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C. Grimm, M. Samardzija, S. Joly, K. Schwerdtfeger; Molecular Signaling During Retinal Degeneration in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa. The Role of Leukemia Inhibitory Factor and Caspase-1. Invest. Ophthalmol. Vis. Sci. 2007;48(13):571.
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Retinal expression of Caspase-1 (Casp-1) and of several cytokines of the interleukin-6 family is induced during photoreceptor degeneration in the VPP mouse, a model for autosomal dominant Retinitis Pigmentosa (adRP). Here we analyzed the role of leukemia inhibitory factor (LIF) in the degenerative process.
VPP mice were crossed with LIF and Casp-1 knockout mice, respectively, to generate double mutant mice. Single mutant, double mutant and wild type mice were analyzed at different timepoints postnatally. Retinal degeneration was monitored by light-microscopy and by rhodopsin quantification. Molecular signaling was assessed using in situ hybridization, real-time PCR and Western blotting.
VPP-mediated photoreceptor degeneration strongly induced the expression of LIF, cardiotrophin like cytokine (CLC), monocyte chemoattractant protein-1 (MCP-1) and of Pro-Casp-1 among other factors. In addition signal transducer and activator of transcription-3 (STAT3) was activated through phosphorylation. Lack of Casp-1 significantly slowed while lack of LIF significantly accelerated retinal degeneration in the VPP mice. Ablation of Casp-1 superinduced expression of LIF and of MCP-1 and slightly increased the level of p-STAT3 (activated form). In marked contrast, lack of LIF reduced p-STAT3 to basal levels. Surprisingly, lack of LIF also reduced expression of GFAP in Muller cells. In situ hybridization experiments suggested an upregulation of LIF expression in the INL, probably in Muller cells, in a model of light induced retinal degeneration.
Casp-1 and LIF have opposite effects on the progression of photoreceptor apoptosis in the VPP mice. Whereas Casp-1 is a factor supporting degeneration, LIF may be a protective factor. Since Casp-1 activity was not detected in retinal extracts of the VPP mice, Pro-Casp-1 may act through another pathway to modulate cell survival and cell death. Such a pathway may involve the control of MCP-1 expression, a factor with suggested neuroprotective activity. LIF may act neuroprotective through the anti-apoptotic transcription factor STAT3. Without LIF, a putative STAT3-dependent survival pathway may not be activated in the retinas of VPP mice causing the balance of pro- and anti-apoptotic signals to shift in favor of cell death. The expression pattern of LIF and GFAP in degenerating retinas of the various mutant mice suggest a prominent role of Muller cells in the determination of photoreceptor cell fate.
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