We previously demonstrated that endogenous interleukin-6 (IL-6) is upregulated and may be neuroprotective after retinal ischemia. The purpose of this study is to investigate the role of nuclear factor kappa-B (NF-κB) in regulating IL-6 expression after ischemia. NF-κB p65 mRNA levels were significantly elevated between 2 and 12 h after the insult. A high number of NF-κB p65 positive cells were detected in the inner retina at 12 h after ischemia. Activated nuclear NF-κB p65 and IL-6 were colocalized in cells, which were also marked by a microglial/phagocytic cell marker (ED1) in the inner retina. Carbobenzoxy- l -leucyl- l -leucyl- l -leucinal (MG-132, a proteasome inhibitor, which inhibits IκB degradation and hence prevents the activation and translocation of NF-κB into the nucleus) abolished the increase in NF-κB p65 mRNA levels after the insult, while there was no effect by helenalin (an inhibitor which inhibits NF-κB activity by alkylation of the p65 subunit, thereby blocking its binding to the target DNA). However, MG-132 and/or helenalin significantly diminished the increase in IL-6 mRNA levels after the insult. Small interfering RNAs (siRNAs, inhibit target gene expression through the sequence-specific destruction of the target messenger RNA) against NF-κB p65 significantly reduced the increase in NF-κB p65 mRNA levels as well as IL-6 mRNA levels after ischemia. The number of retinal ganglion cells (RGCs) was also significantly decreased using the inhibitors of NF-κB compared with those of the controls after ischemia. These findings support the hypothesis that upregulation of endogenous retinal IL-6 in retinal I/R injury in microglial/phagocytic cells is controlled predominantly by NF-κB p65.
Brain Research – Elsevier
Published: Apr 7, 2006
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