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J. D. Ash, J. Wang, A. J. Chucair-Elliott, Y. Ueki; Stat3 is Essential for Chronic Stress-Induced Endogenous Protection of Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3701.
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We have previously found that gp130 activation, a common signal-transducing receptor for the IL-6 family of cytokines, is essential for stress-induced endogenous protection of photoreceptors. Gp130 is believed to signal through three signal transduction pathways including PI3K/Akt, Erk1/2, and the Jak/STAT3 pathways. The purpose of this study was to determine whether STAT3 and/or Akt are required for endogenous protection of photoreceptors.
Retina-specific gp130 (gp130f/f; Chx10-cre+) and STAT3 (STAT3f/f; Chx10-cre+) knockout (KO) mice were generated using the Cre/lox system. Mice with total knockout of Akt2 were also used. Endogenous protection was experimentally induced by exposure to sublethal cyclic light (800 lux) for 6 days (preconditioning). Light damage was induced with 3000 lux light for 4 hrs. Photoreceptor function and survival were evaluated by electroretinography (ERG) and morphometric analyses. The effect of gp130 or STAT3 loss on the rate of photoreceptor degeneration in a model of autosomal dominant retinitis pigmentosa was assessed by crossing retina-specific gp130 KO and STAT3 KO with VPP transgenic mice. STAT3 activation under chronic stress was measured by Western blot.
Wildtype mice and Akt2 knockout mice had robust preconditioning induced protection from light damage as demonstrated by ERG and histology. In contrast, mice lacking gp130 or STAT3 in the retina had significantly reduced protection of photoreceptors. Mice lacking gp130 or STAT3 in the retina had normal photoreceptors on their own. However, VPP mice lacking gp130 or STAT3 demonstrated significantly faster degeneration than the parental VPP mice.
Our data show that the absence of gp130 or STAT3 in the retina impairs stress-induced endogenous protection and increases sensitivity to both light- and genetically-induced photoreceptor cell death. This study provides direct evidence that gp130-STAT3 activation in the retina is essential for endogenous photoreceptor protection from chronic stress. Data also suggests that activation of STAT3 can compensate for the loss of Akt2, and that Akt2 is not playing a role in preconditioning induced protection.
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