Tumor necrosis factor alpha (TNF alpha) is a pro-inflammatory cytokine involved in innate immune response, as well as in the pathogenesis of many inflammatory diseases. Although several response elements in the TNF alpha promoter region are involved in the activation of gene transcription, few studies have examined the regulatory mechanism that controls TNF alpha autoregulation. In this study, we investigated the role of the Early Growth Response-1 (EGR-1) transcription factor in TNF alpha autoregulation in HaCaT human keratinocytes. The requirement for EGR-1 in TNF alpha autoregulation was confirmed using a construct harboring a point mutation in the EGR-1 binding site within the TNF alpha promoter and the introduction of EGR-1 siRNA. Inhibition of the ERK or JNK pathway suppressed TNF alpha-induced EGR-1 expression, resulting in the inhibition of TNF alpha-induced TNF alpha promoter activation. These results reveal that the ERK and JNK MAPK pathways contribute to the autoregulation of TNF alpha. synthesis via EGR-1 induction in HaCaT keratinocytes. (C) 2008 Elsevier Inc. All rights reserved.