Redox-control of the alarmin, Interleukin-1α

Donald A. McCarthy, Aparna Ranganathan, Sita Subbaram, Nicole L. Flaherty, Nilay Patel, Mohamed Trebak, Nadine Hempel, J. Andrés Melendez

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19 Scopus citations

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-1a 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-1a 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 Ca2+ influx suggesting oxidants may influence calpain activity indirectly through extracellular Ca2+ mobilization. Functionally, as a result of its nuclear activity, IL-1α over-expression 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.

Original languageEnglish (US)
Pages (from-to)218-225
Number of pages8
JournalRedox Biology
Volume1
Issue number1
DOIs
StatePublished - Jan 1 2013

All Science Journal Classification (ASJC) codes

  • Organic Chemistry
  • Clinical Biochemistry

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    McCarthy, D. A., Ranganathan, A., Subbaram, S., Flaherty, N. L., Patel, N., Trebak, M., Hempel, N., & Melendez, J. A. (2013). Redox-control of the alarmin, Interleukin-1α. Redox Biology, 1(1), 218-225. https://doi.org/10.1016/j.redox.2013.03.001