Induction of adaptive response and enhancement of PC12 cell tolerance by lipopolysaccharide primarily through the upregulation of glutathione S-transferase A3 via Nrf2 activation

Increasing evidence indicates that reactive oxygen species and other physiologically existing oxidative stimuli upregulate the antioxidant system, thereby triggering the adaptive response. In this study, We focused oil adaptive cytoprotection induced by lipopolysaccharide (LPS), which induces oxidative stress and inflammatory cytokines, in PC12 cells, a model of the neuronal cell. After treating PC12 cells with LPS at Sublethal concentrations, we found that they developed resistance to subsequent oxidative stress induced by 13S-hydroperoxy-9Z,11E-octadecadienoic acid and 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium. To determine the underlying molecular mechanisms responsible for all adaptive response induced by LPS, we studied the changes in the antioxidant system. LPS treatment resulted in all increase in the gene expression of glutathione S-transferase A3 (GST-A3) by LIP to 60-fold as Well as ill GST enzyme activity. A GST inhibitor and GSTA3 small interfering RNA effectively attenuated the adaptive response. The nuclear factor erythroid 2 p45-related factor 2 (Nrf2) was transcriptionally activated by LPS. Nrf2 small interfering RNA effectively attenuated the increase in GSTA3 mRNA level as well as the adaptive response induced by LIPS. In addition, peripheral injection of LPS at Sublethal concentrations increased GST enzyme activity in mouse brain. These findings, taken together, indicate that stimulation with LPS at Sublethal concentrations induces all adaptive response and enhances PC12 cell tolerance, primarily through the induction of GST A3 via the transcriptional activation of the Nrf2 signaling pathway. Crown Copyright (C) 2008 Published by Elsevier Inc. All rights reserved.