Thioredoxin improves contact dermatitis through an anti-inflammatory mechanism different from glucocorticoids

Thioredoxin (TRX), a redox-regulatory protein of 12 kDa, plays an essential role in modulating oxidative stress and mediating inflammatory processes. In this study, we compared and analyzed the anti-inflammatory effects of topically applied recombinant human TRX (rhTRX), hydrocortisone, and their combination on murine models of contact dermatitis (CD). Topical application of rhTRX, hydrocortisone, and their synergistic combination notably ameliorated ear edema, reduced neutrophilic infiltration within the ear tissues and suppressed the production of cytokines. We explored the distinct anti-inflammatory mechanisms of rhTRX versus hydrocortisone in phorbol-12-myristate-13-acetate (PMA)-induced PAM212 cells. These treatments collectively downregulated the phosphorylation of p-JNK and p-P38 mitogen-activated protein kinases (MAPKs) in the cells. In addition, rhTRX did not impact the proliferation of CD4+ and CD8+ T lymphocytes. Notably, rhTRX directly downregulated macrophage migration inhibitory factor (MIF), whereas it had no effects on the glucocorticoid-induced leucine zipper (GILZ). Collectively, these findings delineated that rhTRX ameliorated CD by curtailing MAPK pathway, and enhancing glucocorticoid responsiveness through the targeted downregulation of MIF. Consequently, it holds promise as a therapeutic agent for the treatment of CD and warrants further investigation in translational research.