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Y. Ueki, J. Wang, S. Chollangi, J. D. Ash; LIF Protection of Photoreceptor from Light Damage Correlates with Stat3 Activation. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3052.
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Activation of the receptor gp130 by IL-6 family cytokines, including leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF), is neuroprotective and prevents photoreceptor cell death in vivo. However, the mechanisms of protection in the retina remain largely unknown. The purpose of this study was to determine the signaling pathways downstream of gp130 that are responsible for neuroprotection.
Recombinant human LIF or a LIF antagonist, LIF05, was injected intravitreally to one eye of 5-6 week-old Balb/c mice. PBS was injected in the other eye as a control (n=6 mice per group). The first experiment was designed to determine if LIF prevented photoreceptor degeneration. To accomplish this, mice were exposed to 3000 lux of light for 4 hours, 2 days post injections. Following light exposure mice were retuned to normal mouse room lighting. Electroretinograms (ERG) were recorded 5 days after the light damage, and eyes were then collected for measurements of photoreceptor cell loss by histological evaluation. In the second experiment, retinas were collected 2 days after the injections for analysis of Stat3, Akt, and ERK1/2 activation. Activation was quantified by Western Blot using antibodies to phosphorylated and unphosphorylated proteins. The cellular localization of active signaling was measured by immunohistochemistry.
We observed LIF prevented loss of photoreceptors in a dose dependent manner. In the ERG analysis the a- and b- wave amplitudes were preserved by LIF injections. In LIF injected eye the thickness of the outer nuclear layer (ONL) was also preserved relative to uninjected, PBS or LIF05 injected eyes. Significant Stat3 activation was detected in LIF, but not in LIF05 or PBS injected retinas at the time of light exposure (2 days). Activated Stat3 was mainly localized in nuclei of inner retinal neurons and Muller cells. Neither LIF nor LIF05 lead to significant activation of Akt or Erk1/2 pathways at the time of light exposure.
LIF, but not PBS or LIF05, protects photoreceptors from degeneration induced by light damage. This protection correlated well with activation of Stat3 but not with activation of Akt or Erk1/2 pathways.
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