Abstract
Peroxisomes are metabolically active organelles which are known to exert anti-inflammatory effects especially associated with the synthesis of mediators of inflammation resolution. However, the role of catalase and effects of peroxisome derived reactive oxygen species (ROS) caused by lipid peroxidation through 4-hydroxy-2-nonenal (4-HNE) on lipopolysaccharide (LPS) mediated inflammatory pathway are largely unknown. Here, we show that inhibition of catalase by 3-aminotriazole (3-AT) results in the generation of peroxisomal ROS, which contribute to leaky peroxisomes in RAW264.7 cells. Leaky peroxisomes cause the release of matrix proteins to the cytosol, which are degraded by ubiquitin proteasome system. Furthermore, 3-AT promotes the formation of 4HNE-IκBα adduct which directly interferes with LPS induced NF-κB activation. Even though, a selective degradation of peroxisome matrix proteins and formation of 4HNE- IκBα adduct are not directly related with each other, both of them are could be the consequences of lipid peroxidation occurring at the peroxisome membrane.
Highlights
Peroxisomes are essential organelle widely known for its role in the oxidation of very-long chain and branched chain fatty acids as well as biosynthesis of bile acid and ether phospholipid [1, 2]
This study provides an interesting evidence that 3-AT mediated inhibition of catalase activity results in the accumulation of peroxisomal reactive oxygen species (ROS) which contribute to a selective degradation of
A proposed mechanism for the interference of NF-κB activation presented here is strikingly different from our earlier reports [16, 17], in which we have suggested that 3-AT protects cells from cobalt chloride mediated cytotoxicity through preventing intracellular ROS generation in a catalase independent manner
Summary
Peroxisomes are essential organelle widely known for its role in the oxidation of very-long chain and branched chain fatty acids as well as biosynthesis of bile acid and ether phospholipid [1, 2]. Numerous independent studies have validated that peroxisome deficiency and condition in which cell loss its’ ability to maintain catalase function lead to an increase of oxidative stress [5,6,7,8]. 3-Aminotriazole (3-AT) is a well-known irreversible catalase inhibitor [13, 14] It has been employed in the numerous studies to analyse the effect of ROS on cytotoxicity and adipogenesis [14, 15]. We have demonstrated that 3-AT attenuates cobalt chloride induced cytotoxicity through inhibiting of ROS generation and pro-inflammatory cytokines in a catalase independent manner [16, 17]. It is reasonable to speculate that 3-AT might modulate LPS induce pro-inflammatory pathway in macrophages either through inhibition of catalase or enhancement of pexophagy. 3-AT prevents phosphorylation of IκBα through promoting the formation of 4HNE-IκBα adduct which directly interferes with LPS induced NF-κB activation and expression of pro-inflammatory cytokines
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