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• W2267502772 abstract "Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that is characterized by extreme pruritus. AD is considered the first stage of atopic march (Leung et al., 2004Leung D.Y. Boguniewicz M. Howell M.D. Nomura I. Hamid Q.A. New insights into atopic dermatitis.J Clin Invest. 2004; 113: 651-657Crossref PubMed Scopus (1197) Google Scholar). From an immunological aspect, AD is closely linked to the disruption of Th1/Th2 cytokine homeostasis that skews to Th2 immunity (Bieber, 2008Bieber T. Atopic dermatitis.N Engl J Med. 2008; 358: 1483-1494Crossref PubMed Scopus (1564) Google Scholar). Immunological approaches to the treatment of AD have mainly focused on stimulating Th1 immunity to recover the Th1/Th2 balance (Leung et al., 2004Leung D.Y. Boguniewicz M. Howell M.D. Nomura I. Hamid Q.A. New insights into atopic dermatitis.J Clin Invest. 2004; 113: 651-657Crossref PubMed Scopus (1197) Google Scholar). Thymic stromal lymphopoietin (TSLP) was recently shown to play a critical role in the progress of AD by inducing Th2 immune responses (Soumelis et al., 2002Soumelis V. Reche P.A. Kanzler H. Yuan W. Edward G. Homey B. et al.Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP.Nat Immunol. 2002; 3: 673-680Crossref PubMed Scopus (1713) Google Scholar, Zhang et al., 2009Zhang Z. Hener P. Frossard N. Kato S. Metzger D. Li M. et al.Thymic stromal lymphopoietin overproduced by keratinocytes in mouse skin aggravates experimental asthma.Proc Natl Acad Sci USA. 2009; 106: 1536-1541Crossref PubMed Scopus (147) Google Scholar). Increased TSLP production in keratinocytes induces the expression of the OX40 ligand (OX40L) in dendritic cells (DCs), which in turn stimulates the differentiation of naïve CD4+ T cells into Th2 cells to produce Th2 cytokines such as IL-4, IL-5, and IL-13 (Leyva-Castillo et al., 2013Leyva-Castillo J.M. Hener P. Michea P. Karasuyama H. Chan S. Soumelis V. et al.Skin thymic stromal lymphopoietin initiates Th2 responses through an orchestrated immune cascade.Nat Commun. 2013; 4: 2847Crossref PubMed Scopus (114) Google Scholar). Thus, the TSLP-OX40L axis is considered integral to the induction of a Th2 cell-mediated allergic cascade in AD (Murakami-Satsutani et al., 2014Murakami-Satsutani N. Ito T. Nakanishi T. Inagaki N. Tanaka A. Vien P.T. et al.IL-33 promotes the induction and maintenance of Th2 immune responses by enhancing the function of OX40 ligand.Allergol Int. 2014; 63: 443-455Abstract Full Text PDF PubMed Scopus (75) Google Scholar). Indeed, high levels of TSLP expression have been observed in epidermal keratinocytes of AD skin lesions (Leyva-Castillo et al., 2013Leyva-Castillo J.M. Hener P. Jiang H. Li M. TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice.J Invest Dermatol. 2013; 133: 154-163Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). Therefore, suppressing TSLP may represent a novel therapeutic approach for treating AD by restoring Th1/Th2 balance. Here, we investigated whether dieckol, a phlorotannin from Ecklonia cava (Figure 1a), can suppress TSLP production to reduce Th2 immunity and effectively alleviate AD-like symptoms in an NC/Nga mouse model in vivo. First, we determined whether dieckol affects the production of TSLP in a mouse keratinocyte cell line, KCMH-1, that constitutively produces high amounts of TSLP (Segawa et al., 2014Segawa R. Yamashita S. Mizuno N. Shiraki M. Hatayama T. Satou N. et al.Identification of a cell line producing high levels of TSLP: advantages for screening of anti-allergic drugs.J Immunol Methods. 2014; 402: 9-14Crossref PubMed Scopus (16) Google Scholar). Dieckol reduced TSLP mRNA and protein levels in KCMH-1 cells (Figure 1b and c). In addition, TSLP expression induced by MC903 in mouse ear skin was reduced by topical application of dieckol (see Supplementary Figure S1 online). NF-κB is an important transcription factor required for TSLP expression. Dieckol significantly reduced NF-κB-dependent luciferase expression in KCMH-1 cells that have high basal activation of NF-κB (Figure 1d). Dieckol blocked IL-1β-induced phosphorylation and degradation of IκBα and NF-κB luciferase activity in mouse keratinocytes (Pam212) (Figure 1e and f, see Supplementary Figure S2a online). Similarly, Joe et al., 2006Joe M.J. Kim S.N. Choi H.Y. Shin W.S. Park G.M. Kang D.W. et al.The inhibitory effects of eckol and dieckol from Ecklonia stolonifera on the expression of matrix metalloproteinase-1 in human dermal fibroblasts.Biol Pharm Bull. 2006; 29: 1735-1739Crossref PubMed Scopus (104) Google Scholar showed that dieckol inhibited phorbol myristate acetate-induced NF-κB activation in HeLa cells, leading to the decrease of matrix metalloproteinase-1 in human dermal fibroblasts (Joe et al., 2006Joe M.J. Kim S.N. Choi H.Y. Shin W.S. Park G.M. Kang D.W. et al.The inhibitory effects of eckol and dieckol from Ecklonia stolonifera on the expression of matrix metalloproteinase-1 in human dermal fibroblasts.Biol Pharm Bull. 2006; 29: 1735-1739Crossref PubMed Scopus (104) Google Scholar). The results confirm that dieckol suppresses TSLP production by inhibiting NF-κB activation in keratinocytes. In contrast, IL-1β-induced early growth response protein 1 (EGR-1) expression and phosphorylation of p38, extracellular signal–related kinase, and c-Jun N-terminal kinase were not inhibited by dieckol in Pam212 cells (see Supplementary Figure S2b). To delineate how dieckol interacts with the NF-κB signaling cascade, ligand-independent NF-κB activation was induced by exogenously overexpressing the signaling component in 293T cells. Dieckol suppressed NF-κB activation induced by inhibitor of NF-κB kinase subunit beta (IKKβ) but not p65 (see Supplementary Figure S3 online), suggesting that dieckol may target IKKβ itself or the complex involving IKKβ but not p65 and its downstream components. We further examined whether the suppression of TSLP production would lead to a decrease in OX40L expression in mouse primary bone marrow-derived DCs (BMDCs). Incubation of BMDCs with conditioned medium from KCMH-1 cells resulted in the induction of OX40L mRNA expression in BMDCs. This induction of OX40L mRNA expression was abolished by dieckol treatment of KCMH-1 cells (Figure 1g), suggesting that inhibition of TSLP production by dieckol in keratinocytes can reduce OX40L expression in DCs. Next, we investigated whether dieckol can suppress TSLP production and AD-like symptoms in vivo using an NC/Nga mouse AD model. Animal care and the experimental protocols were carried out in accordance with the guidelines of the Institutional Animal Care and Use Committee of the Catholic University of Korea (permission no. 2013-020-02). AD-like symptoms were induced in male NC/Nga mice by repeatedly applying a topical allergen—extract of Dermatophagoides farina, a major species of house dust mites (HDM)—and 2,4-dinitrochlorobenzene (DNCB) on the shaved dorsum. Dieckol (1%) was applied topically on NC/Nga mice daily for 4 weeks. Repeated application of HDM/DNCB to NC/Nga mice induced skin dryness, severe erythema, hemorrhage, scarring, dryness, edema, excoriation, and erosion (Figure 2a). Meanwhile, topical application of dieckol greatly improved these AD-like skin symptoms induced by HDM/DNCB as determined by dermatitis score evaluation (Yamamoto et al., 2007Yamamoto M. Haruna T. Yasui K. Takahashi H. Iduhara M. Takaki S. et al.A novel atopic dermatitis model induced by topical application with dermatophagoides farinae extract in NC/Nga mice.Allergol Int. 2007; 56: 139-148Abstract Full Text PDF PubMed Scopus (159) Google Scholar) (Figure 2a and b). Histological assessment of skin tissues by hematoxylin and eosin staining confirmed that AD-like skin lesions characterized by epidermal hyperplasia, edema, and accumulation of inflammatory cells in the dermis/epidermis were significantly alleviated by dieckol (Figure 2c, left). Toluidine blue staining of skin tissues showed that topical application of dieckol significantly reduced the infiltration of dermal mast cells (Figure 2c, right; see Supplementary Figure S4 online). The elevation of serum IgE levels in HDM/DNCB-stimulated mice was also attenuated by topical application of dieckol (Figure 2d). Most importantly, topical application of dieckol nearly abolished HDM/DNCB-induced production of TSLP in AD-like skin lesions in NC/Nga mice (Figure 2e, see Supplementary Figure S5a online), in agreement with the effects observed in KCMH-1 cells. In addition, dieckol blocked the production of IL-33 (Figure 2f, see Supplementary Figure S5b), which is secreted by the cells of barrier tissues and activates Th2 lymphocytes, mast cells, and eosinophils (Savinko et al., 2012Savinko T. Matikainen S. Saarialho-Kere U. Lehto M. Wang G. Lehtimaki S. et al.IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors.J Invest Dermatol. 2012; 132: 1392-1400Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar). IL-33 functions as a positive regulator of the TSLP-OX40L axis, which initiates and maintains Th2 cell–mediated inflammatory responses (Imai et al., 2013Imai Y. Yasuda K. Sakaguchi Y. Haneda T. Mizutani H. Yoshimoto T. et al.Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice.Proc Natl Acad Sci USA. 2013; 110: 13921-13926Crossref PubMed Scopus (326) Google Scholar, Murakami-Satsutani et al., 2014Murakami-Satsutani N. Ito T. Nakanishi T. Inagaki N. Tanaka A. Vien P.T. et al.IL-33 promotes the induction and maintenance of Th2 immune responses by enhancing the function of OX40 ligand.Allergol Int. 2014; 63: 443-455Abstract Full Text PDF PubMed Scopus (75) Google Scholar). The differentiation of naïve T cells into Th1 and Th2 cells is regulated by key transcription factors such as T-bet and GATA-3 for Th1 and Th2 cells, respectively. Topical application of dieckol blocked the enhanced expression of GATA-3 in AD-like skin lesions (Figure 2g), whereas the mRNA levels of T-bet were increased (Figure 2h). Topical application of dieckol reduced the levels of Th2 cytokines such as IL-4 and -5 in AD-like skin lesions (Figure 2i and j, see Supplementary Figure S5c and d). The level of IL-13 was also slightly decreased by dieckol (Figure 2k, see Supplementary Figure S5e). In contrast, the level of interferon gamma, a Th1 cytokine, was increased by dieckol (Figure 2l, see Supplementary Figure S5f). These results show that topical treatment of dieckol suppressed Th2-mediated immune responses and promoted Th1 immune responses. Dieckol did not significantly reduce mRNA level of ROR-α, a hallmark of type 2 innate lymphoid cells (Walker and McKenzie, 2013Walker J.A. McKenzie A.N. Development and function of group 2 innate lymphoid cells.Curr Opin Immunol. 2013; 25: 148-155Crossref PubMed Scopus (141) Google Scholar), increased by HDM/DNCB in the skin (see Supplementary Figure S6 online). Collectively, we show that topical application of dieckol alleviates AD-like symptoms in vivo by suppressing Th2 immunity while stimulating Th1 immunity in skin. The down-regulation of Th2 response by dieckol is mediated through the inhibition of TSLP production in keratinocytes and consequent decrease in OX40L expression in DCs. It needs to be determined in future study whether the increase of Th1 response caused by dieckol is mediated by direct regulation of Th1 cells or by indirect outcome derived from down-regulation of Th2 immunity. These results show that the suppression of TSLP production by phytochemicals, such as dieckol, is an effective strategy to prevent AD symptoms by modulating the balance of Th1/Th2 immune responses. The authors state no conflict of interest. This study was supported by a grant from the National Research Foundation of Korea funded by the Korean government (Ministry of Science, ICT and Future Planning; NRF-2014R1A2A1A11051234). Download .pdf (.27 MB) Help with pdf files Supplementary Figures S1–S6" @default.
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• W2267502772 title "Topical Application of Dieckol Ameliorates Atopic Dermatitis in NC/Nga Mice by Suppressing Thymic Stromal Lymphopoietin Production" @default.
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