Febuxostat, an Inhibitor of Xanthine Oxidase, Suppresses Lipopolysaccharide-Induced MCP-1 Production via MAPK Phosphatase-1-Mediated Inactivation of JNK
Open Access
- 25 September 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (9), e75527
- https://doi.org/10.1371/journal.pone.0075527
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.Keywords
This publication has 27 references indexed in Scilit:
- Use of xanthine oxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis in unilateral ureteral obstructive nephropathyClinical and Experimental Nephrology, 2012
- The role of peroxidases in the pathogenesis of atherosclerosisBMB Reports, 2011
- Febuxostat inhibition of endothelial-bound XO: Implications for targeting vascular ROS productionFree Radical Biology & Medicine, 2011
- The role of nitrite ion in phagocyte function—perspectives and puzzlesArchives of Biochemistry and Biophysics, 2009
- Redox signalling and the inflammatory response in rheumatoid arthritisClinical and Experimental Immunology, 2008
- Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type dietFree Radical Biology & Medicine, 2006
- The Role of Mitogen-activated Protein Kinase Phosphatase-1 in the Response of Alveolar Macrophages to LipopolysaccharideOnline Journal of Public Health Informatics, 2005
- Febuxostat (TMX-67), a novel, non-purine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers.Nucleosides, Nucleotides and Nucleic Acids, 2004
- Role of Increased Production of Superoxide Anions by NAD(P)H Oxidase and Xanthine Oxidase in Prolonged EndotoxemiaHypertension, 1999
- Upregulation of Xanthine Oxidase by Lipopolysaccharide, Interleukin-1, and HypoxiaAmerican Journal of Respiratory and Critical Care Medicine, 1998