Details of a Researcher - KAMEKURA Ryuta

Papers - KAMEKURA Ryuta

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KS-2 IgG4関連涙腺・唾液腺炎の病態形成における濾胞ヘルパーT細胞の機能的役割

亀倉隆太, 高野賢一, 山本元久, 伊藤史恵, 矢部勇人, 川田耕司, 高橋裕樹, 氷見徹夫, 一宮慎吾

日本臨床免疫学会会誌 ( 日本臨床免疫学会 ) 40 ( 4 ) 292b - 292b 2017

【目的】IgG4関連涙腺・唾液腺炎（IgG4-DS）は，涙腺・唾液腺の持続性腫脹と高IgG4血症，局所でのIgG4陽性形質細胞の浸潤を特徴とする疾患である．近年，IgG4産生に関連して，濾胞ヘルパーT（Tfh）細胞と本疾患との関連を示唆する報告が散見されるが，病変部位でのTfh細胞の機能的役割は不明である．【方法】IgG4-DS患者の顎下腺組織からTfh細胞（CD3⁺CD4⁺CXCR5⁺PD-1^hi）を分離し，DNAマイクロアレイやリアルタイムPCRによる遺伝子発現解析に加え，B細胞との共培養の系でIgG4産生について検討した．比較対照としてヒト口蓋扁桃由来のTfh細胞を用いた．【結果】IgG4-DSの顎下腺組織中に存在するCD4陽性T細胞の多くはCXCR5陽性，PD-1強陽性のTfh細胞であり，口蓋扁桃由来のTfh細胞と比較して，Tfh細胞関連分子（BCL6, CXCL13, IL-10）の発現上昇を認めた．また，IgG4-DSの顎下腺由来Tfh細胞とB細胞との共培養で，口蓋扁桃由来のTfh細胞とB細胞との共培養と比較して，より効率的にIgG4の産生が誘導された．さらにDNAマイクロアレイによる解析でIgG4-DSの顎下腺由来のTfh細胞ではCD8A, Granzyme Kといった細胞障害性T細胞関連遺伝子の発現上昇を認めた．【結論】今回の結果から，IgG4-DSの病態形成に強力な抗体産生誘導能と細胞障害能を併せ持つ特殊なTfh細胞が関与している可能性が考えられた．病変部位におけるTfh細胞が，IgG4-DSの新規治療法を開発する上での治療標的となる可能性が示唆された．

DOI CiNii

Importance of "epimmunome" as a new therapeutic target for allergic rhinitis

Ryuta Kamekura, Shingo Ichimiya, Tetsuo Himi

Japanese Journal of Allergology ( Japanese Society of Allergology ) 66 ( 2 ) 91 - 96 2017 [Refereed]

DOI PubMed

Bob1 limits cellular frequency of T-follicular helper cells (vol 46, pg 1361, 2016)

Yamashita Keiji, Kawata Koji, Matsumiya Hiroshi, Kamekura Ryuta, Jitsukawa Sumito, Nagaya Tomonori, Ogasawara Noriko, Takano Ken-ichi, Kubo Terufumi, Kimura Sachiko, Shigehara Katsunori, Himi Tetsuo, Ichimiya Shingo

EUROPEAN JOURNAL OF IMMUNOLOGY 46 ( 8 ) 2054 2016.08 [Refereed]

Novel Mechanisms of Compromised Lymphatic Endothelial Cell Homeostasis in Obesity: The Role of Leptin in Lymphatic Endothelial Cell Tube Formation and Proliferation

Akinori Sato, Ryuta Kamekura, Koji Kawata, Masaya Kawada, Sumito Jitsukawa, Keiji Yamashita, Noriyuki Sato, Tetsuo Himi, Shingo Ichimiya

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 11 ( 7 ) e0158408 2016.07 [Refereed]

Leptin is a hormone produced by adipose tissue that regulates various physiological processes. Recent studies have shown that the level of circulating leptin is elevated in obese patients and have suggested a relationship between obesity and postoperative lymphedema. However, the mechanisms by which postoperative lymphedema develops in obese patients and the mechanisms by which leptin regulates lymphatic endothelial cell homeostasis such as tube formation and cell proliferation remain unknown. Here we report that leptin regulates tube formation and cell proliferation in human dermal lymphatic endothelial cells (HDLECs) by activation of the signal transducer and activator of transcription 3 pathway, which is downstream signaling of the leptin receptor. Additionally, we found that upregulation of suppressor of cytokine signaling 3 underlies the mechanisms by which a high dose of leptin inhibits cell proliferation and tube formation. Leptin also enhanced expression of the proinflammatory cytokine IL-6 in HDLECs. Interestingly, IL-6 rescues the compromised cell proliferation and tube formation caused by treatment with a high dose of leptin in an autocrine or paracrine manner. Taken together, our findings reveal a novel mechanism by which compromised HDLECs maintain their homeostasis during inflammation mediated by leptin and IL-6. Thus, regulating the level of leptin or IL-6 may be a viable strategy to reduce the incidence of postoperative lymphedema.

DOI PubMed

Clinicopathological analysis of salivary gland tissue from patients with IgG4-related disease

Kenichi Takano, Kazuaki Nomura, Ayumi Abe, Ryuta Kamekura, Motohisa Yamamoto, Shingo Ichimiya, Hiroki Takahashi, Tetsuo Himi

ACTA OTO-LARYNGOLOGICA ( TAYLOR & FRANCIS LTD ) 136 ( 7 ) 717 - 721 2016.07 [Refereed]

Conclusion The diagnosis of immunoglobulin G4-related disease (IgG4-RD) should be based on the morphology of tissue biopsy, and this study recommends a submandibular gland (SMG) biopsy for accurate diagnosis and to exclude malignant disease. Objective To clarify which type of biopsy specimen (SMG or labial salivary gland [LSG]) should be taken from patients with IgG4-RD. Methods This study included 33 patients with IgG4-RD (21 women; 12 men) who were subjected to both SMG and LSG biopsies at Sapporo Medical University between 2011-2015. Tissues obtained from the SMG and LSG specimens were evaluated. Results All SMG specimens satisfied the diagnostic criteria for IgG4-RD, whereas 19 (57.6%) LSG specimens satisfied the diagnostic criteria for IgG4-RD. Histological evaluation showed fibrosis in all the SMG specimens and in eight LSG specimens (24.2%). Obliterative phlebitis was seen in nine SMG specimens (27.3%), but it was absent in all the LSG specimens.

DOI PubMed

Bob1 limits cellular frequency of T-follicular helper cells

Keiji Yamashita, Koji Kawata, Hiroshi Matsumiya, Ryuta Kamekura, Sumito Jitsukawa, Tomonori Nagaya, Noriko Ogasawara, Ken-ichi Takano, Terufumi Kubo, Sachiko Kimura, Katsunori Shigehara, Tetsuo Himi, Shingo Ichimiya

EUROPEAN JOURNAL OF IMMUNOLOGY ( WILEY ) 46 ( 6 ) 1361 - 1370 2016.06 [Refereed]

T follicular helper (Tfh) cells are involved in specific humoral immunity at initial and recall phases. The fact that the transcription repressors B-cell lymphoma-6 and Blimp-1 determine lineages of Tfh cells and other types of effector CD4(+) T cells, respectively, suggests that there are unique mechanisms to establish Tfh-cell identity. In this study, we found that Tfh cells preferentially express the transcriptional coactivator Bob1. Bob1 of Tfh cells was dispensable for the expression of B-cell lymphoma-6 and the functional property of the cells for B cell help. However, upon initial immunization of foreign antigens, the percentages of Tfh cells in Bob1(-/-) mice were much higher than those inwild-type (WT) mice. In addition, expansion of Tfh cells within Bob1(-/-)CD4(+) T cells transferred into WT mice revealed that the high frequency of Tfh cells was caused by a T-cell-intrinsic mechanism. These findings were further supported by the results of in vitro studies demonstrating that Bob1(-/-) Tfh cells had greater proliferative activity in response to stimuli by CD3/CD28 monoclonal antibody and were also refractory to CD3-induced cell death in comparison to WT Tfh cells. These results suggest that Tfh cells harbor a Bob1-related mechanism to restrict numerical frequency against stimulation of TCRs.

DOI PubMed

Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3

Yamamoto K, Yamamoto S, Ogasawara N, Takano K, Shiraishi T, Sato T, Miyata R, Kakui T, Kamekura R, Kojima T, Tsutsumi H, Himi T, Yokota S

Pharmacological Research 111 804 - 814 2016 [Refereed]

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Role of Crosstalk between Epithelial and Immune Cells, the Epimmunome, in Allergic Rhinitis Pathogenesis.

Kamekura R, Yamashita K, Jitsukawa S, Nagaya T, Ito F, Ichimiya S, Himi T

Advances in oto-rhino-laryngology 77 75 - 82 2016 [Refereed]

DOI PubMed

Studies of tonsils in basic and clinical perspectives: From the past to the future

Keiji Yamashita, Shingo Ichimiya, Ryuta Kamekura, Tomonori Nagaya, Sumito Jitsukawa, Hiroshi Matsumiya, Kenichi Takano, Tetsuo Himi

Advances in Oto-Rhino-Laryngology ( S. Karger AG ) 77 119 - 124 2016 [Refereed]

The tonsils are located at the entrance of the pharynx as a cardinal constituent of Waldeyer's ring, taking part not only in local immune responses, but also in systemic immunity. Functional deficits of tonsils primarily underlie the pathogenesis of various characteristic disorders, including tonsillar focal infections such as palmoplantar pustulosis and IgA nephropathy, in addition to the highly prevalent sleep disorder called obstructive sleep apnea syndrome. Although the mechanisms underlying these disorders remain unknown, the tonsils have long been postulated as a unique and enigmatic immune organ. Lymphoid cells and tissues from surgically resected tonsils are often employed to analyze the human immune response from a retrospective view. This approach has provided much new fundamental evidence for understanding innate and acquired immune responses, thereby facilitating further studies in the fields of mucosal immunity and specific humoral immunity originating in the germinal center. Future studies of the tonsils in basic and clinical research are expected to reveal the mechanisms of tonsil-related disorders as well as the nature of human immunity. In this review, which is primarily based on our original research over the past 3 decades, we summarize our findings and discuss the future prospects of studies focusing on the tonsils.

DOI PubMed

Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma.

Kamekura R, Shigehara K, Miyajima S, Jitsukawa S, Kawata K, Yamashita K, Nagaya T, Kumagai A, Sato A, Matsumiya H, Ogasawara N, Seki N, Takano K, Kokai Y, Takahashi H, Himi T, Ichimiya S

Clinical immunology (Orlando, Fla.) ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 158 ( 2 ) 204 - 211 2015.06 [Refereed]

Allergic rhinitis (AR), the most common allergic disorder of the airway, is often accompanied by bronchial asthma. However, little is known about the mechanism by which AR advances to AR comorbid with bronchial asthma (AR + Asthma). To determine the pathophysiologic features of AR and AR + Asthma, we examined subsets of follicular helper T (Tfh) cells and regulatory B (Breg) cells in peripheral blood from AR and AR + Asthma patients. The results showed polarization of Tfh2 cells within Tfh cell subsets in both AR and AR + Asthma cases. Interestingly, the %Breg cells in total B cells were decreased in AR cases and, more extensively, in AR + Asthma cases. Moreover, we found significant correlations of fractional exhaled nitricoxide and blood eosinophil levels with the index %Tfh2 cells per %Breg cells. Our findings indicate that relative decrease in Breg cells under the condition of Tfh2 cell skewing is a putative exaggerating factor of AR to bronchial asthma. (C) 2015 The Authors. Published by Elsevier Inc.

DOI PubMed

Alteration of human blood type 2 follicular helper T cells and regulatory B cells underlies comorbid association of allergic rhinitis with bronchial asthma

Kamekura Ryuta, Shigehara Katsunori, Jitsukawa Sumito, Kawata Koji, Himi Tetsuo, Ichimiya Shingo

JOURNAL OF IMMUNOLOGY 194 2015.05 [Refereed]

アレルギー性気道疾患の病態形成における濾胞ヘルパーT細胞と制御性B細胞の役割

亀倉隆太, 重原克則, 實川純人, 小笠原徳子, 高野賢一, 氷見徹夫, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 64 ( 3-4 ) 570 - 570 2015.04

アレルギー性鼻炎の病態形成におけるエピイムノームの役割. 特集アレルギー疾患ガイドラインダイジェストに寄せる

亀倉隆太, 氷見徹夫, 一宮慎吾

アレルギーの臨床 35 57 - 63 2015

Delta Np63 Controls a TLR3-Mediated Mechanism That Abundantly Provides Thymic Stromal Lymphopoietin in Atopic Dermatitis

Terufumi Kubo, Ryuta Kamekura, Ayako Kumagai, Koji Kawata, Keiji Yamashita, Yukari Mitsuhashi, Takashi Kojima, Kotaro Sugimoto, Akihiro Yoneta, Yasuyuki Sumikawa, Toshiharu Yamashita, Noriyuki Sato, Tetsuo Himi, Shingo Ichimiya

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 9 ( 8 ) e105498 2014.08 [Refereed]

In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that Delta Np63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of Delta Np63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked Delta Np63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of Delta Np63 (Delta Np63(lo/-)). Moreover, in the absence of Delta Np63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without Delta Np63, the results indicate that Delta Np63(lo/-) keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.

DOI PubMed

Regulation of Tight Junctions in Upper Airway Epithelium

Takashi Kojima, Mitsuru Go, Ken-ichi Takano, Makoto Kurose, Tsuyoshi Ohkuni, Jun-ichi Koizumi, Ryuta Kamekura, Noriko Ogasawara, Tomoyuki Masaki, Jun Fuchimoto, Kazufumi Obata, Satoshi Hirakawa, Kazuaki Nomura, Takashi Keira, Ryou Miyata, Nobuhiro Fujii, Hiroyuki Tsutsumi, Tetsuo Himi, Norimasa Sawada

BIOMED RESEARCH INTERNATIONAL ( HINDAWI PUBLISHING CORPORATION ) 2013 947072 2013 [Refereed]

The mucosal barrier of the upper respiratory tract including the nasal cavity, which is the first site of exposure to inhaled antigens, plays an important role in host defense in terms of innate immunity and is regulated in large part by tight junctions of epithelial cells. Tight junction molecules are expressed in both M cells and dendritic cells as well as epithelial cells of upper airway. Various antigens are sampled, transported, and released to lymphocytes through the cells in nasal mucosa while they maintain the integrity of the barrier. Expression of tight junction molecules and the barrier function in normal human nasal epithelial cells (HNECs) are affected by various stimuli including growth factor, TLR ligand, and cytokine. In addition, epithelial-derived thymic stromal lymphopoietin (TSLP), which is a master switch for allergic inflammatory diseases including allergic rhinitis, enhances the barrier function together with an increase of tight junction molecules in HNECs. Furthermore, respiratory syncytial virus infection in HNECs in vitro induces expression of tight junction molecules and the barrier function together with proinflammatory cytokine release.. is paper summarizes the recent progress in our understanding of the regulation of tight junctions in the upper airway epithelium under normal, allergic, and RSV-infected conditions.

DOI PubMed

Altered expression of claudin-1, claudin-7, and tricellulin regardless of human papilloma virus infection in human tonsillar squamous cell carcinoma

Atsushi Kondoh, Ken-Ichi Takano, Takashi Kojima, Tsuyoshi Ohkuni, Ryuta Kamekura, Noriko Ogasawara, Mitsuru Go, Norimasa Sawada, Tetsuo Himi

ACTA OTO-LARYNGOLOGICA ( INFORMA HEALTHCARE ) 131 ( 8 ) 861 - 868 2011.08 [Refereed]

Conclusions: Altered expression of claudin-1, claudin-7, and tricellulin in early tonsillar squamous cell carcinoma (SCC) independent of human papilloma virus (HPV) infection may lead to tumor progression. Objectives: Integral tight junction proteins, the claudins and tricellulin, play a crucial role in all tissues. HPV is significantly associated with tonsillar SCC. We sought to determine the expression of claudin-1, claudin-7, and tricellulin in HPV-infected and HPV-free tonsillar SCC. Methods: Twenty-eight tonsillar SCCs were studied by immunohistochemical analysis and real-time reverse transcription polymerase chain reaction with in situ hybridization analysis. Results: Compared with normal tissues, claudin-1 was strongly expressed, whereas claudin-7 and tricellulin were weakly expressed or were absent in primary SCC and metastatic lymph nodes. Claudin-7 and tricellulin were markedly reduced at all stages of tumor development. In situ hybridization analysis showed no correlation between HPV infection and altered expression of the tight junction proteins.

DOI PubMed

Epithelial barrier and antigen uptake in lymphoepithelium of human adenoids

Noriko Ogasawara, Takashi Kojima, Mitsuru Go, Ken-Ichi Takano, Ryuta Kamekura, Tsuyoshi Ohkuni, Jun-Ichi Koizumi, Tomoyuki Masaki, Jun Fuchimoto, Kazufumi Obata, Makoto Kurose, Tomoko Shintani, Norimasa Sawada, Tetsuo Himi

ACTA OTO-LARYNGOLOGICA ( INFORMA HEALTHCARE ) 131 ( 2 ) 116 - 123 2011.02 [Refereed]

Invasion of antigens through the mucosal surface can be prevented by the common mucosal immune system, including Peyer's patches (PPs) and nasopharyngeal-associated lymphoreticular tissue (NALT). The adenoids (nasopharyngeal tonsils) comprise one of the NALTs and constitute the major part of Waldeyer's lymphoid ring in humans. However, the role of the lymphoepithelium, including M cells and dendritic cells (DCs), in the adenoids is unknown compared with the epithelium of PPs. NALTs also have unique functions such as the barrier of epithelial cells and uptake of antigens by M cells and DCs, and may play a crucial role in airway mucosal immune responses. The lymphoepithelium of adenoids has well-developed tight junctions that play an important role in the barrier function, the same as nasal epithelium but not palatine tonsillar epithelium. Tight junction molecules are expressed in both M cells and DCs as well as epithelial cells, and various antigens may be sampled, transported, and released to lymphocytes through the cells while they maintain the integrity of the epithelial barrier. This review summarizes the recent progress in our understanding of how M cells and DCs control the epithelial barrier in the adenoids.

DOI PubMed

Poly(I:C) reduces expression of JAM-A and induces secretion of IL-8 and TNF-alpha via distinct NF-kappa B pathways in human nasal epithelial cells

Tsuyoshi Ohkuni, Takashi Kojima, Noriko Ogasawara, Tomoyuki Masaki, Jun Fuchimoto, Ryuta Kamekura, Jun-ichi Koizumi, Shingo Ichimiya, Masaki Murata, Satoshi Tanaka, Tetsuo Himi, Norimasa Sawada

TOXICOLOGY AND APPLIED PHARMACOLOGY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 250 ( 1 ) 29 - 38 2011.01 [Refereed]

Human nasal epithelium is an important physical barrier and innate immune defense protecting against inhaled substances and pathogens. Toll-like receptor (TLR) signaling, which plays a key role in the innate immune response, has not been well characterized in human nasal epithelial cells (HNECs), including the epithelial tight junctional barrier. In the present study, mRNAs of TLR1-10 were detected in hTERT-transfected HNECs, which can be used as an indispensable and stable model of normal HNECs, similar to primary cultured HNECs. To investigate the changes of tight junction proteins and the signal transduction pathways via TLRs in HNECs in vitro, hTERT-transfected HNECs were treated with TLR2 ligand P(3)CSK(4), TLR3 ligand poly(I:C), TLR4 ligand LPS, TLR7/8 ligand CL097, TLR8 ligand ssRNA40/LyoVec, and TLR9 ligand ODN2006. In hTERT-transfected HNECs, treatment with poly(I:C) significantly reduced expression of the tight junction protein JAM-A and induced secretion of proinflammatory cytokines IL-8 and TNF-alpha. Both the reduction of JAM-A expression and the induction of secretion of IL-8 and TNF-alpha after treatment with poly(I:C) were modulated by distinct signal transduction pathways via EGFR. PI3K, and p38 MAPK and finally regulated by a TLR3-mediated NF-kappa B pathway. The control of TLR3-mediated signaling pathways in HNECs may be important not only in infection by viral dsRNA but also in autoimmune diseases caused by endogenous dsRNA released from necrotic cells. (C) 2010 Elsevier Inc. All rights reserved.

DOI PubMed

Mucosal Immune Barrier and Antigen-Presenting System in Human Nasal Epithelial Cells

Tetsuo Himi, Ken-ichi Takano, Noriko Ogasawara, Mitsuru Go, Makoto Kurose, Jun-ichi Koizumi, Ryuta Kamekura, Atsushi Kondo, Tsuyoshi Ohkuni, Tomoyuki Masaki, Takashi Kojima, Norimasa Sawada, Hiroyuki Tsutsumi

RECENT ADVANCES IN TONSILS AND MUCOSAL BARRIERS OF THE UPPER AIRWAYS ( KARGER ) 72 28 - + 2011 [Refereed]

The upper respiratory tract including the nasal cavity, which is the first site of invading antigen exposure, plays a crucial role in host defense via the mucosal immune response. The epithelium of nasal mucosa forms a continuous barrier against a wide variety of exogenous antigens. The epithelial barrier function is regulated in large part by the apical-most intercellular junction, referred to as the tight junction. Antigen-presenting cells, particularly dendritic cells (DCs), are known to play an important role in human nasal mucosa. Recently, the author and colleagues discovered a new mechanism for pathogen uptake in the nasal mucosa, by which DCs open the tight junctions between epithelial cells and send dendrites outside the epithelium to directly sample the pathogen. In order to preserve the integrity of the epithelial barrier and penetrate beyond well-developed epithelial tight junctions, DCs express tight junction proteins. We also found that these DCs are activated by nasal epithelial-derived TSLP induced by stimuli such as cytokines and Toll-like receptor ligands. In this lecture, I will talk about the novel mechanisms in host defense in terms of innate immunity of the nasal mucosa from the point of view of the mucosal barrier function. Copyright (C) 2011 S. Karger AG, Basel

DOI PubMed

PPAR gamma agonists upregulate the barrier function of tight junctions via a PKC pathway in human nasal epithelial cells

Noriko Ogasawara, Takashi Kojima, Mitsuru Go, Tsuyoshi Ohkuni, Jun-ichi Koizumi, Ryuta Kamekura, Tomoyuki Masaki, Masaki Murata, Satoshi Tanaka, Jun Fuchimoto, Tetsuo Himi, Norimasa Sawada

PHARMACOLOGICAL RESEARCH ( ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD ) 61 ( 6 ) 489 - 498 2010.06 [Refereed]

Peroxisome proliferator activated (PPAR)gamma plays a critical role in the control of not only adipocyte differentiation, lipid metabolism and immunity but also the barrier functions of epithelial and endothelial cells. In the present study, to investigate effects of PPAR gamma agonists on the tight junctional barrier of human nasal epithelial cells (HNECs), hTERT-transfected HNECs, which highly express both PPAR gamma and tight junction proteins, were treated with the PPAR gamma agonists rosiglitazone and troglitazone. Treatment with the PPAR gamma agonists enhanced the barrier function of hTERT-transfected HNECs together with the upregulation of tight junction molecules claudin-1 and -4, occludin, and tricellulin at the transcriptional level. A significant increase of tight junction strands was also observed after treatment with rosiglitazone. Treatment with PPAR gamma agonists induced the activity of phospho-PKC in hTERT-transfected HNECs. The upregulation of the tight junction molecules in hTERT-transfected HNECs by rosiglitazone was inhibited by not only PPAR gamma antagonists GW9662 and T0070907, but also the panPKC inhibitor GF109203X. These findings suggest that PPAR gamma agonists upregulate the barrier function of tight junctions of human nasal epithelial cells via a PKC signaling pathway and could be novel drugs for protection against inhaled substances and pathogens in the airway epithelium of human nasal mucosa. (C) 2010 Elsevier Ltd. All rights reserved.

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