Allopurinol suppresses expression of the regulatory T‐cell migration factors TARC/CCL17 and MDC/CCL22 in HaCaT keratinocytes via restriction of nuclear factor‐κB activation

Abstract Recent studies have shown that sparse distribution of regulatory T cells (Tregs) in the skin might be involved in the onset of severe cutaneous adverse drug reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis. Treg migration toward epithelial cells is regulated by certain chemokines, including TARC/CCL17 and MDC/CCL22. In this study, we analyzed the effect of allopurinol (APN), a drug known to cause severe adverse reactions, on the expression of factors affecting Treg migration and the mechanisms involved. APN inhibited the tumor necrosis factor (TNF)‐α‐ and interferon (IFN)‐γ‐associated expression of TARC / CCL17 and MDC / CCL22 mRNA in HaCaT cells in a dose‐dependent manner. Consistent with this, APN also suppressed TNF‐α‐ and IFN‐γ‐induced production of TARC/CCL17 and MDC/CCL22 proteins and the migration of C‐C chemokine receptor type 4‐positive cells. Activity of the transcription factors NF‐κB and STAT1, which are involved in TARC/CCL17 and MDC/CCL22 expression, was also investigated. APN inhibited activation of NF‐κB, but not that of STAT1. Furthermore, it restricted p38 MAPK phosphorylation. These results suggest that APN inhibits TNF‐α‐ and IFN‐γ‐induced TARC/CCL17 and MDC/CCL22 production through downregulation of p38 MAPK and NF‐κB signaling, resulting in the sparse distribution of Tregs in the skin of patients with APN‐associated Stevens–Johnson syndrome/toxic epidermal necrolysis.