Bcl‐3 induced by IL‐22 via STAT3 activation acts as a potentiator of psoriasis‐related gene expression in epidermal keratinocytes

Abstract

IL-22 induces STAT3 phosphorylation and mediates psoriasis-related gene expression.However, the signaling mechanism leading from pSTAT3 to the expression of these genes remains unclear. We focused on Bcl-3, which is induced by STAT3 activation and mediates gene expression. In cultured human epidermal keratinocytes, IL-22 increased Bcl-3, which was translocated to the nucleus with p50 via STAT3 activation. The increases in CXCL8, S100As and human β-defensin 2 mRNA expression caused by IL-22 were abolished by siRNA against Bcl-3. Although CCL20 expression was also augmented by IL-22, the knockdown of Bcl-3 increased its level. Moreover, the combination of IL-22 and IL-17A enhanced Bcl-3 production, IL-22-induced gene expression, and the expression of other psoriasis-related genes, including those encoding IL-17C, IL-19, and IL-36γ. The expression of these genes (except for CCL20) was also suppressed by the knockdown of Bcl-3. Bcl-3 overexpression induced CXCL8 and HBD2 expression but not S100As expression. We also compared Bcl-3 expression between psoriatic skin lesions and normal skin. Immunostaining revealed strong signals for Bcl-3 and p50 in the nucleus of epidermal keratinocytes from psoriatic skin. The IL-22-STAT3-Bcl-3 pathway may be important in the pathogenesis of psoriasis.Keywords: Bcl-3 r IL-22 r p50 r Psoriasis r STAT3 Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction IL-22 mainly affects epithelial cells and is important for defense against environmental insults such as infection and injury [1][2][3]. When skin is injured or invaded by a pathogen, IL-22 is produced by skin homing cells or recruited cells and signals through the IL-22 receptor (IL-22R) expressed on epidermal keratinocytes, Correspondence: Dr. Mikiko Tohyama e-mail: tohm@m.ehime-u.ac.jp resulting in an increased epidermal thickness and enhanced mRNA expression of various compounds, including S100 calcium-binding protein (S100A) family proteins, β-defensins, cytokines, and chemokines [4][5][6]. This response enhances cutaneous defenses and causes inflammation. These defense responses are enhanced in psoriasis, a chronic inflammatory cutaneous disease in which the skin exhibits a robust structure composed of a thick horny epidermal layer with altered keratinocyte differentiation and overexpression of antimicrobial peptides, cytokines, and chemokines from keratinocytes. It is thought that IL-22 and IL-17A mediate gene expression in the inflammatory response of psoriasis [7,8].www.eji-journal.eu Eur. J. Immunol. 2018. 48: 168-179 Allergy and inflammation 169Several studies have revealed important roles for STAT3 activation in the pathogenesis of psoriasis [9,10], and STAT3 is the principal mediator of IL-22 signaling [11,12]. Therefore, studies of IL-22-STAT3 signaling may be significant for elucidating the pathomechanisms of psoriasis. IL-22-responsive genes include CCL2 and suppressor of cytokine signaling 3 (SOCS3), which are known to be involved downstream o...

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