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Background and purpose:  Subtle changes in the intracellular reduction–oxidation (redox) state can modulate nuclear factor‐κB (NF‐κB) activity. Thioredoxin‐1 (Trx) is a small, ubiquitous, redox‐active thiol (‐SH) protein that, with thioredoxin reductase‐1 (TrxR), modifies the redox status of NF‐κB pathway components. PMX464 is a novel thiol‐reactive quinol thought to inhibit the Trx/TrxR system. The aim of this work was to investigate whether PMX464 inhibited NF‐κB‐mediated proinflammatory activation of human type II alveolar epithelial cells (A549).    Experimental approach:  Intercellular adhesion molecule‐1 (ICAM‐1), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and CXCL8, NF‐κB DNA binding, nuclear translocation of NF‐κB p65 subunit, IκBα degradation, IκB phosphorylation and IκB kinase (IKK) activity were assessed in A549 cells stimulated with IL‐1β with or without PMX464 pretreatment. Effects of PMX464 on ICAM‐1 expression in human lung microvascular endothelial cells (HLMVEC) were also investigated. For comparison, selected measurements (ICAM‐1 and IκB‐α phospho‐IκB‐α) were made on A549 cells after RNA interference‐mediated silencing (siRNA) of Trx.    Key results:  PMX464 reduced ICAM‐1, GM‐CSF and CXCL8 expression in IL‐1β‐stimulated A549 cells and ICAM‐1 in HLMVEC. PMX464 inhibited IL‐1β‐induced NF‐κB DNA binding, nuclear translocation of NF‐κB p65 subunit and factors involved in NF‐κB activation; specifically, IκBα degradation, IκB phosphorylation and IκB kinase (IKK) activity in A549. By contrast, Trx siRNA did not alter ICAM‐1 expression or IκBα degradation/phosphorylation in IL‐1β‐stimulated A549 cells.    Conclusion and implications:  PMX464 inhibits a proinflammatory response in A549 cells targeting the NFκB pathway above IKK. The lack of effect with Trx siRNA suggests that PMX464 acts on thiol proteins, in addition to Trx, to elicit anti‐inflammatory responses in lung epithelial cells.   British Journal of Pharmacology  (2008)  155 , 661–672; doi: fn1 ; published online 30 June 2008

PMX464, a thiol‐reactive quinol and putative thioredoxin inhibitor, inhibits NF‐κB‐dependent proinflammatory activation of alveolar epithelial cells