photoreceptors

CHUCAIR-ELLIOTT A.J.; WANG J; ELLIOTT MH; MOISEYEV GP; MA JX; POLITI LE; ROTSTEIN NP; AKIRA S; UEMATSU S; ASH J

JOURNAL OF BIOLOGICAL CHEMISTRY (ONLINE)

American Society for Biochemistry and Molecular Biology

Año: 2012 vol. 287 p. 24092 - 24102

1083-351X

Leukemia inhibitory factor (LIF), an interleukin-6 (IL-6) family neurocytokine, is upregulated 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 downregulate RPE65, the central enzyme in the visual cycle that provides the 11-cis Retinal (11-cis RAL) chromophore to photoreceptors, in vivo. We generated conditional knockout 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 downregulation 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 RAL.