IL-17A plays a central role in the expression of psoriasis signature genes through the induction of IκB-ζ in keratinocytes

Abstract

In psoriasis lesions, a diverse mixture of cytokines is up-regulated that influence each other generating a complex inflammatory situation. Although this is the case, the inhibition of IL-17A alone showed unprecedented clinical results in patients, indicating that IL-17A is a critical inducer of psoriasis pathogenesis. To elucidate IL-17A-driven keratinocyte-intrinsic signaling pathways, we treated monolayers of normal human epidermal keratinocytes in vitro with a mixture of six cytokines (IL-17A, TNF-α, IL-17C, IL-22, IL-36γ and IFN-γ) involved in psoriasis to mimic the inflammatory milieu in psoriasis lesions. Microarray and gene set enrichment analysis revealed that this cytokine mixture induced similar gene expression changes with the previous transcriptome studies using psoriasis lesions. Importantly, we identified a set of IL-17A-regulated genes in keratinocytes, which recapitulate typical psoriasis genes exemplified by DEFB4A, S100A7, IL19 and CSF3, based on the differences in the expression profiles of cells stimulated with six cytokines versus cells stimulated with only five cytokines lacking IL-17A. Furthermore, a specific IL-17A-induced gene, NFKBIZ, which encodes IκB-ζ, a transcriptional regulator for NF-κB, was demonstrated to have a significant role for IL-17A-induced gene expression. Thus, we present novel in vitro data from normal human keratinocytes that would help elucidating the IL-17A-driven keratinocyte activation in psoriasis.

Human S100A7 Induces Mature Interleukin1α Expression by RAGE-p38 MAPK-Calpain1 Pathway in Psoriasis

“…[33] In order to identify which cytokine is relevant to hS100A7 expression, we treated with NHEKs by different inflammatory cytokines. As shown in Fig 6A, hS100A7 is strongly induced by IL-17a, and IL-22 and IL-36γ also up-regulate the expression of hS100A7.…”

Yin and yang of interleukin-17 in host immunity to infection

“…Moreover, P. gingivalis infection predisposes the patient to the potential risk of acquiring autoimmune disorders, specifically rheumatoid arthritis (RA) 161, 162 through excessive inflammation (induced by IL-17) or generation of autoantibodies. As a result, diseases such as psoriasis 163 , RA 164 , and contact dermatitis 165 are emerging as particularly strong IL-17-driven disorders. Similarly, excessive IL-17 leads to the upregulation of neutrophil-attracting chemokines and subsequent neutrophil infiltration and inflammation during COPD 166, 167 .…”

IκBζ is a key player in the antipsoriatic effects of secukinumab

“…[10][11][12] The exact mechanism by which IkBz is regulated on IL-17A stimulation is not known, although Act1 has been demonstrated to play an essential role in human keratinocytes. 13 The facts that NFKBIZ is identified as a psoriasis susceptibility locus 13 and that IkBz is demonstrated to be important in the development of psoriasis by mediating IL-17A downstream effects 14,15 highly suggest that IkBz plays an important role in the pathogenesis of psoriasis.…”