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Characterization of TNFα- and IL-17A-mediated synergistic induction of DEFB4 gene expression in human keratinocytes through IκBζ

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Human β-defensin 2 (hBD2), encoded by the DEFB4 gene, is an antimicrobial peptide playing an essential role in inflammatory processes in the skin. hBD2 expression is regulated synergistically by TNFα and IL-17A, however, the underlying regulatory mechanisms behind are unknown. The purpose of this study was to characterize the molecular mechanism by which TNFα and IL-17A synergistically induce hBD2 expression. In cultured human keratinocytes we demonstrate that a constitutive non-inducible binding of the transcription factor OCT1 to the DEFB4 promoter is crucial for IL-17A/TNFα-mediated synergistic induction of hBD2, but not the synergistic induction of CCL20, IL-8, IL-17C and LCN2. Interestingly, stimulation with IL-17A results in a p38 MAPK-dependent accumulation of IκBζ, which is a necessity for synergistic induction of hBD2. Finally, co-stimulation with TNFα induces DNA binding of NF-κB and AP-1 to two specific sites in the DEFB4 promoter region. Hence, our study demonstrates how two inflammatory stimuli are integrated by three different signaling pathways into the regulation of one specific target gene involving the three specific transcription factors OCT1, NF-κB, and AP-1 as well as the transcriptional co-factor, IκBζ. These findings may be important in psoriasis where TNFα and IL-17A have been identified as key pathogenic cytokines.

Original languageEnglish
JournalThe Journal of Investigative Dermatology
Publication statusPublished - 23 Apr 2016

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