Abstract
Excess reactive oxygen species (ROS) formation can trigger various pathological conditions such as inflammation, in which xanthine oxidase (XO) is one major enzymatic source of ROS. Although XO has been reported to play essential roles in inflammatory conditions, the molecular mechanisms underlying the involvement of XO in inflammatory pathways remain unclear. Febuxostat, a selective and potent inhibitor of XO, effectively inhibits not only the generation of uric acid but also the formation of ROS. In this study, therefore, we examined the effects of febuxostat on lipopolysaccharide (LPS)-mediated inflammatory responses. Here we show that febuxostat suppresses LPS-induced MCP-1 production and mRNA expression via activating MAPK phosphatase-1 (MKP-1) which, in turn, leads to dephosphorylation and inactivation of JNK in macrophages. Moreover, these effects of febuxostat are mediated by inhibiting XO-mediated intracellular ROS production. Taken together, our data suggest that XO mediates LPS-induced phosphorylation of JNK through ROS production and MKP-1 inactivation, leading to MCP-1 production in macrophages. These studies may bring new insights into the novel role of XO in regulating inflammatory process through MAPK phosphatase, and demonstrate the potential use of XO inhibitor in modulating the inflammatory processes.
Highlights
Inflammation plays a fundamental role in a variety of chronic diseases such as atherosclerosis, rheumatoid arthritis, and chronic obstructive lung disease [1,2,3]
We have studied the effects of modulating xanthine oxidase (XO) activity by LPS, in particular its effects on MCP-1, a potent chemotactic factor for monocytes and dendritic cells, and investigated if inhibition of XO leads to an altered inflammatory response
To determine the effects of febuxostat on LPS-induced inflammatory responses, we examined whether febuxostat suppresses LPS-induced MCP-1 production in macrophages
Summary
Inflammation plays a fundamental role in a variety of chronic diseases such as atherosclerosis, rheumatoid arthritis, and chronic obstructive lung disease [1,2,3]. Excess ROS production by activated cells can provoke inflammation and tissue damage. Pharmacological inhibitors of XO, such as febuxostat, allopurinol and oxypurinol have been reported to have an anti-inflammatory effect in various diseases such as atherosclerosis, chronic heart failure, acute lung injury, renal interstitial fibrosis and ischemic-reperfusion injury [10,11,12,13,14,15]. These findings demonstrate the essential role of XO in inflammatory conditions. The mechanisms that link XO production to inflammation are not well understood
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