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Biomedical subjects

K Izuhara

Publications and source records attributed to K Izuhara.

At least 19 recordsLinked to original sources
PubMed2006

IL-13: a promising therapeutic target for bronchial asthma.

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.

Asthma↗
PubMed2005

The squamous cell carcinoma antigens as relevant biomarkers of atopic dermatitis.

BACKGROUND: 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. OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Adult↗
PubMed2004

Characterization of novel squamous cell carcinoma antigen-related molecules in mice.

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.

Amino Acid Sequence↗
PubMed2004

Induction of drug-metabolizing enzymes and transporters in human bronchial epithelial cells by beclomethasone dipropionate.

Inhaled steroids are the most potent anti-inflammatory therapy commonly used in bronchial asthma. There are, however, a small number of asthmatic patients who do not respond to inhaled steroid-treatment. The stimulation of metabolism and excretion of inhaled drugs at bronchial tissues might lead to a decrease in the effect of the drugs, although the molecular mechanism of this resistance is unclear. In this study, we found that beclomethasone dipropionate (BDP) stimulated the expression of mRNAs for uridine 5'-diphosphate glucuronosyl transferase 2B4 and 2B11, and transporters such as multidrug resistance P-glycoprotein, multidrug resistance-associated protein 1 and 2 in cultured bronchial epithelial cells. It is possible that the individual differences of expression of drug metabolizing enzymes and transporters and their enhancement with BDP are implicated in the individual differences of reactivity over steroid medical treatment.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

Signal transduction of IL-13 and its role in the pathogenesis of bronchial asthma.

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.

Animals↗
PubMed2002

IL-4 and IL-13: their pathological roles in allergic diseases and their potential in developing new therapies.

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.

Animals↗
PubMed2001

PKCdelta and zeta mediate IL-4/IL-13-induced germline epsilon transcription in human B cells: a putative regulation via PU.1 phosphorylation.

We have investigated the role of PKC isozymes in the function of IL-4 and IL-13 in human B cells. In a Burkitt's B lymphoma cell line, DND39, IL-4 induced the translocation of PKCdelta and zeta from the cytosol to the membrane fraction. The activation of germline epsilon promoter by IL-4 was abrogated not only by the expression of dominant negative mutants of PKCdelta and zeta but also by isozyme-selective PKC inhibitors, rottlerin and PKCzeta pseudosubstrate peptide. These inhibitors also suppressed IL-4/IL-13-induced germline epsilon transcription in the IL-13Ralpha1-transfected DND39 cells as well as in normal human B cells, but had no influence on the induction of CD23b in the latter cells. As a downstream event of PKC, we found threonine phosphorylation of PU.1 in IL-4-stimulated DND39 cells. This phosphorylation was suppressed by the PKC inhibitors, although STAT6 activation was unaffected. These results suggest that, in human B cells, IL-4/IL-13 utilize PKCdelta and zeta for the STAT6-independent signaling pathway and thereby modulate the transcriptional activity of PU.1.

B-Lymphocytes↗
PubMed2001

Localization of human interleukin 13 receptor in non-haematopoietic cells.

Although the functional roles of interleukin (IL-)13 in haematopoietic cells are well investigated, those in non-haematopoietic cells remain to be addressed. IL-13 exerts its actions by binding to the IL-13 receptor (IL-13R) on target cells, which is composed of IL-13Ralpha1 and the IL-4 receptor alpha chain (IL-4Ralpha). However, there has been no study of localization of IL-13R in each tissue. To address this question, we generated monoclonal anti-IL-13Ralpha1 antibody, and performed immunohistochemistry using this antibody and anti-IL-4Ralpha antibody. Distribution of these two components was the same in all examined tissues. Staining was positive in keratinocytes, hair follicles, and sebaceous and sweat glands in skin; in ciliated respiratory epithelial cells in nasal tissue; in heart muscle cells; in foveola cells, gastric glands, and the smooth muscle layer in stomach; and in hepatocytes in liver. However, staining was undetectable in brain and bone marrow. Fibroblasts and endothelial cells were stained in some tissues. These results provide clues to elucidate the known pathological roles of IL-13 in atopic dermatitis and allergic rhinitis, as well as its unknown physiological roles.

Animals↗
PubMed2001

Interleukin-13 and interleukin-13 receptor in Hodgkin's disease: possible autocrine mechanism and involvement in fibrosis.

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Adolescent↗
PubMed2001

[Involvement of interleukin-4, and -13 in the pathogenesis of allergic diseases].

Allergic diseases are immunologic disorders in which various kinds of cells and many mediators are involved. Among them, the importance of interleukin(IL)-4 and IL-13 has recently emerged, based on the analyses of cytokine expression profiles in lesions, model mice, genetic factors, and responses to newly developed reagents. It is known that IL-4 and IL-13 are involved in the pathogenesis of allergic diseases, particularly bronchial asthma, by inducing class switching in B cells and expansion of Th2-type cells. However, IL-4 and IL-13 have a pivotal role in causing bronchial asthma by acting directly on bronchial tissues. Furthermore, it has been demonstrated that a single nucleotide polymorphism in the IL-13 gene is genetically correlated with bronchial asthma. These analyses provide new information for developing better methods of diagnosing and treating bronchial asthma.

Animals↗
PubMed2000

Augmentation of signal transducer and activation of transcription (STAT)6 and STAT3 expression in stimulated B and T cells.

Signal transducer and activation of transcription (STAT)6 has a central role in the signal transduction of interleukin (IL)-4 and IL-13. It has recently been revealed that STAT3 is also involved. STAT6 and STAT3 are expressed ubiquitously; however, it remains unknown how STAT6 and STAT3 expression is regulated. In this study, we found that STAT6 expression was augmented at the transcription level in B and T cells stimulated with anti-IgM antibody and anti-CD40 antibody or PMA and ionomycin, respectively, and that STAT3 expression was similarly augmented in the stimulated B cells. The stimulated B and T cells showed enhancement of STAT6 activation and CD23 expression induced by IL-4 and IL-13. Augmentation of STAT6 and STAT3 would be a mechanism of the amplification of the IL-4 and IL-13 signals in stimulated B and T cells.

B-Lymphocytes↗
PubMed2000

Genetic variants of IL-13 signalling and human asthma and atopy.

Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.

Adult↗
PubMed2000

Lipopolysaccharide increases cyclo-oxygenase-2 expression in a colon carcinoma cell line through nuclear factor-kappa B activation.

Both nonneoplastic colon epithelium and colon carcinoma cells in situ are continuously exposed to lipopolysaccharide (LPS). Few reports have addressed possible direct effects of LPS in promotion of colon carcinoma and underlying mechanisms. We found evidence that LPS directly stimulated growth of the human colon carcinoma cell line CE-1 through an increase in the production of prostaglandin E2 (PGE2) as a result of cyclo-oxygenase-2 (COX-2) expression. LPS induced significant increases in PGE2 production in CE-1 cells, which were found to express a high-affinity LPS receptor, CD14. Positive correlations were found between PGE2 production and activation of nuclear factor (NF)-kappa B as well as expression of both COX-2 mRNA and protein in LPS-stimulated CE-1 cells. When CE-1 cells were exposed to exogenous PGE2, DNA synthesis increased. These results indicate that LPS may stimulate DNA synthesis in certain colon carcinoma cells as a result of PGE2 production involving increased COX-2 expression that might result in turn from activation of NF-kappa B by LPS. Further investigation of the pathways mediating LPS-induced stimulation of colon carcinoma cells may provide insights into LPS effects in in vivo tumor biology.

Adenocarcinoma↗
PubMed2000

Atopy and the human IL-4 receptor alpha chain.

BACKGROUND: 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. OBJECTIVE: We examined the relationship between the variation at amino acid 50 of hIL-4Ralpha and atopic asthma. METHODS: 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). RESULTS: 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). CONCLUSION: The Ile(50) variant of hIL-4Ralpha may be related to atopic asthma, particularly in children.

Amino Acid Substitution↗
PubMed2000

Characterization of IL-4 and IL-13 signals dependent on the human IL-13 receptor alpha chain 1: redundancy of requirement of tyrosine residue for STAT3 activation.

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.

Animals↗
PubMed2000

Childhood atopic asthma: positive association with a polymorphism of IL-4 receptor alpha gene but not with that of IL-4 promoter or Fc epsilon receptor I beta gene.

We examined the relative contributions of three representative candidate genes for atopy (Fc epsilon receptor I beta, IL-4, and IL-4 receptor alpha) to the development of atopic asthma. Four polymorphisms of the three candidate genes including Ile50Val and Gln551Arg of IL-4 receptor alpha, -590C/T of IL-4 promoter and Glu237Gly of Fc epsilon receptor I beta were studied in 100 patients with atopic asthma and 100 nonatopic controls in the northern Kyushu area in Japan. Among the four polymorphisms of the three candidate genes, the Ile50 allele of the IL-4 receptor alpha chain gene demonstrated an association with atopic asthma subjects (p = 0.044), especially in patients with onset at 2 years of age or earlier (p = 0.034) and in patients with moderate to severe atopic asthma (p = 0. 031). Gln551Arg of IL-4 receptor alpha, -590C/T of IL-4 promoter and Glu237Gly of Fc epsilon receptor I beta showed no association with atopic asthma. A slight linkage disequilibrium between Ile50Val and Gln551Arg polymorphisms of the IL-4 receptor alpha chain gene was observed in both patients and nonatopic controls. The identification of additional atopy genes in areas with a certain genetic background is essential for genetic diagnosis and to establish new therapeutic modalities for atopic asthma.

Adolescent↗
PubMed2000

Recent advances in understanding how interleukin 13 signals are involved in the pathogenesis of bronchial asthma.

The prevalence of allergic disease has dramatically increased in recent decades, especially in urban and industrialized areas. Allergic diseases are disorders of the immune system, the results of complex interactions among various genetic and environmental factors. Among them, the important role of interleukin 13 (IL-13), a Th2-type cytokine, has recently emerged in the pathogenesis of bronchial asthma. Based on studies using mice, great attention has been paid to the direct effects of IL-13 on bronchial tissues. In this review, we describe recent advances in understanding the signal transduction mechanism of IL-13, the involvement of IL-13 signal-related genes as genetic factors in the pathogenesis of bronchial asthma, and the expression of IL-13 receptor on bronchial tissues. We describe potential strategies for targeting IL-13 signals to improve allergic states.

Animals↗