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Jiangang Wang, Jing Zhang, John Ash; Leukemia inhibitory factor expression can be induced by agonist of TLR-2 or gp130, and may require NF-kappa B or STAT3 binding to promoter elements. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3251.
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We and others have shown that stressed induced expression of leukemia inhibitory factor (LIF) in Müller cells is necessary for promoting photoreceptor survival in mice with inherited retinal degeneration mutations. The purpose of this study is to determine the role of Toll like receptor 2 (TLR2), the receptor gp130, and the transcription factors NF-kappa B or STAT3 in induced LIF expression.
TLR2, or gp130 knockout mice were exposed to damaging light. Electroretinography was measured to identify the retinal function and retinal histology was used to quantify the photoreceptor loss. For gene expression analysis, total RNA was extracted using Trizol (Invitrogen) and real-time PCR was used to confirm expression changes. Chromatin immunoprecipitation was used to identify the binding capacity to LIF promoter. Agonists of TLR2 or gp130 were given by intravitreal injections.
LIF expression was induced by either TLR2 agonist, LIF, or light stress. Induction by TLR2 agonist or light stress was abolished in the absence of TLR2. Cultured muller cells treated with TLR2 agonist also induced LIF expression, but not in the presence of NF-kappa B inhibitor. ChIP data demonstrate that both NF-kappa B and STAT3 bind the LIF promoter following injections of TLR2 agonists or LIF. In silico analysis of the LIF promoter identified multiple binding sites for both NF-kappa B and STAT3.
Our results suggest that activation of the TLR2/NF-kappa B pathway in Muller glial cells is necessary for induction of LIF expression, but that LIF can autoregulate its own expression after induction. The results also suggest that LIF can be induced by other members of the IL-6 family, or other cytokines that signal through NF-kappa B or STAT3.
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