Induction of peroxiredoxin I gene expression by LPS involves the Src/PI3K/JNK signalling pathway

Peroxiredoxin I (Prx I) belongs to a family of proteins with thiol-dependent peroxidase activity and is involved in the cellular protection against oxidative stress, the modulation of intracellular signalling cascades as well as the regulation of cell proliferation and apoptosis. In RAW 264.7 mouse macrophage cells Prx I was up-regulated on the mRNA and protein level by lipopolysaccharide (LPS). Treatment of cells with LPS increased the phosphorylation of c-Jun-NH2 terminal kinase (JNK) and protein kinase B (PKB). Both SP600125, an inhibitor of JNK, and LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), dose-dependently decreased LPS-induced Prx I mRNA expression. Furthermore, up-regulation of Prx I mRNA by LPS was diminished by the Src tyrosine kinase inhibitor PP2 and the iNOS inhibitor L-NMMA. LPS-dependent induction of Prx I is likely mediated by an activator protein-1 site within the Prx I promoter region binding JunB and c-Fos. In contrast, NFκB was not involved in the activation of Prx I transcription. Our results suggest that the up-regulation of Prx I gene expression by LPS is part of the cellular response to stress and may protect against oxidative stress-related injury in RAW 264.7 cells.