- Email: [email protected]
IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes
G Model DESC 2954 No. of Pages 4
Journal of Dermatological Science xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Dermatological Science journal homepage: www.jdsjournal.com
Correspondence IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes Keywords: AD ERK FLG Skin barrier STAT3 IL-33
Atopic dermatitis (AD) is characterized by immune dysregulation and skin barrier disruption. Filaggrin (FLG) is an important structural protein in corneocytes that form the outermost layer of skin and provide skin barrier function, and its intracellular metabolite functions as a hydrator of the stratum corneum and a regulator of skin pH. AD is thought to develop in persons with genetic risk factors for skin barrier dysfunction and immune dysregulation. Eventually, it can be considered to be a reciprocal action in which immune dysregulation by increasing inflammatory cytokines cause skin barrier dysfunction and immune dysregulation. It follows the outside-inside-outside pathogenic loop in AD which was suggested by Elias. Elias et al. [1] suggested that barrier disruption makes allergen and bacterial penetration easy in atopic dermatitis and this causes an increase in cytokines and subsequently these cytokines in turn compromise barrier function. AD is characterized by defective barrier function that is associated with filaggrin deficit. Since Palmar et al. [2] demonstrated that AD is related to filaggrin mutation, there have been many reports showing the relationship between FLG mutation and severe AD. However, there are many AD patients without FLG null mutation who have decreased expression of FLG. Therefore, acquired factors are thought to be involved in the process of barrier formation. Gutowskia-Owsiak and Ogg [3] demonstrated several cytokines involved in down-regulation of FLG expression. Interleukin (IL)-4, IL-13, tumor necrosis factor (TNF)-a, IL-17, IL-22, IL-25, and IL-31 are associated with decreased FLG production. Recent report mentioned IL-33 as an important cytokine in the pathogenesis of AD, and IL-33 is also thought to be related to decreased production of FLG [4]. IL-33 plays a role as an ‘alarmin’, when is released in tissue damage, and also activate T-helper type 2 (Th2) immune responses [5]. Nonetheless, the IL-33 pathway responsible for decreasing FLG production has not yet been elucidated. IL-33 is a well-known IL-1 family cytokine which can activates mast cell and Th2 lymphocytes. Also, IL-33 activates innate immune response immediately in tissue damage [5]. IL-33 is suggested to play a role in this pathogenic mechanism of outside– inside–outside loop in AD. However, the regulatory mechanism of IL-33 in AD patients is not fully understood in keratinocytes yet.
This study was conducted to determine whether IL-33 may contribute to decrease the FLG expression in human keratinocytes to elucidate the pathogenetical role of IL-33 in barrier dysruption of AD. Therefore, we investigated the regulatory mechanism of IL-33-reduced FLG expression. In this study, change in expression of FLG using different concentrations (1, 10, 100 ng/ml) of IL-33 in normal human epidermal keratinocytes (NHEKs) was measured. As shown in Fig. 1A, the mRNA expression of FLG was decreased by IL-33 in a dose-dependent manner. The protein expression of FLG was downregulated by IL-33 in a concentration-dependent manner (Fig. 1B). To confirm this finding by immunofluorescence analysis, NHEKs were treated with different dosage of IL-33. FLG expression was down-regulated as the concentration of IL-33 increased (Fig. 1C). We focused on signal transducer and activator of transcription3 (STAT3) to investigate the regulatory mechanism of IL-33reduced FLG expression because the FLG promoter has an STAT3 binding sequence by sequence based analysis using TFSEARCH (www.cbrc.jp/research/db/TFSEARCH.html). The recent study reports that IL-33 activates STAT3 phosphorylation via c-kit [6]. Also, the STAT3 has an essential role in the allergic inflammation of murine asthma model [7]. Accordingly, we performed western blot analysis of phosphorylated STAT3 to investigate the IL-33 signaling pathway involved in downregulation of FLG (Fig. 1D). IL-33 stimulation caused significant phosphorylation of STAT3. The increased expression of phosphorylated STAT3 was well observed in immunofluorescence as well (Fig. 1E). As shown in Fig. 2A,B, IL-33 also induced phosphorylation of extracellular signal-regulated kinases (ERK) among mitogenactivated protein kinases (MAPKs). However, IL-33 stimulation did not result in phosphorylation of c-Jun N-terminal kinases (JNKs), and P38 mitogen-activated protein kinases (p38). These results demonstrated that IL-33 can activate the phosphorylation of STAT3 and ERK signaling in human keratinocytes. Also, reduction in the expression of FLG was blocked by ERK 1/2 inhibitors (Fig. 2C). Similarly, the specific inhibitor of STAT3 (STA-21) restored the expression of FLG which was suppressed by IL-33 treatment (Fig. 2D). Therefore, this indicates that the activation of STAT-3 and ERK occurs upstream of the reduction of FLG by IL-33. Also, NF-kB, which is the well-known transcriptional mediator of IL-33 signaling was not regulating IL-33-reduced FLG expression. In the treatment with IL-33, MyD88 silencing by MyD88 specific siRNA did not affect the protein expression level of FLG (Fig. 2E). In the previous study, the authors demonstrated that thymic stromal lymphopoietin (TSLP) down-regulates FLG expression by STAT3 and ERK signaling pathways [8]. We also observed that IL-33 induces TSLP expression in human keratinocytes [9]. We investigated the effect of TSLP in filaggrin regulation by IL-33 using TSLP neutralizing antibody. As shown in Fig. 2F, the FLG expression which is decreased by IL-33 was weakly restored by neutralizing
http://dx.doi.org/10.1016/j.jdermsci.2016.01.011 0923-1811/ ã 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: W.-I. Ryu, et al., IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.01.011
G Model DESC 2954 No. of Pages 4
2
Correspondence / Journal of Dermatological Science xxx (2015) xxx–xxx
Fig. 1. (Continued)
Fig. 1. Effects of IL-33 on FLG and p-STAT3 expression in NHEKs. (A) The level of FLG expression was measured by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). (B) IL-33 down-regulated FLG protein expression in a dose-dependent manner. (C) Immunofluorescence assay was performed to confirm FLG protein expression in NHEKs. DAPI stained NHEKs were exposed to different doses (0, 1, 10, 100 ng/ml) of IL-33 for 24 h. The phosphorylated STAT3 expression was measured by western blot (D) and immunofluorescence analysis (E). As the concentration of IL-33 increased, IL-33 treated NHEKs showed increased phosphorylated STAT3 expression in the nucleus (arrows). Bar = 250 mm. Asterisks indicate statistical significance at **P < 0.01, ***P < 0.001.
antibody to TSLP. The results showed the possibility that TSLP could also affect the IL-33-suppressed FLG expression. A further investigation is warranted to assess these points. The present study proved that IL-33 functions not only as an alarming cytokine induced by mechanical injury of the skin [10]. but it oppositely affects barrier function by reducing FLG production. IL-33, which is a representative Th2 cytokine, affect as a crucial factor of skin barrier dysfunction by reducing FLG expression in human keratinocytes. Also, we found that the phosphorylation of ERK and STAT3 might be an important role in IL-33-suppressed FLG expression. These results would be helpful for understanding the role of IL-33 in barrier dysfunction and find the new therapeutic target of AD. Conflict of interest The authors state no conflict of interest. Acknowledgment This study was supported by Amorepacific grant 2014. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. jdermsci.2016.01.011.
Please cite this article in press as: W.-I. Ryu, et al., IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.01.011
G Model DESC 2954 No. of Pages 4
Correspondence / Journal of Dermatological Science xxx (2015) xxx–xxx
3
Fig. 2. IL-33 regulates FLG expression via ERK and STAT3 phosphorylation in NHEKs. (A) IL-33 increased ERK phosphorylation in NHEKs compared to control cells. (B) The phosphorylation of ERK was increased within 2 h after the treatment. b-actin was used as a loading control. (C) When NHEKs were preincubated with the specific inhibitor of ERK (U0126, 5 mM) for 1 hour before stimulation with IL-33 (10 ng/ml), phosphorylated ERK was decreased with elevated expression of FLG. (D) When NHEKs were preincubated with the specific inhibitor of STAT3 (STA-21, 5 mM) for 1 h before stimulation with IL-33 (10 ng/ml), phosphorylated STAT3 was decreased with elevated expression of FLG. (E) FLG reduction by IL-33 was independent to MyD88. NHEKs were treated by IL-33 at 48 h after MyD88 siRNA transfection. (F) The neutralizing antibody to TSLP or control IgG was treated for 2 h prior to the addition of IL–33. After the harvest, the FLG protein expression was evaluated by western blot. Asterisks indicate statistical significance at *P < 0.05, ***P < 0.001.
References [1] P.M. Elias, Y. Hatano, M.L. Williams, Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms, J. Allergy Clin. Immunol. 121 (2008) 1337–1343. [2] C.N. Palmer, A.D. Irvine, A. Terron-Kwiatkowski, Y. Zhao, H. Liao, S.P. Lee, et al., Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis, Nat. Genet. 38 (2006) 441–446. [3] D. Gutowska-Owsiak, G.S. Ogg, Cytokine regulation of the epidermal barrier, Clin. Exp. Allergy 43 (2013) 586–598. [4] J. Seltmann, L.M. Roesner, F.W. von Hesler, M. Wittmann, T. Werfel, IL33 impacts on the skin barrier by downregulating the expression of filaggrin, J. Allergy Clin. Immunol. 135 (2015) 1659–1661 e1654.
[5] C. Moussion, N. Ortega, J.P. Girard, The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin'? PLoS One 3 (10) (2008) e3331. [6] S. Drube, S. Heink, S. Walter, T. Löhn, M. Grusser, A. Gerbaulet, et al., The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells, Blood 115 (19) (2010) 3899–3906. [7] M.C. Simeone-Penney, M. Severgnini, P. Tu, R.J. Homer, T.J. Mariani, L. Cohn, et al., Airway epithelial STAT3 is required for allergic inflammation in a murine model of asthma, J. Immunol. 178 (10) (2007) 6191–6199. [8] J.H. Kim, H.C. Bae, N.Y. Ko, S.H. Lee, S.H. Jeong, H. Lee, et al., Thymic stromal lymphopoietin downregulates filaggrin expression by signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) phosphorylation in keratinocytes, J. Allergy Clin. Immunol. 136 (1) (2015) 205–208.
Please cite this article in press as: W.-I. Ryu, et al., IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.01.011
G Model DESC 2954 No. of Pages 4
4
Correspondence / Journal of Dermatological Science xxx (2015) xxx–xxx
[9] W.I. Ryu, H. Lee, J.H. Kim, H.C. Bae, H.J. Ryu, Son SW: IL-33 induces Egr-1dependent TSLP expression via the MAPK pathways in human keratinocytes, Exp. Dermatol. (2015), doi:http://dx.doi.org/10.1111/exd.12788. [10] C. Cayrol, J.P. Girard, The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 9021–9026.
Woo-In Ryu, Hana Lee Hyun Cheol Bae Department of Dermatology and Division of Brain Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, South Korea
Medicine, Seoul, South Korea, bDepartment of Dermatology, Korea University College of Medicine, Seoul, South Korea * Corresponding author at: Department of Dermatology, Korea University College of Medicine, Seoul, South Korea. Fax: +82 2 2286 1431.
Hwa Jung Ryu* Department of Dermatology, Korea University College of Medicine, Seoul, South Korea
** Corresponding author at: Department of Dermatology and Division of Brain Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, South Korea. Fax: +82 2 2286 1431. E-mail addresses: [email protected] (H. Ryu), [email protected] (S. Son).
Sang Wook Sona,b,** Department of Dermatology and Division of Brain Korea 21 Project for Biomedical Science, Korea University College of
Received 15 September 2015 Received in revised form 6 January 2016 Accepted 26 January 2016
a
Please cite this article in press as: W.-I. Ryu, et al., IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.01.011
Journal of Dermatological Science xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Dermatological Science journal homepage: www.jdsjournal.com
Correspondence IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes Keywords: AD ERK FLG Skin barrier STAT3 IL-33
Atopic dermatitis (AD) is characterized by immune dysregulation and skin barrier disruption. Filaggrin (FLG) is an important structural protein in corneocytes that form the outermost layer of skin and provide skin barrier function, and its intracellular metabolite functions as a hydrator of the stratum corneum and a regulator of skin pH. AD is thought to develop in persons with genetic risk factors for skin barrier dysfunction and immune dysregulation. Eventually, it can be considered to be a reciprocal action in which immune dysregulation by increasing inflammatory cytokines cause skin barrier dysfunction and immune dysregulation. It follows the outside-inside-outside pathogenic loop in AD which was suggested by Elias. Elias et al. [1] suggested that barrier disruption makes allergen and bacterial penetration easy in atopic dermatitis and this causes an increase in cytokines and subsequently these cytokines in turn compromise barrier function. AD is characterized by defective barrier function that is associated with filaggrin deficit. Since Palmar et al. [2] demonstrated that AD is related to filaggrin mutation, there have been many reports showing the relationship between FLG mutation and severe AD. However, there are many AD patients without FLG null mutation who have decreased expression of FLG. Therefore, acquired factors are thought to be involved in the process of barrier formation. Gutowskia-Owsiak and Ogg [3] demonstrated several cytokines involved in down-regulation of FLG expression. Interleukin (IL)-4, IL-13, tumor necrosis factor (TNF)-a, IL-17, IL-22, IL-25, and IL-31 are associated with decreased FLG production. Recent report mentioned IL-33 as an important cytokine in the pathogenesis of AD, and IL-33 is also thought to be related to decreased production of FLG [4]. IL-33 plays a role as an ‘alarmin’, when is released in tissue damage, and also activate T-helper type 2 (Th2) immune responses [5]. Nonetheless, the IL-33 pathway responsible for decreasing FLG production has not yet been elucidated. IL-33 is a well-known IL-1 family cytokine which can activates mast cell and Th2 lymphocytes. Also, IL-33 activates innate immune response immediately in tissue damage [5]. IL-33 is suggested to play a role in this pathogenic mechanism of outside– inside–outside loop in AD. However, the regulatory mechanism of IL-33 in AD patients is not fully understood in keratinocytes yet.
This study was conducted to determine whether IL-33 may contribute to decrease the FLG expression in human keratinocytes to elucidate the pathogenetical role of IL-33 in barrier dysruption of AD. Therefore, we investigated the regulatory mechanism of IL-33-reduced FLG expression. In this study, change in expression of FLG using different concentrations (1, 10, 100 ng/ml) of IL-33 in normal human epidermal keratinocytes (NHEKs) was measured. As shown in Fig. 1A, the mRNA expression of FLG was decreased by IL-33 in a dose-dependent manner. The protein expression of FLG was downregulated by IL-33 in a concentration-dependent manner (Fig. 1B). To confirm this finding by immunofluorescence analysis, NHEKs were treated with different dosage of IL-33. FLG expression was down-regulated as the concentration of IL-33 increased (Fig. 1C). We focused on signal transducer and activator of transcription3 (STAT3) to investigate the regulatory mechanism of IL-33reduced FLG expression because the FLG promoter has an STAT3 binding sequence by sequence based analysis using TFSEARCH (www.cbrc.jp/research/db/TFSEARCH.html). The recent study reports that IL-33 activates STAT3 phosphorylation via c-kit [6]. Also, the STAT3 has an essential role in the allergic inflammation of murine asthma model [7]. Accordingly, we performed western blot analysis of phosphorylated STAT3 to investigate the IL-33 signaling pathway involved in downregulation of FLG (Fig. 1D). IL-33 stimulation caused significant phosphorylation of STAT3. The increased expression of phosphorylated STAT3 was well observed in immunofluorescence as well (Fig. 1E). As shown in Fig. 2A,B, IL-33 also induced phosphorylation of extracellular signal-regulated kinases (ERK) among mitogenactivated protein kinases (MAPKs). However, IL-33 stimulation did not result in phosphorylation of c-Jun N-terminal kinases (JNKs), and P38 mitogen-activated protein kinases (p38). These results demonstrated that IL-33 can activate the phosphorylation of STAT3 and ERK signaling in human keratinocytes. Also, reduction in the expression of FLG was blocked by ERK 1/2 inhibitors (Fig. 2C). Similarly, the specific inhibitor of STAT3 (STA-21) restored the expression of FLG which was suppressed by IL-33 treatment (Fig. 2D). Therefore, this indicates that the activation of STAT-3 and ERK occurs upstream of the reduction of FLG by IL-33. Also, NF-kB, which is the well-known transcriptional mediator of IL-33 signaling was not regulating IL-33-reduced FLG expression. In the treatment with IL-33, MyD88 silencing by MyD88 specific siRNA did not affect the protein expression level of FLG (Fig. 2E). In the previous study, the authors demonstrated that thymic stromal lymphopoietin (TSLP) down-regulates FLG expression by STAT3 and ERK signaling pathways [8]. We also observed that IL-33 induces TSLP expression in human keratinocytes [9]. We investigated the effect of TSLP in filaggrin regulation by IL-33 using TSLP neutralizing antibody. As shown in Fig. 2F, the FLG expression which is decreased by IL-33 was weakly restored by neutralizing
http://dx.doi.org/10.1016/j.jdermsci.2016.01.011 0923-1811/ ã 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: W.-I. Ryu, et al., IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.01.011
G Model DESC 2954 No. of Pages 4
2
Correspondence / Journal of Dermatological Science xxx (2015) xxx–xxx
Fig. 1. (Continued)
Fig. 1. Effects of IL-33 on FLG and p-STAT3 expression in NHEKs. (A) The level of FLG expression was measured by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). (B) IL-33 down-regulated FLG protein expression in a dose-dependent manner. (C) Immunofluorescence assay was performed to confirm FLG protein expression in NHEKs. DAPI stained NHEKs were exposed to different doses (0, 1, 10, 100 ng/ml) of IL-33 for 24 h. The phosphorylated STAT3 expression was measured by western blot (D) and immunofluorescence analysis (E). As the concentration of IL-33 increased, IL-33 treated NHEKs showed increased phosphorylated STAT3 expression in the nucleus (arrows). Bar = 250 mm. Asterisks indicate statistical significance at **P < 0.01, ***P < 0.001.
antibody to TSLP. The results showed the possibility that TSLP could also affect the IL-33-suppressed FLG expression. A further investigation is warranted to assess these points. The present study proved that IL-33 functions not only as an alarming cytokine induced by mechanical injury of the skin [10]. but it oppositely affects barrier function by reducing FLG production. IL-33, which is a representative Th2 cytokine, affect as a crucial factor of skin barrier dysfunction by reducing FLG expression in human keratinocytes. Also, we found that the phosphorylation of ERK and STAT3 might be an important role in IL-33-suppressed FLG expression. These results would be helpful for understanding the role of IL-33 in barrier dysfunction and find the new therapeutic target of AD. Conflict of interest The authors state no conflict of interest. Acknowledgment This study was supported by Amorepacific grant 2014. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. jdermsci.2016.01.011.
Please cite this article in press as: W.-I. Ryu, et al., IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.01.011
G Model DESC 2954 No. of Pages 4
Correspondence / Journal of Dermatological Science xxx (2015) xxx–xxx
3
Fig. 2. IL-33 regulates FLG expression via ERK and STAT3 phosphorylation in NHEKs. (A) IL-33 increased ERK phosphorylation in NHEKs compared to control cells. (B) The phosphorylation of ERK was increased within 2 h after the treatment. b-actin was used as a loading control. (C) When NHEKs were preincubated with the specific inhibitor of ERK (U0126, 5 mM) for 1 hour before stimulation with IL-33 (10 ng/ml), phosphorylated ERK was decreased with elevated expression of FLG. (D) When NHEKs were preincubated with the specific inhibitor of STAT3 (STA-21, 5 mM) for 1 h before stimulation with IL-33 (10 ng/ml), phosphorylated STAT3 was decreased with elevated expression of FLG. (E) FLG reduction by IL-33 was independent to MyD88. NHEKs were treated by IL-33 at 48 h after MyD88 siRNA transfection. (F) The neutralizing antibody to TSLP or control IgG was treated for 2 h prior to the addition of IL–33. After the harvest, the FLG protein expression was evaluated by western blot. Asterisks indicate statistical significance at *P < 0.05, ***P < 0.001.
References [1] P.M. Elias, Y. Hatano, M.L. Williams, Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms, J. Allergy Clin. Immunol. 121 (2008) 1337–1343. [2] C.N. Palmer, A.D. Irvine, A. Terron-Kwiatkowski, Y. Zhao, H. Liao, S.P. Lee, et al., Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis, Nat. Genet. 38 (2006) 441–446. [3] D. Gutowska-Owsiak, G.S. Ogg, Cytokine regulation of the epidermal barrier, Clin. Exp. Allergy 43 (2013) 586–598. [4] J. Seltmann, L.M. Roesner, F.W. von Hesler, M. Wittmann, T. Werfel, IL33 impacts on the skin barrier by downregulating the expression of filaggrin, J. Allergy Clin. Immunol. 135 (2015) 1659–1661 e1654.
[5] C. Moussion, N. Ortega, J.P. Girard, The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin'? PLoS One 3 (10) (2008) e3331. [6] S. Drube, S. Heink, S. Walter, T. Löhn, M. Grusser, A. Gerbaulet, et al., The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells, Blood 115 (19) (2010) 3899–3906. [7] M.C. Simeone-Penney, M. Severgnini, P. Tu, R.J. Homer, T.J. Mariani, L. Cohn, et al., Airway epithelial STAT3 is required for allergic inflammation in a murine model of asthma, J. Immunol. 178 (10) (2007) 6191–6199. [8] J.H. Kim, H.C. Bae, N.Y. Ko, S.H. Lee, S.H. Jeong, H. Lee, et al., Thymic stromal lymphopoietin downregulates filaggrin expression by signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) phosphorylation in keratinocytes, J. Allergy Clin. Immunol. 136 (1) (2015) 205–208.
Please cite this article in press as: W.-I. Ryu, et al., IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.01.011
G Model DESC 2954 No. of Pages 4
4
Correspondence / Journal of Dermatological Science xxx (2015) xxx–xxx
[9] W.I. Ryu, H. Lee, J.H. Kim, H.C. Bae, H.J. Ryu, Son SW: IL-33 induces Egr-1dependent TSLP expression via the MAPK pathways in human keratinocytes, Exp. Dermatol. (2015), doi:http://dx.doi.org/10.1111/exd.12788. [10] C. Cayrol, J.P. Girard, The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 9021–9026.
Woo-In Ryu, Hana Lee Hyun Cheol Bae Department of Dermatology and Division of Brain Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, South Korea
Medicine, Seoul, South Korea, bDepartment of Dermatology, Korea University College of Medicine, Seoul, South Korea * Corresponding author at: Department of Dermatology, Korea University College of Medicine, Seoul, South Korea. Fax: +82 2 2286 1431.
Hwa Jung Ryu* Department of Dermatology, Korea University College of Medicine, Seoul, South Korea
** Corresponding author at: Department of Dermatology and Division of Brain Korea 21 Project for Biomedical Science, Korea University College of Medicine, Seoul, South Korea. Fax: +82 2 2286 1431. E-mail addresses: [email protected] (H. Ryu), [email protected] (S. Son).
Sang Wook Sona,b,** Department of Dermatology and Division of Brain Korea 21 Project for Biomedical Science, Korea University College of
Received 15 September 2015 Received in revised form 6 January 2016 Accepted 26 January 2016
a
Please cite this article in press as: W.-I. Ryu, et al., IL-33 down-regulates filaggrin expression by inducing STAT3 and ERK phosphorylation in human keratinocytes, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.01.011