Redox-control of the alarmin, Interleukin-1alpha.
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McCarthy DA, Ranganathan A, Subbaram S, Flaherty NL, Patel N, Trebak M, Hempel N, Melendez JA
Redox-control of the alarmin, Interleukin-1alpha.
Redox Biol. 2013 Apr 17;1:218-25. doi: 10.1016/j.redox.2013.03.001. eCollection 2013.
- PubMed ID
- 24024155 [ View in PubMed]
- Abstract
The pro-inflammatory cytokine Interleukin-1alpha (IL-1alpha) 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-1alpha are redox-dependent. Shifts in steady-state H2O2 concentrations (SS-[H2O2]) resulting from enforced expression of manganese superoxide dismutase (SOD2) drive IL-1alpha mRNA and protein expression. The redox-dependent expression of IL-1alpha is accompanied by its increased nuclear localization. Both IL-1alpha expression and its nuclear residency are abrogated by catalase co-expression. Sub-lethal doses of H2O2 also cause IL-1alpha nuclear localization. Mutagenesis revealed IL-1alpha nuclear localization does not involve oxidation of cysteines within its N terminal domain. Inhibition of the processing enzyme calpain prevents IL-1alpha 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-1alpha 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-1alpha and suggest that antioxidant-based therapies may prove useful in limiting inflammatory disease progression.