Purpose: Growth arrest and DNA damage protein 45b (Gadd45b) functions as an intrinsic neuroprotective molecule protecting retinal ganglion cells (RGCs) from injury. This study was performed to elucidate further the induction pathway of Gadd45b expression in RGCs.
Methods: The induction of Gadd45b expression in response to TGFβNFκB signaling was investigated in RGC5 cultures in vitro and murine retina in vivo. Gadd45b mRNA and protein expression were detected by quantitative real-time RT-PCR, immunoblot assay, immunohistochemistry, and immunocytochemistry. Activation of NFκB and TGFβ/Gadd45b signaling were assessed by measuring phosphorylation of NFκB and using specific inhibitors. Gadd45b siRNA was transfected into RGC5 to silence Gadd45b mRNA expression.
Results: Expression of TGFβ receptors I and II was detected in RGC5 in vitro and RGCs in vivo. TGFβ induced abundant Gadd45b mRNA and protein expression, exhibiting a dose-dependent response in vitro. Exogenous TGFβ1 induced upregulation of Gadd45b expression in RGCs in murine retina in vivo. TGFβ stimulated phosphorylation of NFκB, and inhibition of NFκB phosphorylation blocked induction of Gadd45b by TGFβ in RGC5 cells. Induction of Gadd45b by TGFβ increased the resistance of RGC5 cells against TNFα cytotoxicity and paraquat oxidative stress.
Conclusions: TGFβ signaling induced Gadd45b expression in RGCs. Modulation of the TGFβ/NFκB/Gadd45b signaling pathway may provide a means to enhance the neuroprotective effect of Gadd45b in RGCs.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565994 | PMC |
| http://dx.doi.org/10.1167/iovs.12-10142 | DOI Listing |
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