Psoriasis is a common chronic inflammatory and immune-mediated skin disease. Antagonists of TNF-alpha and, recently, IL-17 have proven to be highly effective in the treatment for psoriasis; however, the molecular mechanisms involved in the pathogenesis of psoriasis are poorly understood. Recently, we presented evidence that I kappa B zeta is a key regulator in the development of psoriasis through its role in mediating IL-17A-driven effects. Like IL-17A, IL-17F is produced by a variety of immune cells, and the expression of IL-17F is increased in psoriatic skin. The purpose of this study was to characterize the role of IL-17F in the regulation of I kappa B zeta expression and to investigate whether IL-17F regulates psoriasis-associated genes in human keratinocytes through I kappa B zeta. Here, we demonstrate that IL-17F stimulation induces I kappa B zeta expression at both the mRNA and the protein levels in normal human keratinocytes. Moreover, silencing I kappa B zeta by siRNA revealed that I kappa B zeta is a key regulator of specific IL-17F-inducible psoriasis-associated genes and proteins, including DEFB4/hBD2, S100A7, CCL20, IL-8 and CHI3L1. In addition, IL-17F-induced I kappa B zeta expression is mediated by a mechanism involving the p38 MAPK and NF-kappa B signalling pathways, as shown by the clear reduction in IL-17F-mediated expression of I kappa B zeta during chemical inhibition of these two signalling pathways. In summary, we present I kappa B zeta as a novel key regulator of IL-17F-driven effects in psoriasis. Thus, antagonists to I kappa B zeta could potentially provide a more targeted approach for treating psoriasis as well as for treating the other inflammatory and immune-mediated diseases for which IL-17-targeting drugs have recently been approved.