Oxidants and inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha) activate transcription factors such as NF-kappaB. Interleukin-8 (IL-8) is a ubiquitous inflammatory chemokine that mediates a multitude of inflammatory events in the lung. Ergothioneine is a naturally occurring thiol compound, which possesses antioxidant property. The aim of this study was to determine whether ergothioneine can inhibit the hydrogen peroxide (H2O2)- and TNF-alpha-mediated activation of NF-kappaB and the release of IL-8 in human alveolar epithelial cells (A549). Treatment of A549 cells with H2O2 (100 muM) and TNF-alpha (10 ng/ml) significantly increased NF-kappaB activation using a reporter assay. Ergothioneine inhibited both H2O2- and TNF-alpha-mediated activation of NF-kappaB. Both H2O2 and TNF-alpha significantly increased IL-8 release, which was inhibited by pre-treatment of A549 cells with ergothioneine compared to the control untreated cells. Ergothioneine also abolished the transcriptional activation of IL-8 in an IL-8-chloramphenicol acetyltransferase (CAT) reporter system, transfected into A549 cells. This indicates a molecular mechanism for the anti-inflammatory effects of ergothioneine. (C) 2003 Published by Elsevier Science (USA).