Sofie Kaas Ovesen, Klaus Schulze-Osthoff, Lars Iversen, Claus Johansen
DOI: 10.2340/00015555-3749

The interleukin (IL)-36 cytokine family plays an essential role in inflammatory processes in the skin and is implicated in the pathogenesis of psoriasis. This study explored the role of IL-36 in psoriasis and investigated the molecular mechanism involved in tumour necrosis factor-α (TNFα)/IL-17A-mediated IL-36 induction. In human keratinocytes IL-36 expression was strongly upregulated by combined TNFα and IL-17A stimulation. Moreover, IκBζ, encoded by NFKBIZ, was identified as a key regulator required for TNFα/IL-17A-induced IL-36γ expression. TNFα/IL-17A-induced IL-36γ expression also involved the nuclear factor κB (NF-κB), p38 mitogen-activated protein kinase and ERK1/2 signalling pathways. Furthermore, a specific NF-κB DNA-binding site in the promoter region of IL36G responsible for the TNFα/IL-17A-induced IL36G gene expression was identified. Finally, in a cohort of patients with psoriasis receiving anti-IL-17A treatment, a positive correlation was found between the expression of NFKBIZ and IL36G. In conclusion, these data reveal a novel crucial regulatory mechanism by which TNFα and IL-17A regulate IL-36γ expression.

Psoriasis is a common chronic skin disease. The skin cells play a crucial role in the psoriasis disease mechanism by producing key disease promoting factors such as interleukin-36γ and IκBζ in response to interleukin-17A and tumour necrosis factor-α. In this study, we identify IκBζ as an essential regulatory factor for interleukin-17A- and tumour necrosis factor α-mediated induction of interleukin-36γ in human skin cells. Moreover, we identified a specific DNA sequence in the promoter region of IL36G (the gene encoding interleukin-36γ) which was responsible for the interleukin-36γ expression. In addition, in a cohort of psoriasis patients receiving anti-interleukin-17A treatment, we demonstrated a strong correlation between the expression of IκBζ and interleukin-36γ.

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