Unsaturated oxidated fatty acid 12(S)-HETE attenuates TNF-alpha expression in TNF-alpha/IFN-gamma-stimulated human keratinocytes

Chronic skin inflammatory diseases are associated with abnormal immune responses characterized by skin barrier dysfunction. Keratinocytes participate in immune homeostasis regulated by immune cells. Immune homeostasis dysfunction contributes to the pathogenesis of skin diseases mediated by pro-inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-alpha, which are produced by activated keratinocytes. 12(S)Hydroxy eicosatetraenoic acid [12(S)-HETE], an arachidonic acid metabolite, has anti-inflammatory properties. However, the role of 12(S)-HETE in chronic skin inflammatory diseases has not been elucidated yet. In this study, we investigated the effect of 12(S)-HETE on TNF-alpha/interferon (IFN)-gamma-induced pro-inflammatory cytokine and chemokine expression. Our data showed that 12(S)-HETE modulates TNF- alpha mRNA and protein expression in TNF-alpha-/IFN-gamma-treated human keratinocytes. Molecular docking analyses demonstrated that 12(S)-HETE bound to extracellular signal-regulated kinase (ERK)1/2, thus preventing ERK activation and downregulating phosphorylated ERK expression. We also demonstrated that 12(S)-HETE treatment inhibited I kappa B and ERK phosphorylation and nuclear factor (NF)-kappa B, p65/p50, and CCAAT/enhancer binding protein beta (C/EBP beta) translocation. Overall, our results showed that 12(S)-HETE attenuated TNF- alpha expression and secretion by inhibiting the mitogenactivated protein kinase ERK/NF-kappa B and C/EBP beta signaling pathways. Overall, these results suggest that 12(S)HETE effectively resolved TNF-alpha-induced inflammation.

Automated summary

Chronic skin inflammatory diseases are associated with abnormal immune responses characterized by skin barrier dysfunction. Keratinocytes participate in immune homeostasis regulated by immune cells. Immune homeostasis dysfunction contributes to the pathogenesis of skin diseases mediated by pro-inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-alpha, which are produced by activated keratinocytes. Overall, these results suggest that 12(S)HETE effectively resolved TNF-alpha-induced inflammation.