188 - Peroxiredoxin-5 as a Novel Actor in Inflammation and Tumor Suppression

Abstract

Peroxiredoxins are a superfamily of peroxidases widely distributed among prokaryotes and eukaryotes. Peroxiredoxin-5 (Prdx5) is the last isoform identified and characterized among the six mammalian peroxiredoxins. Prdx5 is ubiquitously expressed in tissues and its role as cytoprotective antioxidant enzyme has been largely reported in vitro. The goal of this work was to study Prdx5 function in vivo through the generation of transgenic mice in which Prdx5 gene has been disrupted using a gene-trap strategy. Prdx5 knockout (KO) mice are viable and fertile. Young KO mice do not suffer from any apparent defects. Behavioral tests and complete histological analyses of adult Prdx5 KO mice did not reveal major abnormalities. Microarray-based mRNA profiles of KO and WT mice showed that several CYP450 genes were highly upregulated in liver and brain of KO mice. Because Prdx5 gene has been shown to be upregulated in mouse macrophages upon pro-inflammatory stimulation, the vulnerability of Prdx5 KO mice to lipopolysaccharide (LPS) was examined. Our results show that Prdx5 KO mice mortality is higher after intraperitoneal injection of 20mg/kg and 10mg/kg of LPS, suggesting that Prdx5 may play key roles in inflammation either by protecting cells against oxidative damages by modulating inflammatory redox signaling or acting as damage-associated molecular pattern molecule. Finally, after 14 months, 20% of Prdx5 KO mice developed malignant cancers, mainly lymphoma, suggesting that Prdx5 may also function as a tumor suppressor.