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Publications (21)63.65 Total impact

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    ABSTRACT: Background: Epidermal hyperplasia is a histological hallmark observed in both atopic dermatitis (AD) and psoriasis, although the clinical features and the underlying immunological disorders of these diseases are different. We previously showed that periostin, a matricellular protein, plays a critical role in epidermal hyperplasia in AD, using a mouse model and a 3-dimensional organotypic coculture system. In this study, we explore the hypothesis that periostin is involved in epidermal hyperplasia in psoriasis. Methods: To examine expression of periostin in psoriasis patients, we performed immunohistochemical analysis on skin biopsies from six such patients. To investigate periostin's role in the pathogenesis of psoriasis, we evaluated periostin-deficient mice in a psoriasis mouse model induced by topical treatment with imiquimod (IMQ). Results: Periostin was substantially expressed in the dermis of all investigated psoriasis patients. Epidermal hyperplasia induced by IMQ treatment was impaired in periostin-deficient mice, along with decreased skin swelling. However, upon treatment with IMQ, periostin deficiency did not alter infiltration of inflammatory cells such as neutrophils; production of IL-17, -22, or -23; or induction/expansion of IL-17- and IL-22-producing group 3 innate lymphoid cells. Conclusions: Periostin plays an important role during epidermal hyperplasia in IMQ-induced skin inflammation, independently of the IL-23-IL-17/IL-22 axis. Periostin appears to be a mediator for epidermal hyperplasia that is common to AD and psoriasis.
    Full-text · Article · Jan 2015 · Allergology International
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    ABSTRACT: Proliferation and differentiation of keratinocytes are normally well balanced, but this balance can be perturbed in wound healing and is dysregulated in pathological conditions such as atopic dermatitis. Epithelial-mesenchymal interaction affects this event via the cross-talk of cytokines and growth factors. Periostin, a matricellular protein, has an important role during reepithelialization in wound healing and is critical for hyperproliferation of keratinocytes in atopic dermatitis. Here we investigated how periostin regulates proliferation and differentiation of keratinocytes in the epithelial-mesenchymal interactions using a three-dimensional organotypic air-liquid interface coculture system. The release of IL-1α from keratinocytes and subsequent IL-6 production from fibroblasts were critical for keratinocyte proliferation and differentiation. Periostin secreted from fibroblasts was required for IL-1α-induced IL-6 production and enhanced IL-6 production by activation of the NF-κB pathway synergistically with IL-1α. Thus, the combination of an autocrine loop of periostin and a paracrine loop composed of IL-1α and IL-6 regulates keratinocyte proliferation and differentiation in the epithelial-mesenchymal interactions, and periostin tunes the magnitude of keratinocyte proliferation and differentiation by interacting with the paracrine IL-1α/IL-6 loop.Journal of Investigative Dermatology advance online publication, 19 December 2013; doi:10.1038/jid.2013.500.
    No preview · Article · Nov 2013 · Journal of Investigative Dermatology
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    ABSTRACT: To diagnose atopic dermatitis (AD), an appearance of eczema examined by experienced dermatologists is required. Therefore, biomarkers to diagnose AD or to reflect the severity of AD would be of a great use for non-specialists in the clinic or hospitals. We can apply such a biomarker for realization of personalized medicine for AD in the future. Interleukin-4 (IL-4) and IL-13 have been known to play important roles in the pathogenesis of allergic diseases including AD. In addition to these, we previously identified SCCA1, SCCA2, and periostin as IL-4/IL-13-inducible genes. We recently established ELISA systems to measure serum levels of SCCA1, SCCA2, and periostin and evaluated their usefulness in the treatment of AD patients. Serum SCCA1 and SCCA2 are up-regulated in AD patients and can distinguish AD patients from non-atopic controls, and their serum levels reflect eczema grades. Periostin concentration is also elevated in the serum of AD patients. These results demonstrate that SCCA1, SCCA2, and periostin might be promising biomarkers for personalized medicine in allergic diseases including AD.
    No preview · Article · Mar 2013 · Rinsho byori. The Japanese journal of clinical pathology
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    ABSTRACT: Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease where Th2-type immune responses are dominant. Keratinocytes persistently secrete proinflammatory cytokines and chemokines, amplifying Th2-type responses in AD. We have recently reported that periostin, an extracellular matrix protein induced by Th2 cytokines, plays a critical role in AD. In the present study, we have further investigated the characteristics of our allergen-induced AD model mice and the role of periostin in the pathogenesis of AD. Methods: The ears of C57BL/6 mice, BALB/c mice, and Rag-2-/- γ(c)-/- mice (BALB/c background) were epicutaneously sensitized repeatedly with HDM. Mice were analyzed after the final sensitization. To examine the direct role of periostin, we reconstituted skin in vitro by coculture of keratinocytes with wild-type or periostin-deficient fibroblasts. Results: Epicutaneous sensitization with HDM induced AD-like phenotypes and accumulation of periostin in dermis in C57BL/6 mice but not in Rag-2-/- γ(c)-/- mice. In vitro organotypic coculture systems revealed that periostin promoted survival and proliferation of keratinocytes and directly induced production of thymic stromal lymphopoietin (TSLP). Conclusions: Our results suggest that periostin exacerbates the pathogenesis of AD through TSLP production from keratinocytes.
    Full-text · Article · Aug 2012 · Allergology International
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    ABSTRACT: Background: Pendrin and periostin are newly identified mediators of the inflammatory process. The expression of these proteins in human sinonasal tissue and their roles in allergic rhinitis and chronic rhinosinusitis remain to be elucidated. This study investigated the expression of pendrin and periostin in sinonasal tissue of patients with allergic rhinitis, chronic rhinosinusitis, and aspirin-induced asthma. Prospective control study conducted at Yamagata University, Japan. Methods: Surgical samples were investigated by means of real-time reverse transcription-polymerase chain reaction to evaluate the expression of pendrin and periostin mRNA. The presence and location of pendrin and periostin were determined by immunohistochemistry and Western blotting. Results: Pendrin and periostin production was significantly higher in patients with nasal disorders than in controls. Further significant increases in periostin expression were noted in patients with chronic rhinosinusitis with nasal polyps and in those with aspirin-induced asthma. Immunohistochemistry revealed positive staining for pendrin in epithelial cells and submucosal glands and for periostin in the basement membrane in all three disorders, and additionally for periostin in nasal polyp tissue in chronic rhinosinusitis and aspirin-induced asthma. Conclusions: Production of pendrin and periostin is upregulated in allergic rhinitis, chronic rhinosinusitis with nasal polyps, and aspirin-induced asthma. These findings suggest that pendrin can induce mucus production and that periostin can induce tissue fibrosis and remodeling in the nasal mucosa. Therefore, these mediators may be therapeutic target candidates for allergic rhinitis, chronic rhinosinusitis with nasal polyps, and aspirin-induced asthma.
    Full-text · Article · Aug 2012 · Allergology International
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    ABSTRACT: Allergic inflammation triggered by exposure of an allergen frequently leads to the onset of chronic inflammatory diseases such as atopic dermatitis (AD) and bronchial asthma. The mechanisms underlying chronicity in allergic inflammation remain unresolved. Periostin, a recently characterized matricellular protein, interacts with several cell surface integrin molecules, providing signals for tissue development and remodeling. Here we show that periostin is a critical mediator for the amplification and persistence of allergic inflammation using a mouse model of skin inflammation. Th2 cytokines IL-4 and IL-13 stimulated fibroblasts to produce periostin, which interacted with αv integrin, a functional periostin receptor on keratinocytes, inducing production of proinflammatory cytokines, which consequently accelerated Th2-type immune responses. Accordingly, inhibition of periostin or αv integrin prevented the development or progression of allergen-induced skin inflammation. Thus, periostin sets up a vicious circle that links Th2-type immune responses to keratinocyte activation and plays a critical role in the amplification and chronicity of allergic skin inflammation.
    Full-text · Article · Jun 2012 · The Journal of clinical investigation
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    ABSTRACT: Cutaneous wound repair is a highly ordered and well-coordinated process involving various cell lineages and many molecular effectors. Cell-matrix interactions through integrin molecules provide key signals important for wound repair. Periostin is a matricellular protein that may provide signals important during tissue development and remodelling by interacting with several integrin molecules, via the phosphatidylinositol 3-kinase/Akt and MAP kinase pathways. In this study, we examined the role of periostin in the process of cutaneous wound repair using periostin-deficient mice and by analysing the effects of periostin on dermal fibroblasts. We first determined the expression profile and localization of periostin in a well-characterized wound repair model mice. Periostin was robustly deposited in the granulation tissues beneath the extended epidermal wound edges and at the dermal-epidermal junctions in wounded mice. Moreover, periostin-deficient mice exhibited delayed in vivo wound repair, which could be improved by direct administration of exogenous periostin. In vitro analyses revealed that loss of periostin impaired proliferation and migration of dermal fibroblasts, but exogenous supplementation or enforced periostin expression enhanced their proliferation. Combined, these results demonstrate that periostin accelerates the process of cutaneous wound repair by activating fibroblasts.
    Full-text · Article · May 2012 · Experimental Dermatology
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    ABSTRACT: The squamous cell carcinoma antigen (SCCA) is widely used as a serological biomarker for various cancers. There are two known SCCA molecules, SCCA1 and SCCA2. We previously found that interleukin-4 or interleukin-13, two related Th2-type cytokines that play an important role in allergic diseases, induce expression of SCCA1 and SCCA2. In this study, we examined whether combined measurements of SCCA1 and SCCA2 are useful for diagnosing atopic dermatitis (AD). We established new enzyme-linked immunosorbent assays (ELISAs) to specifically detect SCCA1 or SCCA2. We applied serum samples from AD patients with food allergies and from cervical cancer patients to these ELISAs. We performed receiver operating characteristic analyses to diagnose AD and to distinguish AD from cervical cancer. Serum concentrations of both SCCA1 and SCCA2 were elevated in AD patients. The serum concentrations of SCCA1 and SCCA2 positively correlated with the clinical severity of AD, showing high specificity (0.86-0.88) and sensitivity (0.86) against control donors. The serum concentrations of SCCA1 and SCCA2 were elevated in cervical cancer patients; however, the SCCA2/SCCA1 ratios clearly distinguished AD patients from cervical cancer patients with high specificity (0.87) and sensitivity (0.87). Expression of SCCA2 was predominant in AD patients, whereas cervical cancer patients showed a predominance of SCCA1. Combined measurements of SCCA1 and SCCA2 are very useful in estimating the severity of allergic diseases, making it possible to distinguish allergic diseases from cancers.
    No preview · Article · Mar 2012 · Annals of Clinical Biochemistry
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    Full-text · Chapter · Feb 2012
  • K. Izuhara · K. Arima · S. Suzuki · H. Shiraishi · S. Ohta

    No preview · Article · Feb 2012 · Kokyu to junkan. Respiration & circulation
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal form of interstitial lung disease (ILD). The precise molecular mechanisms of IPF remain poorly understood. However, analyses of mice receiving bleomycin (BLM) as a model of IPF established the importance of preceding inflammation for the formation of fibrosis. Periostin is a recently characterized matricellular protein involved in modulating cell functions. We recently found that periostin is highly expressed in the lung tissue of patients with IPF, suggesting that it may play a role in the process of pulmonary fibrosis. To explore this possibility, we administered BLM to periostin-deficient mice, and they subsequently showed a reduction of pulmonary fibrosis. We next determined whether this result was caused by a decrease in the preceding recruitment of neutrophils and macrophages in the lungs because of the lower production of chemokines and proinflammatory cytokines. We performed an in vitro analysis of chemokine production in lung fibroblasts, which indicated that periostin-deficient fibroblasts produced few or no chemokines in response to TNF-α compared with control samples, at least partly explaining the lack of inflammatory response and, therefore, fibrosis after BLM administration to periostin-deficient mice. In addition, we confirmed that periostin is highly expressed in the lung tissue of chemotherapeutic-agent-induced ILD as well as of patients with IPF. Taking these results together, we conclude that periostin plays a unique role as an inducer of chemokines to recruit neutrophils and macrophages important in the process of pulmonary fibrosis in BLM-administered model mice. Our results suggest a therapeutic potential for periostin in IPF and drug-induced ILD.
    Preview · Article · Jan 2012 · American Journal of Respiratory Cell and Molecular Biology
  • K. Izuhara · S. Ohta · H. Shiraishi · S. Suzuki

    No preview · Article · Jul 2011

  • No preview · Conference Paper · May 2011
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    ABSTRACT: Idiopathic interstitial pneumonias (IIPs) are histopathologically classified into several types, including usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) and cryptogenic organising pneumonia (COP). We investigated whether periostin, a matrix protein, could be used as a biomarker to assess histopathological types of IIPs. We performed immunohistochemical analyses in each histopathological type of IIP, examined serum levels of periostin in IIP patients and analysed the relationship between serum levels of periostin and the pulmonary functions in patients with idiopathic pulmonary fibrosis (IPF). Periostin was strongly expressed in lungs of UIP and fibrotic NSIP patients, whereas expression of periostin was weak in the lungs of cellular NSIP and COP patients, as well as in normal lungs. Serum levels of periostin in IPF were significantly higher than those of healthy subjects and COP patients. Furthermore, periostin levels in IPF patients were inversely correlated with their pulmonary functions. Thus, we have found that periostin is a novel component of fibrosis in IIP. Periostin may be a potential biomarker to distinguish IIP with fibrosis.
    No preview · Article · Dec 2010 · European Respiratory Journal
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    ABSTRACT: Prior exposure of dendritic cells (DCs) and monocytes/macrophages to LPS causes unresponsiveness to subsequent LPS stimulation, a phenomenon called endotoxin tolerance (ET). ET impairs antigen presentation of these cells to T cells by down-regulating expression of MHC class II and co-stimulatory molecules such as CD86 and CD40. Some epidemiological studies have shown that endotoxin acts as a protective factor for allergic diseases. Accordingly, LPS has beneficial effects on the onset of airway allergic inflammation in model animals by T(h)1 skewing or induction of regulatory T cells. However, results derived from asthma model animals are controversial, probably due to the difficulty of handling LPS. We previously generated a monoclonal agonistic antibody against Toll-like receptor (TLR) 4, named UT12, which mimics the biological activities of LPS, exhibiting more potent and sustained ET than does LPS. In this study, we took advantage of UT12 to generate prolonged ET to explore the possibility that ET is involved in the inhibitory effects of the TLR4 signals on asthma model mice. Induction of ET by UT12 inhibited the capacity of DCs to expand ovalbumin (OVA)-specific T(h)2 and T(h)17 cells, without inducing T(h)1 cell or regulatory T-cell populations or producing inhibitory cytokines. Accordingly, administration of UT12 before the OVA sensitization significantly suppressed airway allergic inflammation by OVA inhalation. Taken together, these results demonstrate that ET induced by activating TLR4 signals attenuates airway allergic inflammation through direct suppression of the T-cell stimulatory effect of DCs in asthma model mice.
    Preview · Article · Sep 2010 · International Immunology
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    ABSTRACT: Both interleukin-4 (IL-4) and IL-13 can bind to the shared receptor composed of the IL-4 receptor alpha chain and the IL-13 receptor alpha1 chain (IL-13Ralpha1); however, the mechanisms by which these ligands bind to the receptor chains are different, enabling the principal functions of these ligands to be different. We have previously shown that the N-terminal Ig-like domain in IL-13Ralpha1, called the D1 domain, is the specific and critical binding unit for IL-13. However, it has still remained obscure which amino acid has specific binding capacity to IL-13 and why the D1 domain acts as the binding site for IL-13, but not IL-4. To address these questions, in this study we performed mutational analyses for the D1 domain, combining the structural data to identify the amino acids critical for binding to IL-13. Mutations of Lys-76, Lys-77, or Ile-78 in c' strand in which the crystal structure showed interaction with IL-13, and those of Trp-65 and Ala-79 adjacent to the interacting site, resulted in significant impairment of IL-13 binding, demonstrating that these amino acids generate the binding site. Furthermore, mutations of Val-35, Leu-38, or Val-42 at the N-terminal beta-strand also resulted in loss of IL-13 binding, probably from decreased structural stability. None of the mutations employed here affected IL-4 binding. These results demonstrate that the D1 domain of IL-13Ralpha1 acts as an affinity converter, through direct cytokine interactions, that allows the shared receptor to respond differentially to IL-4 and IL-13.
    Preview · Article · Aug 2009 · Journal of Biological Chemistry
  • K Izuhara · S Ohta · H Shiraishi · S Suzuki · K Taniguchi · S Toda · T Tanabe · M Yasuo · K Kubo · T Hoshino · H Aizawa
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    ABSTRACT: Mucus production is a cardinal feature of bronchial asthma, contributing to morbidity and mortality in the disease. Goblet cells are major mucus-producing cells, and goblet cell hyperplasia (GCH) is one feature of airway remodeling, defined as structural changes occurring in the airway. A number of studies have demonstrated that Th2-type cells play critical roles in this process and that particularly interleukin-13 (IL-13), among Th2-type cytokines, is a central mediator for GCH. However, the mechanism underlying how Th2 cytokines induce mucus production or GCH is poorly understood. Mouse calcium-activated chloride channel-3 (mCLCA-3; gob-5)/human CLCA-1 acts as a downstream molecule of Th2 cytokines, IL-4/IL-9/IL-13 signals, playing an important role in mucus production. Moreover, we have recently found that pendrin, an anion transporter, is induced by IL-13 and causes mucus production in airway epithelial cells. It is hoped that if we can clarify how mucus is produced, this will lead to development of novel therapeutic reagents to suppress mucus production in bronchial asthma.
    No preview · Article · Feb 2009 · Current Medicinal Chemistry
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    ABSTRACT: It is known that IL-13, a Th2-type cytokine, is critical for the onset of bronchial asthma, and therefore, various anti-IL-13 antagonists are now being developed as reagents for treating asthma patients. However, there is no good way to select allergic patients into who such IL-13 antagonists should be administered. We previously found that squamous cell carcinoma antigens (SCCAs) 1 and 2 were IL-13-inducible gene products in bronchial epithelial cells and that serum SCCA level was elevated in the patients of bronchial asthma and atopic dermatitis. In this study, we tried to establish specific ELISA systems for SCCA1 and SCCA2. We generated several hybridoma clones secreting rat or mouse antibodies recognizing specifically SCCA1 or SCCA2, or both. By combining two among these antibodies, we found that the ELISA systems using rat anti-SCCA2 antibody (SS14B) as the coated antibody and rat-SCCA1 antibody (SS11G) or rat-SCCA2 antibody (SS8G) as the primary antibodies showed with high sensitivities specific recognition of SCCA1 and SCCA2, respectively. These results demonstrated that we could establish the specific ELISA system for SCCA1 and SCCA2. These specific ELISA systems for SCCA1 and SCCA2 are useful to analyze the correlation between serum SCCA level and the pathogenesis of allergic diseases and have a potential to apply to enforcement of the personalized medicine for allergic diseases.
    No preview · Article · Dec 2008 · Rinsho byori. The Japanese journal of clinical pathology
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    ABSTRACT: IL-4 and IL-13, two related Th2-type cytokines, play critical and redundant roles in the defense against gastrointestinal nematodes. These cytokines exert various immunological and physiological effects to expel these worms; however, it had not been known whether protease/protease inhibitor interaction was involved in the defense mechanism against these parasites. Many protozoan and helminth parasites generate cysteine proteases, the majority of which are orthlogues of mammalian cathepsin L, and these cysteine proteases play key roles in the life cycle of parasites as they infect and/or adapt to the hosts. We previously found that the squamous cell carcinoma antigens (SCCA1) and SCCA2, members of the ovalbumin serpin family, were secreted from epithelial cells upon stimulation by IL-4 or IL-13. SCCA1 and SCCA2 show different inhibitory profiles. We recently found that SCCA1, but not SCCA2, inhibited several parasite-derived cysteine proteases. Furthermore, SCCA molecules employed a unique inhibitory mechanism against cysteine proteases: they interacted with proteases without forming a covalent complex followed by irreversible impairment of the protease activities and they resisted cleavage by the target proteases. These results indicate that the interaction between cysteine proteases of parasites and SCCA molecules may be a novel immunodefense mechanism of Th2-type responses against parasites, particularly helminths. In this article, we summarize the roles of IL-4/IL-13 on the defense mechanism against parasites, the effects of SCCA molecules against extrinsic cysteine proteases, and the correlation between induction of SCCA molecules and allergic diseases.
    No preview · Article · Aug 2008 · Medicinal Chemistry
  • K Izuhara · S Ohta · S Kanaji · H Shiraishi · K Arima
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    ABSTRACT: The inhibitory mechanism against proteases is important in the maintenance of homeostasis or health in the body. The human ovalbumin serpin (ov-serpin)/clade B serpin family is one group of the human serpins, a family of serine protease inhibitors. They have acquired diversity in the profiles of target proteases, inhibitory mechanisms, and localization patterns during their evolution. Most serpins target serine proteases, however, some ov-serpins target only cysteine proteases or both serine and cysteine proteases and furthermore, several ov-serpins do not possess inhibitory activities. Although the ov-serpins act primarily as intracellular serpins, some show extracellular and nuclear localizations. Such diversity enables the ov-serpins to play multiple physiological roles in the body. Recent analyses have revealed that the functions of human ov-serpins are more diversified than we previously knew. In this article, we describe recent progress in our understanding of how the human ov-serpin/clade B serpin family demonstrates diversity.
    No preview · Article · Jul 2008 · Cellular and Molecular Life Sciences CMLS