title: Crucial involvement of xanthine oxidase in the intracellular signalling networks associated with human myeloid cell function.
abstract: Xanthine oxidase (XOD) is an enzyme which plays a central role in purine catabolism by converting hypoxanthine into xanthine and then further into uric acid. Here we report that XOD is activated in THP-1 human myeloid cells in response to pro-inflammatory and growth factor stimulation. This effect occurred following stimulation of THP-1 cells with ligands of plasma membrane associated TLRs 2 and 4, endosomal TLRs 7 and 8 as well as stem cell growth factor (SCF). Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) transcription complexes were found to be responsible for XOD upregulation. Importantly, the mammalian target of rapamycin (mTOR), a major myeloid cell translation regulator, was also found to be essential for XOD activation. Specific inhibition of XOD by allopurinol and sodium tungstate led to an increase in intracellular AMP levels triggering downregulation of mTOR activation by phosphorylation of its T2446 residue. Taken together, our results demonstrate for the first time that XOD is not only activated by pro-inflammatory stimuli or SCF but also plays an important role in maintaining mTOR-dependent translational control during the biological responses of human myeloid cells.
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB, United Kingdom.
authors.forename: Maryam
authors.initials: M
authors.lastname: Abooali
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB, United Kingdom.
authors.forename: Gurprit S
authors.initials: GS
authors.lastname: Lall
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Coughlan
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB, United Kingdom.
authors.forename: Harjinder S
authors.initials: HS
authors.lastname: Lall
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB, United Kingdom.
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Gibbs
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB, United Kingdom.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Sumbayev
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000502:physiology*; D010457:Peptidoglycan; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D019089:Stem Cell Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017973:Tungsten Compounds / Q000494:pharmacology; D014527:Uric Acid / Q000032:analysis; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D000493:Allopurinol; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D019089:Stem Cell Factor; D058570:TOR Serine-Threonine Kinases; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D018808:Transcription Factor AP-1; D017973:Tungsten Compounds; D014527:Uric Acid; D014969:Xanthine Oxidase; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C025399:sodium tungstate(VI); C546842:MTOR protein, human