Etanercept suppresses regenerative hyperplasia in psoriasis by acutely downregulating epidermal expression of interleukin (IL)-19, IL-20 and IL-24

Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
British Journal of Dermatology (Impact Factor: 4.28). 03/2012; 167(1):92-102. DOI: 10.1111/j.1365-2133.2012.10961.x
Source: PubMed


Psoriasis is a Th17/Th1-mediated skin disease that often responds to antitumour necrosis factor (TNF)-α therapies, such as etanercept.
To better define mechanisms by which etanercept improves psoriasis and to gain insight into disease pathogenesis.
We investigated the early biochemical and cellular effects of etanercept on skin lesions in responder patients prior to substantial clinical improvement (≤ 4 weeks).
By 1 week, etanercept acutely suppressed gene expression of the interleukin (IL)-20 subfamily of cytokines (IL-19, IL-20, IL-24), which were found to be predominantly epidermis-derived and which are implicated in stimulating epidermal hyperplasia. Additionally, by 1 week of therapy, suppression of other keratinocyte-derived products (chemokines, antimicrobial proteins) occurred, while suppression of epidermal regenerative hyperplasia occurred within 1-3 weeks. Th17 elements (IL-23p19, IL-12p40, IL-17A, IL-22) were suppressed by 3-4 weeks. In vitro, TNF-α and IL-17A coordinately stimulated the expression of the IL-20 subfamily in normal keratinocytes.
Based on the rapid suppression of regenerative hyperplasia, chemokines and other keratinocyte-derived products, including the IL-20 subfamily, we propose that epidermal activation is a very early target of etanercept. As many of these keratinocyte markers are stimulated by TNF-α, their rapid downregulation is likely to reflect etanercept's antagonism of TNF-α. Additionally, decreased epidermal hyperplasia might result specifically from acute suppression of the IL-20 subfamily, which is also a likely consequence of etanercept's antagonism of TNF-α. Thus, the IL-20 subfamily has potential importance in the pathogenesis of psoriasis and therapeutic response to etanercept.

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    • "IL-20 has been shown to play a role in skin inflammation, along with several related cytokines (Uto-Konomi et al., 2012). The regenerative hyperplasia seen in psoriasis also has been linked to IL-20 (Wang et al., 2012; Wegenka, 2010); this may be relevant to the robust regenerative response of BK5.EP4 mice to DMBA-induced cell death, which in turn resembles the regenerative cell cycle progression in keratinocytes following TPA treatment (Kirkhus et al., 1992). Some of the other upregulated genes, including Kcnk2 (TREK-1), have been linked to ovarian and prostate cancer (Innamaa et al., 2013; Voloshyna et al., 2008). "
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    • "More recently, cytokines of the interleukin-10 (IL-10) family, including IL-19, IL-20, IL-22, and IL-24, have been implicated in the pathogenesis of psoriasis (Kunz et al., 2006; Leng et al., 2011; Rømer et al., 2003; Weiss et al., 2004; Wolk et al., 2009a). Increased expression of IL-19, IL-20, IL-22, and IL-24 was detected in psoriatic compared to normal skin (Kunz et al., 2006; Rømer et al., 2003; Wang et al., 2012; Weiss et al., 2004; Wolk et al., 2009b). In the skin, IL-22 is produced mainly by T cells, whereas IL-19, IL-20, and IL-24 are produced by keratinocytes, myeloid cells, and T cells (Conti et al., 2003; Kunz et al., 2006; Zheng et al., 2007). "
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