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
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.
Available from: Susan M Fischer
- "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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ABSTRACT: Pharmacological and genetic approaches have shown that prostaglandins (PGs) synthesized by cyclooxygenase-2 (COX-2) have tumor promoting/progression activity in murine skin. To determine whether the EP4 receptor for PGE2 contributes to this tumor promoting/progression activity, EP4 over-expressing mice (BK5.EP4) were generated and subjected to several carcinogenesis protocols. A two-stage 7,12-dimethylbenz[a]anthracene (DMBA)-12-O-tetradecanoylphorbol-13-acetate (TPA) protocol resulted in 25-fold more squamous cell carcinomas (SCCs) in the BK5.EP4 mice than wild type (WT) mice. A similar increase in SCCs was observed following treatment with DMBA alone (no TPA) and following UV irradiation. DMBA caused a cytotoxicity in BK5.EP4, but not WT mice, that was characterized by increased apoptosis, increased metalloproteinase(MMP)-9 and MMP-7 expression, and sloughing of the interfollicular epidermis, followed by regeneration and SCC development. An analysis of cytochrome P450 levels, wound healing time and keratinocyte stem cells showed no difference between BK5.EP4 and WT mice. A comparison of transcriptomes between BK5.EP4 and WT mice treated with PGE2 showed a significant upregulation of a number of genes known to be associated with tumor development, including interleukin-20 (IL-20), which was verified at the protein level, supporting a pro-tumorigenic role for the EP4 receptor.
Available from: Snehlata Kumari
- "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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ABSTRACT: Psoriasis is a common chronic inflammatory skin disease with a prevalence of about 2% in the Caucasian population. Tumor necrosis factor (TNF) plays an essential role in the pathogenesis of psoriasis, but its mechanism of action remains poorly understood. Here we report that the development of psoriasis-like skin inflammation in mice with epidermis-specific inhibition of the transcription factor NF-κB was triggered by TNF receptor 1 (TNFR1)-dependent upregulation of interleukin-24 (IL-24) and activation of signal transducer and activator of transcription 3 (STAT3) signaling in keratinocytes. IL-24 was strongly expressed in human psoriatic epidermis, and pharmacological inhibition of NF-κB increased IL-24 expression in TNF-stimulated human primary keratinocytes, suggesting that this mechanism is relevant for human psoriasis. Therefore, our results expand current views on psoriasis pathogenesis by revealing a new keratinocyte-intrinsic mechanism that links TNFR1, NF-κB, ERK, IL-24, IL-22R1, and STAT3 signaling to disease initiation.
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ABSTRACT: The 15 years between the First International Congress 'Psoriasis: from Gene to Clinic' and the Sixth Congress held in London from 1 to 3 December 2011 have seen extraordinary progress in the sciences that are relevant to psoriasis and therapeutics that have transformed its treatment. Over this time, 'Psoriasis: from Gene to Clinic' has emerged as the premier conference for clinicians and scientists interested in this field. Its popularity is attested to by the 450 registered delegates from the U.K. and around the world, which necessitated a change of venue to the excellent facilities of the Queen Elizabeth II Conference Centre. Although the content has evolved over the years, the structure of this 3-day conference has remained similar. The first day was given to genetics, comorbidities and outcome measures. Immunology and immunity were covered on the second day and therapeutics on the third. The stature of the three keynote lecturers and eight invited speakers was truly world class and their presentations were interspersed with 23 free communications. Here we review highly selected personal highlights of the meeting that we hope will be of general interest.
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