title: Redox-control of the alarmin, Interleukin-1α.
abstract: The pro-inflammatory cytokine Interleukin-1α (IL-1α) has recently emerged as a susceptibility marker for a wide array of inflammatory diseases associated with oxidative stress including Alzheimer's, arthritis, atherosclerosis, diabetes and cancer. In the present study, we establish that expression and nuclear localization of IL-1α are redox-dependent. Shifts in steady-state H2O2 concentrations (SS-[H2O2]) resulting from enforced expression of manganese superoxide dismutase (SOD2) drive IL-1α mRNA and protein expression. The redox-dependent expression of IL-1α is accompanied by its increased nuclear localization. Both IL-1α expression and its nuclear residency are abrogated by catalase co-expression. Sub-lethal doses of H2O2 also cause IL-1α nuclear localization. Mutagenesis revealed IL-1α nuclear localization does not involve oxidation of cysteines within its N terminal domain. Inhibition of the processing enzyme calpain prevents IL-1α nuclear localization even in the presence of H2O2. H2O2 treatment caused extracellular Ca(2+) influx suggesting oxidants may influence calpain activity indirectly through extracellular Ca(2+) mobilization. Functionally, as a result of its nuclear activity, IL-1α overexpression promotes NF-kB activity, but also interacts with the histone acetyl transferase (HAT) p300. Together, these findings demonstrate a mechanism by which oxidants impact inflammation through IL-1α and suggest that antioxidant-based therapies may prove useful in limiting inflammatory disease progression.
authors.affiliation: College of Nanoscale Sciences and Engineering, University at Albany, SUNY, Albany, NY 12203, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: McCarthy
authors.forename: Aparna
authors.initials: A
authors.lastname: Ranganathan
authors.forename: Sita
authors.initials: S
authors.lastname: Subbaram
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Flaherty
authors.forename: Nilay
authors.initials: N
authors.lastname: Patel
authors.forename: Mohamed
authors.initials: M
authors.lastname: Trebak
authors.forename: Nadine
authors.initials: N
authors.lastname: Hempel
authors.forename: J Andrés
authors.initials: JA
authors.lastname: Melendez
mesh_terms: D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000235:genetics* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D002118:Calcium; D002154:Calpain; D003545:Cysteine; D050881:E1A-Associated p300 Protein; D006861:Hydrogen Peroxide; D053582:Interleukin-1alpha; D016328:NF-kappa B; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C494360:EP300 protein, human
keywords: Catalase; Hydrogen peroxide; Inflammation; Interleukin-1α; Nuclear localization; Superoxide dismutase
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