Publications by authors named "Yasutaka Mitamura"

26 Publications

  • Page 1 of 1

Cutaneous and systemic hyperinflammation drives maculopapular drug exanthema in severely ill COVID-19 patients.

Allergy 2021 Jun 22. Epub 2021 Jun 22.

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Background: Coronavirus disease-2019 (COVID-19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID-19 may impact the development of the MDR.

Methods: Blood and skin samples from COVID-19 patients (based on a positive nasopharyngeal PCR) suffering from MDR (COVID-MDR), healthy controls, non-COVID-19-related patients with drug rash with eosinophilia and systemic symptoms (DRESS), and MDR were analyzed. We utilized imaging mass cytometry (IMC) to characterize the cellular infiltrate in skin biopsies. Furthermore, RNA sequencing transcriptome of skin biopsy samples and high-throughput multiplexed proteomic profiling of serum were performed.

Results: IMC revealed by clustering analyses a more prominent, phenotypically shifted cytotoxic CD8 T cell population and highly activated monocyte/macrophage (Mo/Mac) clusters in COVID-MDR. The RNA sequencing transcriptome demonstrated a more robust cytotoxic response in COVID-MDR skin. However, severe acute respiratory syndrome coronavirus 2 was not detected in skin biopsies at the time point of MDR diagnosis. Serum proteomic profiling of COVID-MDR patients revealed upregulation of various inflammatory mediators (IL-4, IL-5, IL-6, TNF, and IFN-γ), eosinophil and Mo/Mac -attracting chemokines (MCP-2, MCP-3, MCP-4 and CCL11). Proteomics analyses demonstrated a massive systemic cytokine storm in COVID-MDR compared with the relatively milder cytokine storm observed in DRESS, while MDR did not exhibit such features.

Conclusion: A systemic cytokine storm may promote activation of Mo/Mac and cytotoxic CD8 T cells in severe COVID-19 patients, which in turn may impact the development of MDR.
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http://dx.doi.org/10.1111/all.14983DOI Listing
June 2021

IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis.

Int J Mol Sci 2020 Dec 10;21(24). Epub 2020 Dec 10.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan.

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.
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http://dx.doi.org/10.3390/ijms21249412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764126PMC
December 2020

Advances and recent developments in asthma in 2020.

Allergy 2020 12 16;75(12):3124-3146. Epub 2020 Oct 16.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis, and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis, and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping, and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers, are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2, and COVID-19.
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http://dx.doi.org/10.1111/all.14607DOI Listing
December 2020

Outside-in hypothesis revisited: The role of microbial, epithelial, and immune interactions.

Ann Allergy Asthma Immunol 2020 11 23;125(5):517-527. Epub 2020 May 23.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland.

Objective: Our understanding of the origin of allergic diseases has increased in recent years, highlighting the importance of microbial dysbiosis and epithelial barrier dysfunction in affected tissues. Exploring the microbial-epithelial-immune crosstalk underlying the mechanisms of allergic diseases will allow the development of novel prevention and treatment strategies for allergic diseases.

Data Sources: This review summarizes the recent advances in microbial, epithelial, and immune interactions in atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, and asthma.

Study Selections: We performed a literature search, identifying relevant recent primary articles and review articles.

Results: Dynamic crosstalk between the environmental factors and microbial, epithelial, and immune cells in the development of atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, and asthma underlies the pathogenesis of these diseases. There is substantial evidence in the literature suggesting that environmental factors directly affect barrier function of the epithelium. In addition, T-helper 2 (T2) cells, type 2 innate lymphoid cells, and their cytokine interleukin 13 (IL-13) damage skin and lung barriers. The effects of environmental factors may at least in part be mediated by epigenetic mechanisms. Histone deacetylase activation by type 2 immune response has a major effect on leaky barriers and blocking of histone deacetylase activity corrects the defective barrier in human air-liquid interface cultures and mouse models of allergic asthma with rhinitis. We also present and discuss a novel device to detect and monitor skin barrier dysfunction, which provides an opportunity to rapidly and robustly assess disease severity.

Conclusion: A complex interplay between environmental factors, epithelium, and the immune system is involved in the development of systemic allergic diseases.
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http://dx.doi.org/10.1016/j.anai.2020.05.016DOI Listing
November 2020

Type 2 immunity in the skin and lungs.

Allergy 2020 07 10;75(7):1582-1605. Epub 2020 May 10.

Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, Madrid, Spain.

There has been extensive progress in understanding the cellular and molecular mechanisms of inflammation and immune regulation in allergic diseases of the skin and lungs during the last few years. Asthma and atopic dermatitis (AD) are typical diseases of type 2 immune responses. interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin are essential cytokines of epithelial cells that are activated by allergens, pollutants, viruses, bacteria, and toxins that derive type 2 responses. Th2 cells and innate lymphoid cells (ILC) produce and secrete type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. IL-4 and IL-13 activate B cells to class-switch to IgE and also play a role in T-cell and eosinophil migration to allergic inflammatory tissues. IL-13 contributes to maturation, activation, nitric oxide production and differentiation of epithelia, production of mucus as well as smooth muscle contraction, and extracellular matrix generation. IL-4 and IL-13 open tight junction barrier and cause barrier leakiness in the skin and lungs. IL-5 acts on activation, recruitment, and survival of eosinophils. IL-9 contributes to general allergic phenotype by enhancing all of the aspects, such as IgE and eosinophilia. Type 2 ILC contribute to inflammation in AD and asthma by enhancing the activity of Th2 cells, eosinophils, and their cytokines. Currently, five biologics are licensed to suppress type 2 inflammation via IgE, IL-5 and its receptor, and IL-4 receptor alpha. Some patients with severe atopic disease have little evidence of type 2 hyperactivity and do not respond to biologics which target this pathway. Studies in responder and nonresponder patients demonstrate the complexity of these diseases. In addition, primary immune deficiency diseases related to T-cell maturation, regulatory T-cell development, and T-cell signaling, such as Omenn syndrome, severe combined immune deficiencies, immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and DOCK8, STAT3, and CARD11 deficiencies, help in our understanding of the importance and redundancy of various type 2 immune components. The present review aims to highlight recent advances in type 2 immunity and discuss the cellular sources, targets, and roles of type 2 mechanisms in asthma and AD.
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http://dx.doi.org/10.1111/all.14318DOI Listing
July 2020

Aryl Hydrocarbon Receptor Activation Downregulates IL-33 Expression in Keratinocytes via Ovo-Like 1.

J Clin Med 2020 Mar 24;9(3). Epub 2020 Mar 24.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Background: IL-33, one of the IL-1 superfamily cytokines, has been shown to be associated with pruritus and inflammation in atopic dermatitis (AD). Furthermore, IL-33 production derived from keratinocytes reportedly has a crucial role in the development of AD; however, the mechanism of IL-33 expression has not been fully understood.

Methods: We analyzed IL-33 expression in normal human epidermal keratinocytes (NHEKs) treated with IL-4.

Results: IL-4 induced the upregulation of IL-33 expression in NHEKs. Based on the findings 1) that ovo-like 1 (OVOL1), a susceptible gene of AD, upregulates filaggrin (FLG) and loricrin (LOR) expression in NHEKs and 2) that reduced expression of FLG and LOR leads to production of IL-1 superfamily cytokines, we examined the involvement of OVOL1 in IL-33 expression in NHEKs. Knockdown of OVOL1 induced upregulation of IL-33 expression. Moreover, because Glyteer, an activator of aryl hydrocarbon receptor (AHR), reportedly upregulates OVOL1 expression, we examined whether treatment with Glyteer inhibited IL-33 expression in NHEKs. Treatment with Glyteer inhibited IL-4-induced upregulation of IL-33 expression, which was canceled by knockdown of either AHR or OVOL1.

Conclusions: Activation of the AHR-OVOL1 axis inhibits IL-4-induced IL-33 expression, which could be beneficial for the treatment of AD.
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http://dx.doi.org/10.3390/jcm9030891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141508PMC
March 2020

IL-24: A new player in the pathogenesis of pro-inflammatory and allergic skin diseases.

Allergol Int 2020 Jul 21;69(3):405-411. Epub 2020 Jan 21.

Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan.

Interleukin (IL)-24 is a member of the IL-20 family of cytokines and is produced by various types of cells, such as CD4 T cells, NK cells, mast cells, keratinocytes, bronchial epithelial cells, and myofibroblasts. Previous studies suggest that IL-24 plays an essential role in the pathogenesis of pro-inflammatory autoimmune disorders such as psoriasis, arthritis, and inflammatory bowel diseases. However, the role of IL-24 in the pathogenesis of allergic diseases has been elusive. It has already been reported that IL-24 is involved in the pathogenesis of allergic lung and skin diseases. Moreover, we have recently revealed for the first time the pivotal functions of IL-24 in IL-13-mediated skin barrier dysfunction in atopic dermatitis (AD), which is known to be a characteristic of AD caused by Th2 cytokines such as IL-4 or IL-13. In this review, we show recent advances in the basic characteristics of IL-24 and its novel functions in the pathogenesis of allergic skin inflammation, focusing on AD. A better understanding of the role of IL-24 in allergic diseases can lead to the development of new therapeutic options.
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http://dx.doi.org/10.1016/j.alit.2019.12.003DOI Listing
July 2020

Serum squamous cell carcinoma antigen (SCCA)-2 correlates with clinical severity of pediatric atopic dermatitis in Ishigaki cohort.

J Dermatol Sci 2019 Aug 24;95(2):70-75. Epub 2019 Jul 24.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: We sometimes encounter difficulties in assessing the severity of pediatric atopic dermatitis (AD) using currently available biomarkers such as thymus and activation-regulated chemokine (TARC) due to the higher baseline values in non-AD children. Recent case control studies have indicated the usefulness of squamous cell carcinoma antigens (SCCAs) in pediatric and adult AD. Notably, SCCAs are induced by IL-4 and IL-13, vital Th2 cytokines that play important roles in AD etiology.

Objectives: Relatively low prevalence and mild disease severity of pediatric AD are observed in our Ishigaki cohort presumably due to the moisturising subtropical climate, which could conversely mean possible higher allergic potential of non-AD subjects towards AD. Thus, the purpose of this study was to further investigate the feasibility of using SCCAs together with TARC and periostin as biomarkers for pediatric AD even in the Ishigaki cohort.

Methods: We enrolled 1459 nursery school children and identified 96 as having AD through 2009-2011. As statistical analyses, we performed Student's t-test, correlation analysis, and receiver and operating characteristic (ROC) analysis.

Results: Serum SCCA1, SCCA2, periostin and TARC levels were all significantly increased in AD compared with those in non-AD, but only serum SCCA2 showed a significant increase in AD when assessed in each age group or in subgroup analysis. Among the biomarkers tested, serum SCCA2 also showed the best correlations with clinical AD severity and TARC and showed the best diagnosability for AD in ROC analysis.

Conclusions: SCCA2 is a potent biomarker for pediatric AD in the Ishigaki cohort.
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http://dx.doi.org/10.1016/j.jdermsci.2019.07.005DOI Listing
August 2019

Establishment of a Mouse Model of Atopic Dermatitis by Deleting Ikk2 in Dermal Fibroblasts.

J Invest Dermatol 2019 06 19;139(6):1274-1283. Epub 2019 Jan 19.

Department of Clinical Laboratory and Molecular Pathology, Graduate School of Medical and Pharmaceutical Science, University of Toyama, Toyama, Japan. Electronic address:

Atopic dermatitis is a chronic inflammatory skin disease with persistent pruritus. To clarify its molecular mechanism, it is important to establish a mouse model similar to the phenotypes of atopic dermatitis patients, particularly in exhibiting scratching behavior. Ikk2, a component of the IκB kinase complex, exerts pro-inflammatory responses, whereas its deficiency in keratinocytes paradoxically causes skin inflammation. In this study, we sought to generate a mouse model exhibiting skin inflammation by which dermal fibroblasts lack Ikk2 expression and evaluate whether cutaneous inflammatory phenotypes are similar to those of atopic dermatitis patients. To generate Ikk2-deficient mice (Nestin;Ikk2) in which Ikk2 is deleted in dermal fibroblasts, we crossed female Ikk2 mice to male Nestin;Ikk2mice. These mice spontaneously developed skin inflammation limited to the face, with the appearance of Ikk2-deficient fibroblasts in the facial skin. These mice showed phenotypes similar to those of atopic dermatitis patients, including scratching behaviors, which are resistant to immunosuppressive or molecularly targeted drugs. These findings suggest that the Nestin;Ikk2 mouse is an atopic dermatitis model that will be useful in clarifying atopic dermatitis pathogenesis and in developing a novel therapeutic agent for atopic dermatitis symptoms.
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http://dx.doi.org/10.1016/j.jid.2018.10.047DOI Listing
June 2019

NRF2 Activation Inhibits Both TGF-1- and IL-13-Mediated Periostin Expression in Fibroblasts: Benefit of Cinnamaldehyde for Antifibrotic Treatment.

Oxid Med Cell Longev 2018 7;2018:2475047. Epub 2018 Aug 7.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Systemic fibrosing or sclerotic disorders are life-threatening, but only very limited treatment modalities are available for them. In recent years, periostin (POSTN), a major extracellular matrix component, was established by several studies as a novel key player in the progression of systemic fibrotic disease. In this research, we revealed the involvement of oxidative stress in the expression of POSTN induced by TGF-1 and IL-13 in dermal fibroblasts. We found that the antioxidant cinnamaldehyde activated the NRF2/HMOX1 pathway. Cinnamaldehyde also alleviated TGF-1- and IL-13-mediated production of reactive oxygen species and subsequent POSTN upregulation in dermal fibroblasts. In contrast, NRF2 silencing abolished the cinnamaldehyde-mediated downregulation of POSTN. These results suggest that cinnamaldehyde is a broad inhibitor of POSTN expression covering both TGF-1 and IL-13 signaling. Cinnamaldehyde may thus be beneficial for the treatment of systemic fibrotic diseases.
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http://dx.doi.org/10.1155/2018/2475047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112270PMC
January 2019

Hierarchical control of interleukin 13 (IL-13) signals in lung fibroblasts by STAT6 and SOX11.

J Biol Chem 2018 09 3;293(38):14646-14658. Epub 2018 Aug 3.

From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan,

Interleukin (IL)-13 is a signature cytokine of type 2 inflammation important for the pathogenesis of various diseases, including allergic diseases. Signal transducer and activator of transcription (STAT) 6 is a critical transcriptional factor for the IL-13 signals; however, it remains unknown how expression of the IL-13-induced genes is differentiated by the transcriptional machineries. In this study, we identified IL-13-induced transcriptional factors in lung fibroblasts using DNA microarrays in which SOX11 was included. Knockdown of SOX11 down-regulated expression of periostin and CCL26, both of which are known to be downstream molecules of IL-13, whereas enforced expression of SOX11 together with IL-13 stimulation enhanced expression of periostin. Moreover, we found that in DNA microarrays combining IL-13 induction and SOX11 knockdown there exist both SOX11-dependent and -independent molecules in IL-13-inducible molecules. In the former, many inflammation-related and fibrosis-related molecules, including periostin and CCL26, are involved. These results suggest that SOX11 acts as a -acting transcriptional factor downstream of STAT6 and that in lung fibroblasts the IL-13 signals are hierarchically controlled by STAT6 and SOX11.
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http://dx.doi.org/10.1074/jbc.RA117.001364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153291PMC
September 2018

Constitutive overexpression of periostin delays wound healing in mouse skin.

Wound Repair Regen 2018 01 7;26(1):6-15. Epub 2018 Mar 7.

Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan.

Periostin is a matricellular protein involved in development, maintenance, and regulation of tissues and organs via by binding to cell surface integrin receptors. Pathologically, periostin plays an important role in the process of wound healing: as a deficiency of the Postn gene delays wound closure and periostin is consistently up-regulated in response to injury and skin diseases. However, the functional role of elevated periostin in the process of wound healing has not been tested. In this study, we generated Postn-transgenic mice under the control of the CAG promoter/enhancer to investigate the effects of constitutive overexpression of full length periostin during its pathophysiological roles. Transgenic mice showed significant overexpression of periostin in skin, lung, and heart, but no morphological changes were observed. However, when these transgenic mice were injured, periostin overexpression delayed the closure of excisional wounds. Expression of IL-1β and TNFα, pro-inflammatory cytokines important for wound healing, was significantly decreased in the transgenic mice, prior to delayed healing. Infiltration of neutrophils and macrophages, the main sources of IL-1β and TNFα, was also down-regulated in the transgenic wound sites. From these data, we conclude that enforced expression of periostin delays wound closure due to reduced infiltration of neutrophils and macrophages followed by down-regulation of IL-1β and TNFα expression. This suggests that regulated spatiotemporal expression of periostin is important for efficient wound healing and that constitutive periostin overexpression interrupts the normal process of wound closure.
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http://dx.doi.org/10.1111/wrr.12616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906136PMC
January 2018

The Significance of Hypothiocyanite Production via the Pendrin/DUOX/Peroxidase Pathway in the Pathogenesis of Asthma.

Oxid Med Cell Longev 2017 22;2017:1054801. Epub 2017 Nov 22.

Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan.

Inhaled corticosteroids (ICSs) are used as first-line drugs for asthma, and various novel antiasthma drugs targeting type 2 immune mediators are now under development. However, molecularly targeted drugs are expensive, creating an economic burden on patients. We and others previously found pendrin/SLC26A4 as a downstream molecule of IL-13, a signature type 2 cytokine critical for asthma, and showed its significance in the pathogenesis of asthma using model mice. However, the molecular mechanism of how pendrin causes airway inflammation remained elusive. We have recently demonstrated that hypothiocyanite (OSCN) produced by the pendrin/DUOX/peroxidase pathway has the potential to cause airway inflammation. Pendrin transports thiocyanate (SCN) into pulmonary lumens at the apical side. Peroxidases catalyze SCN and HO generated by DUOX into OSCN. Low doses of OSCN activate NF-B in airway epithelial cells, whereas OSCN in high doses causes necrosis of the cells, inducing the release of IL-33 and accelerating inflammation. OSCN production is augmented in asthma model mice and possibly in some asthma patients. Heme peroxidase inhibitors, widely used as antithyroid agents, diminish asthma-like phenotypes in mice, indicating the significance of this pathway. These findings suggest the possibility of repositioning antithyroid agents as antiasthma drugs.
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http://dx.doi.org/10.1155/2017/1054801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735670PMC
August 2018

Periostin in inflammation and allergy.

Cell Mol Life Sci 2017 12 8;74(23):4293-4303. Epub 2017 Sep 8.

Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1, Nabeshima, Saga, 849-8501, Japan.

We found for the first time that IL-4 and IL-13, signature type 2 cytokines, are able to induce periostin expression. We and others have subsequently shown that periostin is highly expressed in chronic inflammatory diseases-asthma, atopic dermatitis, eosinophilc chronic sinusitis/chronic rhinosinusitis with nasal polyp, and allergic conjunctivitis-and that periostin plays important roles in the pathogenesis of these diseases. The epithelial/mesenchymal interaction via periostin is important for the onset of allergic inflammation, in which periostin derived from fibroblasts acts on epithelial cells or fibroblasts, activating their NF-κB. Moreover, the immune cell/non-immune cell interaction via periostin may be also involved. Now the significance of periostin has been expanded into other inflammatory or fibrotic diseases such as scleroderma and pulmonary fibrosis. The cross-talk of periostin with TGF-β or pro-inflammatory cytokines is important for the underlying mechanism of these diseases. Because of its pathogenic importance and broad expression, diagnostics or therapeutic drugs can be potentially developed to target periostin as a means of treating these diseases.
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http://dx.doi.org/10.1007/s00018-017-2648-0DOI Listing
December 2017

Clarithromycin attenuates IL-13-induced periostin production in human lung fibroblasts.

Respir Res 2017 02 20;18(1):37. Epub 2017 Feb 20.

Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

Background: Periostin is a biomarker indicating the presence of type 2 inflammation and submucosal fibrosis; serum periostin levels have been associated with asthma severity. Macrolides have immunomodulatory effects and are considered a potential therapy for patients with severe asthma. Therefore, we investigated whether macrolides can also modulate pulmonary periostin production.

Methods: Using quantitative PCR and ELISA, we measured periostin production in human lung fibroblasts stimulated by interleukin-13 (IL-13) in the presence of two 14-member-ring macrolides-clarithromycin or erythromycin-or a 16-member-ring macrolide, josamycin. Phosphorylation of signal transducers and activators of transcription 6 (STAT6), downstream of IL-13 signaling, was evaluated by Western blotting. Changes in global gene expression profile induced by IL-13 and/or clarithromycin were assessed by DNA microarray analysis.

Results: Clarithromycin and erythromycin, but not josamycin, inhibited IL-13-stimulated periostin production. The inhibitory effects of clarithromycin were stronger than those of erythromycin. Clarithromycin significantly attenuated STAT6 phosphorylation induced by IL-13. Global gene expression analyses demonstrated that IL-13 increased mRNA expression of 454 genes more than 4-fold, while decreasing its expression in 390 of these genes (85.9%), mainly "extracellular," "plasma membrane," or "defense response" genes. On the other hand, clarithromycin suppressed 9.8% of the genes in the absence of IL-13. Clarithromycin primarily attenuated the gene expression of extracellular matrix protein, including periostin, especially after IL-13.

Conclusions: Clarithromycin suppressed IL-13-induced periostin production in human lung fibroblasts, in part by inhibiting STAT6 phosphorylation. This suggests a novel mechanism of the immunomodulatory effect of clarithromycin in asthmatic airway inflammation and fibrosis.
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http://dx.doi.org/10.1186/s12931-017-0519-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319114PMC
February 2017

Induction of Airway Allergic Inflammation by Hypothiocyanite via Epithelial Cells.

J Biol Chem 2016 12 18;291(53):27219-27227. Epub 2016 Nov 18.

From the Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan and

Hypothiocyanite (OSCN) serves as a potent innate defense system against microbes in the lungs. OSCN is generated by the catalysis of peroxidases using thiocyanate transported via several anion transporters, including pendrin/SLC26A4 and hydrogen peroxide (HO) generated by Duox1 and Duox2. We previously demonstrated that expression of pendrin, peroxidases, and Duox1/Duox2 is up-regulated in bronchial asthma patients and/or asthma model mice and that these molecules are important in accelerating airway inflammation. However, it remained unclear how activating these molecules would lead to airway inflammation. In this study, we examined whether OSCN produced via the pendrin/peroxidase/Duox pathway causes inflammation via airway epithelial cells. In an in vitro OSCN production system, OSCN, but not HO, activated NF-κB, a transcription factor critical for inflammatory responses, in the airway epithelial cells. OSCN was sensed by protein kinase A (PKA) followed by formation of the dimerization of PKA. The dimerized PKA, the active form, was critical in activating NF-κB. Detoxifying HO, mainly by catalase, enabled the dominant abilities of OSCN to dimerize PKA and activate NF-κB, compared with untreated HO Furthermore, OSCN in high doses caused necrosis of the cells, inducing release of IL-33, a trigger to initiate type 2 inflammation. These results demonstrate that OSCN in low doses activates NF-κB via PKA in airway epithelial cells, whereas OSCN in high doses causes necrosis, suggesting an important role in airway allergic inflammation for the production of OSCN via the pendrin/peroxidase/Duox pathway.
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http://dx.doi.org/10.1074/jbc.M116.746909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207149PMC
December 2016

Case of sarcomatoid carcinoma occurring in a patient with Werner syndrome.

J Dermatol 2016 Nov 14;43(11):1362-1364. Epub 2016 Apr 14.

Department of Dermatology, Federation of National Public Service Personnel Mutual Aid Associations, Hamanomachi Hospital, Fukuoka, Japan.

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http://dx.doi.org/10.1111/1346-8138.13399DOI Listing
November 2016

Localization of S100A2, S100A4, S100A6, S100A7, and S100P in the human hair follicle.

Fukuoka Igaku Zasshi 2014 Jul;105(7):148-56

The hair follicle is a highly differentiated structure. In this study, we examined immunohistological localization of S100A2, S100A4, S100A6, S100A7, and S100P using specific monoclonal antibodies. S100A2 was strongly expressed in the entire outer-root sheath (ORS), but more weakly in cuticle and medulla in the bulb. S100A6, S100A7, and S100P were expressed in the innermost cells of ORS. The cuticular area was weakly positive for S100A2, S100A6, S100A7, and S100P. S100A4 was expressed in dendritic Langerhans cells and melanocytes. Sebaceous cells were variably immunopositive for S100A2, S100A6, and S100A7. A subset of dermal papilla cells expressed S100A4 and S100A6. None of the antibodies labeled the inner-root sheath. The distinct spatiostructural distributions of the S100 family proteins suggest that each protein is differentially involved in the physiological function of normal hair follicles.
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July 2014

Localization of S100A2, S100A4, S100A6, S100A7, and S100P in the human hair follicle.

Fukuoka Igaku Zasshi 2014 Jul;105(7):148-56

The hair follicle is a highly differentiated structure. In this study, we examined immunohistological localization of S100A2, S100A4, S100A6, S100A7, and S100P using specific monoclonal antibodies. S100A2 was strongly expressed in the entire outer-root sheath (ORS), but more weakly in cuticle and medulla in the bulb. S100A6, S100A7, and S100P were expressed in the innermost cells of ORS. The cuticular area was weakly positive for S100A2, S100A6, S100A7, and S100P. S100A4 was expressed in dendritic Langerhans cells and melanocytes. Sebaceous cells were variably immunopositive for S100A2, S100A6, and S100A7. A subset of dermal papilla cells expressed S100A4 and S100A6. None of the antibodies labeled the inner-root sheath. The distinct spatiostructural distributions of the S100 family proteins suggest that each protein is differentially involved in the physiological function of normal hair follicles.
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July 2014

S100A6 and c-Kit-Positive Spindle Cell Melanoma of the Dorsal Foot.

Case Rep Dermatol 2014 May 16;6(2):140-4. Epub 2014 May 16.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Spindle cell melanoma, which is a rare form of melanoma, is clinically and histopathologically difficult to diagnose from a variety of nonmelanocytic spindle cell tumors. We describe a 42-year-old Japanese woman with amelanotic melanoma that comprised spindle cells with positive c-kit and S100A6 staining. The use of c-kit and S100A6 might be useful for improving the diagnosis.
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http://dx.doi.org/10.1159/000363097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049021PMC
May 2014

Clear cell hidradenocarcinoma mimicking pyogenic granuloma after repeated surgical excision.

Dermatol Surg 2014 Feb 19;40(2):211-2. Epub 2013 Dec 19.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1111/dsu.12403DOI Listing
February 2014

Increased expression of S100A6 in malignant granular cell tumours.

Acta Derm Venereol 2014 Sep;94(5):595-6

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan.

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http://dx.doi.org/10.2340/00015555-1782DOI Listing
September 2014

Bilateral nevus comedonicus syndrome.

Yonago Acta Med 2013 Jun 12;56(2):59-61. Epub 2013 Jul 12.

Division of Dermatology, Department of Medicine of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan ; †Department of Dermatology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-0065, Japan.

Nevus comedonicus is an uncommon skin abnormality characterized by an aggregation of dilated follicular orifices filled with keratinous material. Nevus comedonicus is occasionally complicated with other conditions including cataracts, skeletal defects, central nervous system abnormalities or other extra-cutaneous diseases (nevus comedonicus syndrome). Although most cases of nevus comedonicus occur unilaterally on the face, neck and chest, the lesions occasionally show a bilateral distribution (bilateral nevus comedonicus). We report here an unusual case of bilaterally disseminated nevus comedonicus with various systemic complications. A 62-year-old Japanese man presented with a 50-year history of numerous keratotic papules and comedo-like lesions, which gradually worsened with time. Physical examination revealed that the papules were skin-colored and 1-4 mm in diameter. Some papules had dark-black keratinous materials on their surface, giving them a comedo-like appearance. The lesions were located predominantly on the face, head, neck and trunk with symmetric distribution, following Blaschko's lines. The patient's past medical history was noteworthy; he had undergone surgical treatments for thyroid cancer, pneumothorax and schwannoma in the cauda equina. He also suffered from scoliosis, cervical spondylosis and atrial fibrillation. Histopathologic examination revealed dilated and invaginated follicular structures filled with lamellar keratin, compatible with nevus comedonicus. Our patient's case did not fit with any previously reported diseases, and we thought a diagnosis of "bilateral nevus comedonicus syndrome" was the most appropriate for our patient's condition. He was treated with topical retinoic acid and activated vitamin D3 ointment for 3 months each, but the lesions remained unchanged.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771205PMC
June 2013

Antiphospholipid syndrome complicated by unilateral pleural effusion.

Case Rep Dermatol 2013 May 25;5(2):198-202. Epub 2013 Jul 25.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Antiphospholipid syndrome (APS) with pleural effusion is extremely rare. A 75-year-old man was admitted to our hospital for spreading erythema on his trunk and extremities, as well as dyspnea. One year before admission, he had visited us with a 1-year history of erythema and purpura on his legs and occasional fever. Given the diagnosis of APS, we initiated a combination therapy of aspirin and warfarin, but the skin lesions had gradually worsened. A biopsy specimen revealed marked thrombosis in the dermal and subcutaneous small vessels. In addition, chest X-ray and computed tomography demonstrated a large pleural effusion in the left lung. He underwent repeated drainage of the pleural effusion but the effusion recurred. We added oral prednisolone 30 mg daily to his prior anticoagulant therapy. The skin lesions and pleural effusion rapidly improved and disappeared without any complication. Corticosteroids might be a choice of treatment for intractable pleural effusion in APS patients.
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http://dx.doi.org/10.1159/000354135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728615PMC
May 2013
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