Redox-control of the alarmin, Interleukin-1α

The pro-inflammatory cytokine Interleukin-1 alpha (IL-1 alpha) 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-1 alpha are redox-dependent. Shifts in steady-state H2O2 concentrations (SS-[H2O2]) resulting from enforced expression of manganese superoxide dismutase (SOD2) drive IL-1 alpha mRNA and protein expression. The redox-dependent expression of IL-1 alpha is accompanied by its increased nuclear localization. Both IL-1 alpha expression and its nuclear residency are abrogated by catalase co-expression. Sub-lethal doses of H202 also cause IL-1 alpha nuclear localization. Mutagenesis revealed IL-1 alpha nuclear localization does not involve oxidation of cysteines within its N terminal domain. Inhibition of the processing enzyme calpain prevents IL-1 alpha nuclear localization even in the presence of H202. H202 treatment caused extracellular Ca2+ influx suggesting oxidants may influence calpain activity indirectly through extracellular Ca2+ mobilization. Functionally, as a result of its nuclear activity, IL-1 alpha 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-1 alpha and suggest that antioxidant-based therapies may prove useful in limiting inflammatory disease progression. (C) 2013 The Authors. Published by Elsevier By. Open access under CCM hcense