K Izuhara

Saga University, Сага Япония, Saga, Japan

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Publications (34)130.9 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/μl) in the high serum periostin group. A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.
    Allergy 03/2014; · 5.88 Impact Factor
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    ABSTRACT: Background Atopic dermatitis (AD) is a chronic inflammatory skin disease in which T helper 2 (Th2)-type immune responses are dominant. Keratinocytes persistently secrete proinflammatory cytokines and chemokines, amplifying Th2-type responses in AD. Recent findings indicate that periostin, an extracellular matrix protein induced by Th2 cytokines, plays a critical role in the pathogenesis of AD. Objective To determine whether serum periostin level is associated with the clinical phenotype in adult AD patients. Methods An enzyme-linked immunosorbent assay was performed to determine serum periostin levels in 257 adult AD patients, 66 patients with psoriasis vulgaris (PV) as a disease control and 25 healthy control subjects. Serum periostin levels were analysed together with clinical characteristics and laboratory parameters including thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), blood eosinophil count and total immunoglobulin E (IgE). Immunohistochemical analysis was performed to evaluate periostin expression in association with various clinical phenotypes of AD. The effect of treatment on serum periostin level was also assessed. ResultsSerum periostin was significantly higher in AD patients than in PV patients and healthy control subjects. The periostin level was found to be positively correlated with disease severity, TARC level, LDH level and eosinophil count, but not IgE level. Higher serum periostin level was observed in extrinsic AD patients compared to intrinsic AD patients, and the positive correlation of disease severity disappeared in patients with intrinsic AD. Robust expression of periostin was detected in the dermis of AD patients with erythroderma, lichenification and, to a lesser extent, scaly erythema. Serial measurement of serum periostin revealed decreased levels of periostin after treatment for AD. Conclusions The periostin level reflects disease severity and clinical phenotype of adult AD patients. Our results suggest that periostin may play a critical role in disease severity and chronicity in the pathogenesis of AD.This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 03/2014; · 3.76 Impact Factor
  • Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 05/2013; 110(5):387-8. · 3.45 Impact Factor
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    ABSTRACT: Background:  Periostin, a matricellular protein, serves as a regulator of wound healing and fibrosis. The role of periostin in the pathogenesis of systemic sclerosis (SSc) is unknown. Objective:  To determine periostin levels in association with severity of skin fibrosis in patients with SSc. Methods:  Expression of periostin was immunohistochemically examined in the skin obtained from SSc patients and healthy controls. Enzyme-linked immunosorbent assay was performed to evaluate serum periostin levels in association with clinical characteristics in 56 patients with SSc (diffuse cutaneous SSc (dSSc), n=16; and limited cutaneous SSc (lSSc), n=40) and 66 healthy controls. Results:  Periostin was strongly expressed in the affected dermis from SSc patients. Periostin was co-localized in α-SMA-positive myofibroblasts and PECAM-1-positive endothelial cells in SSc dermis. Serum levels of periostin in dSSc patients were markedly elevated compared to those in lSSc patients and control subjects. Patients with lSSc had increased periostin levels compared with healthy controls. In addition, significantly higher levels of periostin were observed in dSSc patients with disease duration ≤5 years compared with those with disease duration >5 years. Furthermore, the modified Rodnan total skin thickness score (MRSS) was positively correlated with periostin levels in SSc patients. Serial analysis revealed a correlation between periostin and MRSS; namely, MRSS decreased in line with decreased periostin levels in some dSSc patients as the disease progressed. Conclusion:  An elevated periostin level in SSc patients was associated with severity of skin sclerosis. Periostin may be a potential biomarker for progressive skin fibrosis in SSc.
    British Journal of Dermatology 10/2012; · 3.76 Impact Factor
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    ABSTRACT: May-Hegglin anomaly (MHA) is a rare autosomal dominant disease characterized by macrothrombocytopenia and leukocyte inclusions with microfilaments in the ribosomes. Mutations in the MYH9 gene, encoding non-muscle myosin heavy chain IIA (NMMHC-IIA) have been identified in patients with MHA and other MYH9-related diseases. Two young males (an older and younger brother) presented with macrothrombocytopenia and leukocyte inclusion bodies. Electron microscopy (EM) revealed parallel filaments in leukocyte inclusion bodies characteristic of MHA. Immunofluorescence microscopy (IF) showed NMMHC-IIA antibodies in 1 - 2 leukocyte inclusion bodies. These findings were consistent with MHA and they were identified to express the MYH9 mutation, D1424H. The older brother underwent a renal biopsy because of persistent proteinuria. Histology revealed mesangial proliferative glomerulonephritis with granular deposits of IgG and C1q. EM showed that the dense deposits were located in subendothelial cells, mesangial cells and Bowman's capsule. Immunocytochemistry revealed that NMMHC-IIA antibodies were localized in podocyte and endothelial cells in the glomerulus. Moreover, the expression of nephrin and podocin, slit diagram protein, was normal. An inflammatory mechanism may occur separately from MYH9-related disease. This report presents a case of MHA with immune complex-related nephropathy.
    Clinical nephrology 03/2011; 75(3):255-62. · 1.29 Impact Factor
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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.
    European Respiratory Journal 12/2010; 37(5):1119-27. · 6.36 Impact Factor
  • K Izuhara
    Cellular and Molecular Life Sciences CMLS 05/2009; · 5.62 Impact Factor
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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.
    Current Medicinal Chemistry 02/2009; 16(22):2867-75. · 3.72 Impact Factor
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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.
    Cellular and Molecular Life Sciences CMLS 07/2008; 65(16):2541-53. · 5.62 Impact Factor
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    ABSTRACT: The incidence of allergic diseases has dramatically increased in recent decades, especially in urban and industrialized areas. It is important socially as well as medically to establish more useful strategies to overcome allergic disorders. Bronchial asthma is a complex disease characterized by airway inflammation involving a Th2-cytokine, interleukin (IL)-13. A substantial body of evidence has accumulated pointing to the pivotal role of IL-13 in the pathogenesis of bronchial asthma, based on mainly analyses of mouse models. In addition to such analyses, the high expression of IL-13 in lesions and genetic association of several genes coding IL-13 signaling molecules with bronchial asthma have raised the possibility that IL-13 plays a pivotal role in the onset or exacerbation of human bronchial asthma. Therefore, IL-13 and its signal pathway are thought to be promising targets to develop a therapeutic agent for bronchial asthma. In this article, we describe how IL-13 is involved in the pathogenesis of bronchial asthma and then how therapeutic agents to block IL-13 signals are developed for bronchial asthma.
    Current Medicinal Chemistry 02/2006; 13(19):2291-8. · 3.72 Impact Factor
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    ABSTRACT: Although it is thought that both Th1- and Th2-type inflammations are involved in the pathogenesis of atopic dermatitis (AD), it is controversial which immune response is more involved in regulating the clinical severity of AD. We recently found that the squamous cell carcinoma antigens 1 (SCCA1) and SCCA2 are novel biomarkers of bronchial asthma, downstream of IL-4 and IL-13. We examined whether SCCA1 and SCCA2 could also serve as biomarkers of AD, reflecting its Th2-type immune responses, and whether the expression level of SCCA was correlated with clinical severity of AD. We compared the expression of SCCA1 and SCCA2 at the mRNA and protein levels in both involved and uninvolved skin of AD patients and in normal control skin. We next analysed induction of SCCA by IL-4 or IL-13 in keratinocytes. Finally, we compared the serum level of SCCA with laboratory parameters reflecting Th2-type inflammation and clinical severity in AD patients. SCCA1 and SCCA2 were highly expressed in involved skin of AD patients, compared with their uninvolved skin, at both mRNA and protein levels. SCCA protein was dominantly expressed in suprabasal keratinocytes in the epidermis of AD patients. Either IL-4 or IL-13, but not IFN-gamma or TNF, induced production of SCCA in keratinocytes. These result suggest that SCCA is induced in AD skin, probably due to direct actions of IL-4 and/or IL-13 on keratinocytes. Serum levels of SCCA were well correlated with eosinophil numbers and serum lactate dehydrogenase levels, and weakly with serum IgE levels, in AD patients. Furthermore, serum levels of SCCA were strongly correlated with clinical severity. Th2-type inflammation dominantly regulates the clinical severity of AD, and SCCA is a relevant biomarker of AD, reflecting both Th2-type inflammation and clinical severity.
    Clinical & Experimental Allergy 11/2005; 35(10):1327-33. · 4.79 Impact Factor
  • Medicinal Chemistry Reviews - Online 01/2005; 2(2):149-152.
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    ABSTRACT: The squamous cell carcinoma antigen 1 (SCCA1) and SCCA2 are unique serpins that can inhibit cysteine proteinases. SQN-5, their mouse ortholog, has already been identified, and its inhibitory property has been characterized; however, its biological role has remained undefined. Furthermore, no other mouse homolog of SQN-5 has been known. We characterize three mouse members of SCCA-related molecules including SQN-5 in this article. Serpinb3a (SQN-5) and Serpinb3b, but not Serpinb3c, were functional, inhibiting both serine and cysteine proteinases with different inhibitory profiles due to the difference of two amino acids in their reactive site loops. Serpinb3a was ubiquitously expressed in most tissues, whereas expression of Serpinb3b was limited to keratinocytes. Keratinocytes secreted both SCCA-related proteins, Serpinb3a and Serpinb3b. These results indicate that Serpinb3a and Serpinb3b may play different roles by inhibiting intrinsic or extrinsic proteinases with different expression distributions and different inhibitory profiles.
    Biochemical and Biophysical Research Communications 12/2004; 324(4):1340-5. · 2.28 Impact Factor
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    ABSTRACT: Bronchial asthma is a complicated and diverse disorder affected by genetic and environmental factors. It is widely accepted that it is a Th2-type inflammation originating in lung and caused by inhalation of ubiquitous allergens. The complicated and diverse pathogenesis of this disease is yet to be clarified. Functional genomics is the analysis of whole gene expression profiling under given condition, and microarray technology is now the most powerful tool for functional genomics. Several attempts to clarify the pathogenesis of bronchial asthma have been carried out using microarray technology, providing us some novel pathogenic mechanisms of bronchial asthma as well as the information of gene expression profiling. In this article, we review the outcomes of these analyses by the microarray approach as applied to bronchial asthma.
    Current Pharmacogenomics 11/2004; 2(4):351-356.
  • K Izuhara, K Arima
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    ABSTRACT: Interleukin-13 (IL-13) is a Th2-type cytokine, secreted from CD4(+) T cells, mast cells, basophils and eosinophils. The human IL-13 gene locates at 5q31, generating a cluster with other Th2-type cytokines such as IL-4 and IL-5. Although the homology between IL-13 and IL-4 at the amino acid level is only about 25%, the IL-13 structure determined by NMR is very similar to that of IL-4. Both cytokines share their receptors and signal pathways, giving these two cytokines similar biological properties. However, the important role of IL-13 in the pathogenesis of bronchial asthma has recently been recognized, based mainly on analyses of mouse models. IL-13 and its signal pathway are thought to be promising targets to develop a therapeutic reagent for bronchial asthma. In this article, we summarize the signal transduction pathway of IL-13, the pathological roles of IL-13 in bronchial asthma and the reagents to inhibit IL-13 signals that are now under development.
    Drug News & Perspectives 04/2004; 17(2):91-8. · 3.13 Impact Factor
  • K Izuhara, K Arima, S Yasunaga
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    ABSTRACT: The incidence of allergic diseases has dramatically increased in recent decades, and it is socially and medically important to establish more useful strategies to overcome allergic disorders. Various kinds of drugs are utilized for allergic patients; however, some cases are unresponsive to these drugs and in others there are undesired adverse effects. On the other hand, a substantial body of evidence has accumulated pointing to the pivotal role of Th2-cytokines, interleukin (IL)-4, and IL-13, in the pathogenesis of bronchial asthma. The evidence is categorized as (1) expression of these cytokines in the bronchial lesions, (2) genetic association of the signaling molecules of these cytokines, (3) analyses of mouse models. In addition, the molecular mechanism of the signal transduction of these cytokines has also been well characterized. Based on such information, IL-4 and IL-13 have emerged as promising means of improving allergic states, and several IL-4/IL-13 antagonists have been developed, among which soluble IL-4 receptor is now in human trials. Identifying the structure of the IL-13 variant and of the IL-4/IL-13-inducing genes would be of great use. It is expected that in the near future, several drugs will emerge based on these strategies, which will give us wider choice in treating patients, depending on the pathogenesis of the diseases.
    Current Drug Targets - Inflammation & Allergy 10/2002; 1(3):263-9.
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    ABSTRACT: Hodgkin's disease (HD) is characterized by the presence of Hodgkin and Reed-Sternberg (H-RS) cells against a hyperplastic background of reactive cells such as lymphocytes, histiocytes, plasma cells, eosinophils, neutrophils, and stromal cells. There is ample evidence to suggest that proliferation and survival of HD-derived cells is due to cytokine signalling. Recently, high expression of interleukin (IL)-13 was described in HD-derived cell lines. Here we investigated the possible involvement of IL-13 in the pathophysiology, especially autocrine pathways of H-RS cells. The expression of IL-13 and IL-13 receptor (IL-13R) was determined by immunostaining and reverse transcriptase-polymerase chain reaction in 39 cases of HD, including 17 cases with nodular sclerosis (NS) type, 19 cases with mixed cellularity (MC), and three cases with lymphocyte predominance (LP) type. Expression of IL-13 was confined to H-RS cells and a few lymphocytes. IL-13R was expressed in H-RS cells, lymphocytes, histiocytes, fibroblasts, and endothelial cells. H-RS cells of MC and NS types frequently expressed both IL-13 and IL-13R. However, the number of IL-13-positive H-RS cells was statistically higher in NS-type than in MC-type, but the number of IL-13R was similar. IL-13R-positive fibroblasts were frequently encountered in NS-type. H-RS cells of LP type rarely expressed IL-13. Our results suggest that IL-13 might be involved in autocrine pathways of H-RS cells and fibrosis at least in NS-type. Our results also indicated that in addition to the morphological and phenotypic differences, the neoplastic cells of LP type might be functionally different from H-RS cells of MC- and NS-types.
    Histopathology 05/2001; 38(4):368-75. · 2.86 Impact Factor
  • Biochemical and Biophysical Research Communications 01/2001; 288(1). · 2.28 Impact Factor
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    ABSTRACT: IL-4 and IL-13 are pleiotropic cytokines whose biological activities overlap with each other. IL-13 receptor alpha chain 1 (IL-13R alpha 1) is necessary for binding to IL-13, and the heterodimer composed of IL-13R alpha 1 and IL-4R alpha chain transduces IL-13 and IL-4 signals; however, the functional mapping of the intracellular domain of IL-13R alpha 1 is not fully understood. In this study, we constructed wild and mutated types of human IL-13R alpha 1, and analyzed IL-4 and IL-13 signals using an IL-13R alpha 1-transfected human B cell line. Expression of IL-13R alpha 1 evoked STAT3 activation by IL-4 and IL-13, and in stimulated human B cells, on which IL-13R alpha 1 was highly expressed, IL-4 and IL-13 induced STAT3 activation. Replacement of the two tyrosine residues completely abolished STAT3 activation, although replacing either tyrosine residue alone retained it. Furthermore, we found that the Box1 region and the C-terminal tail of IL-13R alpha 1 were critical for binding to Tyk2, and activation of Jak1, Tyk2, the insulin receptor substrate-1 and STAT6 respectively. These results suggest that STAT3 activation is involved with IL-4 and IL-13 signals in human B cells along with the activation of STAT6, and that there is a unique sequence in IL-13R alpha 1 to activate STAT3.
    International Immunology 12/2000; 12(11):1499-509. · 3.14 Impact Factor
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    ABSTRACT: Atopy is a common inherited disorder characterized by increased IgE responsiveness, but no functional analysis of the candidate genes related to atopy has been performed. IL-4 is important for B-cell production of IgE, and the human IL-4 receptor alpha chain (hIL-4Ralpha) is crucial for the binding and signal transduction of IL-4, so hIL-4Ralpha may be a candidate gene related to atopy. We examined the relationship between the variation at amino acid 50 of hIL-4Ralpha and atopic asthma. We performed a genetic study to investigate the relationship between the variation of amino acid 50 (isoleucine [Ile(50)] or valine [Val(50)]) and atopic asthma in a Japanese population and a functional study with the use of transfectants that expressed hIL4Ralpha bearing either Ile(50) or Val(50). Furthermore, we analyzed CD23 expression and IgE synthesis after IL-4 stimulation of peripheral blood mononuclear cells bearing either Ile(50) or Val(50). The prevalence of Ile(50) was higher than that of Val(50) in individuals with atopic asthma, especially during childhood. In transfectants, germline epsilon transcription activity and Stat6 activity were upregulated by the Ile(50) variant, compared with Val(50), but receptor affinity for IL-4 was similar between the two. CD23 expression and IgE synthesis in response to IL-4 were augmented in Ile(50)-expressing peripheral mononuclear blood cells compared to cells expressing Val(50). The Ile(50) variant of hIL-4Ralpha may be related to atopic asthma, particularly in children.
    Journal of Allergy and Clinical Immunology 08/2000; 106(1 Pt 2):S65-71. · 12.05 Impact Factor

Publication Stats

1k Citations
130.90 Total Impact Points

Institutions

  • 2006–2009
    • Saga University
      • Department of Biomolecular Sciences
      Сага Япония, Saga, Japan
  • 1997–2001
    • Kyushu University
      • • Department of Clinical Chemistry and Laboratory Medicine
      • • Faculty of Medical Sciences
      Hukuoka, Fukuoka, Japan
  • 1998
    • National Institute of Genetics
      • Division of Human Genetics
      Mishima, Shizuoka-ken, Japan
    • Research Institute of Tuberculosis
      Edo, Tōkyō, Japan