APPROACHES FOR EFFICIENT INHABITION OF INFLAMMATORY GENES BY SMALL DOSES OF CORTICOSTEROIDS

• Project/Area Number: 16590905
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Osaka University
• Principal Investigator: KASAYAMA Soji Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (10240839)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000); Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: Vascular endothelial cells / IL-6 / VCAM-1 / Inflammatory genes / Glucocorticoids / PPAR / NF-κB / eNOS / 接着分子 / サイトカイン / 核内受容体 / NO合成酵素 / 転写因子 / 転写共役因子

Research Abstract

Glucocorticoids are one of the strongest anti-inflammatory drugs. Long-term use of relatively large doses of glucocorticoids is restricted because of various kinds of adverse effects. This investigation was aimed to develop the way how smaller doses of glucocorticoids efficiently exert strong anti-inflammatory effects. Glucocortiocids clearly inhibited TNF-α-induced IL-6 gene promoter activity in cultured bovine aortic endothelial cells (BAECs), whereas they failed to TNF-α-induced VCAM-1 gene promoter activity in BAECs. However, when glucocorticoid receptor (GR) expression vector was introduced into these cells, glucocorticoids could significantly inhibit TNF-α-induced VCAM-1 gene promoter activity. Interestingly, lower concentrations of glucocorticoids were efficient for the inhibition in high GR expressed cells, compared with low GR expressed cells. These results suggest a potential for strong anti-inflammatory effects of low concentrations of glucocorticoids, by increasing GR expression levels in target cells.
Activation of PPARα resulted in inhibition of NF-κB binding to specific sequence of the VCAM-1 gene promoter, indicating the inhibitory effect of PPARα on VCAM-1 gene transcription through inhibition of NF-κB activity. MCC-555,an agonist for PPAR three subtypes, was found to inhibit VCAM-1 expression in vascular endothelial cells and monocytes adhesion to these cells. The PPARδ specific agonist GW501516 could also inhibited VCAM-1 expression, while the PPARγ specific agonist pioglitazone did not. Thus, PPARα and δ, but not γ, have the potential to inhibit the VCAM-1 expression in vascular endothelial cells.
Activation of PPARα was also found to increase eNOS protein and its mRNA levels in vascular endothelial cells. PPARα activation failed to increase eNOS gene promoter activity, while it stabilized eNOS mRNA. This observation is interesting for understanding the nuclear receptors-mediated stabilization of mRNA.

Research Products

• [Journal Article] The thiazolidinedione drug troglitazone up-regulates nitric oxide synthase expression in vascular endothelial cells (2006)
  • Author(s): Goya, K. et al.
  • Journal Title: J.Diabetes Complications 印刷中
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] セルフケア行動評価尺度SDSCA(The Summary of Diabetes Self-Care Activities Measure)の日本人糖尿病患者における妥当性および信頼性の検討 (2006)
  • Author(s): 大徳真珠子, ほか
  • Journal Title: 糖尿病 49 Pages: 1-10
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The thiazolidinedione drug troglitazone up-regulates nitric oxide synthase expression in vascular endothelial cells. (2006)
  • Author(s): Goya, K, Sumitani, S, Otsuki, M, Xu, X, Yamamoto, H, Kurebayashi, S, Saito, H, Kouhara, H, Kasayama, S
  • Journal Title: J.Diabetes Complications (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Marked hyperglycemia after androgen deprivation therapy for prostate cancer and usefulness of pioglitazone for its treatment (2005)
  • Author(s): Inaba, M. et al.
  • Journal Title: Metabolism 54 Pages: 55-59
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effects of alendronate on bone mineral density and bone metabolic markers in postmenopausal asthmatic women treated with inhaled corticosteroids (2005)
  • Author(s): Kasayama, S. et al.
  • Journal Title: Metabolism 54 Pages: 85-93
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regeneration of tubular complex is promoted by a free space (2005)
  • Author(s): Kitamura, T. et al.
  • Journal Title: Pancreas 30 Pages: 174-179
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Improvement of reduced bone mineral density by intermittent cyclical etidronate in postmenopausal asthmatic patients receiving inhaled corticosteroids (2005)
  • Author(s): Yamamoto, H. et al.
  • Journal Title: Allergol. Int. 54 Pages: 137-141
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Suppressor of cytokine signaling 1 suppresses muscle differentiation through modulation of IGF-I receptor signal transduction (2005)
  • Author(s): Inaba, M. et al.
  • Journal Title: Biochem. Biophys. Res. Commun. 328 Pages: 953-961
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A novel thiazolidinedione MCC-555 down-regulates tumor necrosis factor-α-induced expression of vascular cell adhesion molecule-1 in vascular endothelial cells (2005)
  • Author(s): Kurebayashi, S. et al.
  • Journal Title: Atherosclerosis 182 Pages: 71-77
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Insulin sensitivity independently influences brachial-ankle pulse wave velocity in non-diabetic subjects (2005)
  • Author(s): Kasayama, S. et al.
  • Journal Title: Diabet.Med. 22 Pages: 1701-1706
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sex-differences of age-dependent changes of insulin sensitivity in Japanese non-diabetic subjects (2005)
  • Author(s): Otsuki, M. et al.
  • Journal Title: Diabetes Care 28 Pages: 2590-2591
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Vascular endothelium as a target of beraprost sodium and fenofibrate for anti-atherosclerotic therapy in type 2 diabetes mellitus (2005)
  • Author(s): Otsuki, M. et al.
  • Journal Title: Vasc. Health Risk Management 1 Pages: 209-215
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 新生児期より低血糖発作を繰り返し成人後に診断されたフルクトース-1,6-ビスフォフファターゼ欠損症の1例 (2005)
  • Author(s): 浅沼伸行, ほか
  • Journal Title: Diabetes Journal 33 Pages: 13-16
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 06-技術講座:喘息患者における高感度CRP測定の意義 (2005)
  • Author(s): 笠山宗正
  • Journal Title: アレルギーの臨床 25 Pages: 757-759
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 抗炎症作用機序。現代ステロイド療法-正しい理解と実践に向けて- (2005)
  • Author(s): 笠山宗正
  • Journal Title: 綜合臨床 54 Pages: 1968-1974
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] わが国における骨粗鬆症診療の実態 (2005)
  • Author(s): 紅林昌吾, ほか
  • Journal Title: 綜合臨床 54 Pages: 2855-2861
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 気管支喘息の病態把握における高感度CRPの意義と限界 (2005)
  • Author(s): 笠山宗正, ほか
  • Journal Title: 喘息 19 Pages: 53-56
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Marked hyperglycemia after androgen deprivation therapy for prostate cancer and usefulness of pioglitazone for its treatment. (2005)
  • Author(s): Inaba, M, Otani, Y, Nishimura, K, Takaha, N, Okuyama, A, Koga, M, Azuma, J, Kawase, I, Kasayama, S
  • Journal Title: Metabolism 54 Pages: 55-59
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of alendronate on bone mineral density and bone metabolic markers in postmenopausal asthmatic women treated with inhaled corticosteroids. (2005)
  • Author(s): Kasayama, S, Fujita, M, Goya, K, Yamnamoto, H, Fujita, K. Morimoto, Y, Kawase, I, Miyatake, A
  • Journal Title: Metabolism 54 Pages: 85-93
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regeneration of tubular complex is promoted by a free space. (2005)
  • Author(s): Kitamura, T, Asanuma, N, Inaba, M, Otsuki, M, Kasayama, S, Kouhara, H, Kawase, I
  • Journal Title: Pancreas 30 Pages: 174-179
  • NAID: 10016139863
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Improvement of reduced bone mineral density by intermittent cyclical etidronate in postmenopausal asthmatic patients receiving inhaled corticosteroids. (2005)
  • Author(s): Yamamoto, H, Kasayama, S., Fujita, M, Fujita, K, Kawase, I, Miyatake, A
  • Journal Title: Allergol.Int. 54 Pages: 137-141
  • NAID: 10014468994
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Suppressor of cytokine signaling 1 suppresses muscle differentiation through modulation of IGF-I receptor signal transduction. (2005)
  • Author(s): Inaba, M, Saito, H, Fujimoto, M, Sumitani, S, Ohkawara, T, Tanaka, T, Kouhara, H, Kasayama, S, Kawase, I, Kishimoto, T, Naka, T
  • Journal Title: Biochem.Biophys.Res.Commun. 328 Pages: 953-961
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel thiazolidinedione MCC-555 down-regulates tumor necrosis factor-α-induced expression of vascular cell adhesion molecule-1 in vascular endothelial cells. (2005)
  • Author(s): Kurebayashi, S, Xu, X, Ishii, S, Shiraishi, M, Kouhara, H, Kasayama, S
  • Journal Title: Atherosclerosis 182 Pages: 71-77
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Insulin sensitivity independently influences brachial-ankle pulse wave velocity in non-diabetic subjects (2005)
  • Author(s): Kasayama, S, Saito, H, Mukai, M, Koga, M
  • Journal Title: Diabet.Med. 22 Pages: 1701-1706
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sex-differences of age-dependent changes of insulin sensitivity in Japanese non-diabetic subjects. (2005)
  • Author(s): Otuski, M, Kasayama, S, Saito, H, Mukai, M, Koga, M
  • Journal Title: Diabetes Care 28 Pages: 2590-2591
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Vascular endothelium as a target of heraprost sodium and fenofibrate for anti-atherosclerotic therapy in type 2 diabetes mellitus. (2005)
  • Author(s): Otsuki, M, Goya, K, Kasayama, S
  • Journal Title: Vasc.Health Risk Management 1 Pages: 209-215
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel thiazolidinedione MCC-555 down-regulates tumor necrosis factor-α-induced expression of vascular cell adhesion molecule-1 in vascular endothelial cells. (2005)
  • Author(s): Kurebayashi S, Xu X, Ishii S, Shiraishi M, Kouhara H, Kasayama S
  • Journal Title: Atherosclerosis 182 Pages: 71-77
• [Journal Article] Marked hyperglycemia after androgen deprivation therapy for prostate cancer and usefulness of pioglitazone for its treatment (2005)
  • Author(s): Inaba M, Otani Y, Nishimura K, Takaha N, Okuyama A, Koga M, Azuma J, Kawase I, Kasayama S.
  • Journal Title: Metabolism 54 Pages: 55-59
• [Journal Article] Suppressor of cytokine signaling 1 suppresses muscle differentiation through modulation of IGF-1 receptor signal transaction. (2005)
  • Author(s): Inaba M, Saito H, Fujimoto M, Sumitani S, Ohkawara T, Tanaka T, Kouhara H, Kasayama S, Kawase I, Kishimoto T, Naka T.
  • Journal Title: Biochem.Biophys.Res.Commun. 328 Pages: 953-961
• [Journal Article] Insulin sensitivity independently influences brachial-ankle pulse wave velocity in non-diabetic subjects. (2005)
  • Author(s): Kasayama S, Saito H, Mukai M, Koga M.
  • Journal Title: Diabet.Med. 22 Pages: 1701-1706
• [Journal Article] Sex-differences of age-dependent changes of insulin sensitivity in Japanese non-diabetic subjects. (2005)
  • Author(s): Otuski M, Kasayama S, Saito H, Mukai M, Koga M.
  • Journal Title: Diabetes Care 28 Pages: 2590-2591
• [Journal Article] Effects of atendronate on bone mineral density and bone metabolic markers in postmenopausal asthmatic women treated with inhaled corticesteroids. (2005)
  • Author(s): Kasayama S, Fujita M, Goya K, Yamamoto H, Fujita K, Morimoto Y, Kawase I, Miyatake A
  • Journal Title: Metabolism 54 Pages: 85-93
• [Journal Article] Effects of alendronate on bone mineral density and bone metabolic markers in postmenopausal asthmatic women treated with inhaled corticosteroids. (2005)
  • Author(s): Kasayama, S, Fujita, M, Goya, K, Yamamoto, H, Fujita, K, Morimoto, Y, Kawase, I, Miyatake, A
  • Journal Title: Metabolism 21 Pages: 85-90
• [Journal Article] A novel thiazolidinedione MCC-555 down-regulates tumor necrosis factor-α-induced expression of vascular cell adhesion molecule-1 in vascular endothelial cells. (2005)
  • Author(s): Kurebayashi, S, Xu, X, Ishii, S, Shiraishi, M, Kouhara, H, Kasayama, S
  • Journal Title: Atherosclerosis 印刷中
• [Journal Article] Functional cooperation between interleukin-17 and TNF α is mediated by C/EBP family members. (2004)
  • Author(s): Ruddy, M.J.et al.
  • Journal Title: J.Biol.Chem. 279 Pages: 2559-2567
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Strong association of C-reactive protein with body mass index and 2-hour post-challenge glucose in non-diabetic, non-smoker subjects without hypertension. (2004)
  • Author(s): Hashimoto, K. et al.
  • Journal Title: Diab.Med. 21 Pages: 581-585
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Peroxisome proliferators-activated receptor α agonists increase nitric oxide synthase (2004)
  • Author(s): Goya, K. et al.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology 24 Pages: 658-663
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pioglitazone induces plasma platelet activating factor-acetylhydrolase and inhibits platelet activating factor-mediated cytoskeletal reorganization in macrophage (2004)
  • Author(s): Sumita, C. et al.
  • Journal Title: Biochimica et Biophysica Acta 1673 Pages: 115-121
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 頚動脈プラークの退縮を経時的に観察し得た2型糖尿病の1例 (2004)
  • Author(s): 正木充, ほか
  • Journal Title: J.Med.Ultrasonics 31
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ステロイド療法の合併症に関する医師の意識と管理状況-ステロイド骨粗鬆症のリスクマネージメントの重要性- (2004)
  • Author(s): 紅林昌吾, ほか
  • Journal Title: Osteoporosis Japan 12 Pages: 377-383
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] インスリン治療による血糖コントロールの改善後、ナテグリニド単独投与でインスリン分泌パターンの改善が認められた一例 (2004)
  • Author(s): 斎藤博, ほか
  • Journal Title: Diabetes Frontier 15 Pages: 521-524
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] GH産生下垂体腫瘍の術後長期フォロー。 (2004)
  • Author(s): 斎藤洋一, ほか
  • Journal Title: 日本内分泌学会雑誌 80(suppl.) Pages: 114-115
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] PPARαリガンドであるフェノフィブラートの血管におけるpleiotropic effect-抗炎症作用、血管内皮細胞に及ぼす効果を踏まえて- (2004)
  • Author(s): 笠山宗正, ほか
  • Journal Title: Progress in Medicine 24 Pages: 3291-3296
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional cooperation between interleukin-17 and TNFα is mediated by C/EBP family members. (2004)
  • Author(s): Ruddy, MJ, Wong, GC, Liu, XK, Yamamoto, H, Kasayama, S, Kirkwood, KL, Gaffen, SL
  • Journal Title: J.Biol.Chem. 279 Pages: 2559-2567
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Strong association of C-reactive protein with body mass index and 2-hour post-challenge glucose in non-diabetic, non-smoker subjects without hypertension. (2004)
  • Author(s): Hashimoto, K, Kasayama, S, Yamamoto, H, Kurebayashi, S, Kawase, I, Koga, M
  • Journal Title: Diab.Med. 21 Pages: 581-585
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Peroxisome proliferators-activated receptor α agonists increase nitric oxide synthase expression in vascular endothelial cells. (2004)
  • Author(s): Goya K, Sumitani, S, Xu, X, Kitamura, T, Yamamoto, H, Kurebayashi, S, Saito, H, Kouhara, H, Kasayama, S, Kawase, I
  • Journal Title: Arterioscler.Thromb.Vasc Biol. 24 Pages: 658-663
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pioglitazone induces plasma platelet activating factor-acetylbydrolase and inhibits platelet activating factor-mediated cytoskeletal reorganization in macrophage. (2004)
  • Author(s): Sumita, C, Maeda, M, Fujio, Y, Kim, J, Fujitsu, J, Kasayama, S, Yamamoto, I, Azuma, J
  • Journal Title: Biochim.Biophys.Acta 1673 Pages: 115-121
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional cooperation between interleukin-17 and TNFα is mediated by C/EBP family members. (2004)
  • Author(s): Ruddy, MJ, Wong, GC, Liu, XK, Yamamoto, H, Kasayama, S, Kirkwood, KL, Gaffen, SL
  • Journal Title: Journal of Biological Chemistry 279 Pages: 2559-2567
• [Journal Article] Peroxisome proliferators-activated receptor α agonists increase nitric oxide synthase (2004)
  • Author(s): Goya, K, Sumitani, S, Xu, X, Kitamura, T, Yamamoto, H, Kurebayashi, S, Saito, H, Kouhara, H, Kasayama, S, Kawase, I
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology 24 Pages: 658-663
• [Journal Article] Pioglitazone induces plasma platelet activating factor-acetylhydrolase and inhibits platelet activating factor-mediated cytoskeletal reorganization in macrophage. (2004)
  • Author(s): Sumita, C, Maeda, M, Fujio, Y, Kim, J, Fujitsu, J, Kasayama, S, Yamamoto, I, Azuma, J
  • Journal Title: Biochimica et Biophysica Acta 1673 Pages: 115-121
• [Journal Article] Strong association of C-reactive protein with body mass index and 2-hour post-challenge glucose in non-diabetic, non-smoker subjects without hypertension. (2004)
  • Author(s): Hashimoto, K, Kasayama, S, Yamamoto, H, Kurebayashi, S, Kawase, I, Koga, M
  • Journal Title: Diabetic Medicine 21 Pages: 581-585
• [Book] 第3回関西間脳下垂体疾患研究会記録集:アクロメガリー患者に対するオクトレオチドLARの長期使用経験(分担) (2005)
  • Author(s): 笠山宗正, ほか
  • Total Pages: 13
  • Publisher: メディカルパブリッシャー
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 第3回関西間脳下垂体疾患研究会記録集:アクロメガリーに対するオクトレオチド術前短期投与-腫瘍縮小効果の予測と術前投与の利点-(分担) (2005)
  • Author(s): 押野悟, ほか
  • Total Pages: 13
  • Publisher: メディカルパブリッシャー
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 見直されたビグアナイド:血糖降下以外に期待されるメトホルミンの臨床効果。AGEs産生抑制(分担) (2005)
  • Author(s): 大月道夫, ほか
  • Total Pages: 163
  • Publisher: フジメディカル出版
  • Description: 「研究成果報告書概要(和文)」より
• [Book] ステロイド骨粗鬆症のマネジメント:呼吸器疾患におけるステロイド骨粗鬆症の現状と治療の実際(分担) (2005)
  • Author(s): 笠山宗正, ほか
  • Total Pages: 104
  • Publisher: 医薬ジャーナル
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Key Word 糖尿病 第2版:サイトカイン(分担) (2004)
  • Author(s): 笠山宗正
  • Total Pages: 245
  • Publisher: 先端医学社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] リウマチ病セミナーXV:ステロイド療法の現在と未来(分担) (2004)
  • Author(s): 笠山宗正
  • Total Pages: 264
  • Publisher: 永井書店
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 2型糖尿病治療におけるナテグリニドの役割:ナテグリニドと「インスリン・ピーク」(分担) (2004)
  • Author(s): 笠山宗正
  • Total Pages: 134
  • Publisher: 協和企画
  • Description: 「研究成果報告書概要(和文)」より
• [Book] アクロン6:Informed consent:新しい薬剤は今までの薬剤とどう違うのですか(分担) (2004)
  • Author(s): 笠山宗正
  • Total Pages: 12
  • Publisher: アルタ出版
  • Description: 「研究成果報告書概要(和文)」より
• [Book] オステオアゴラ、04紅葉号:吸入ステロイド薬でも骨粗鬆症になりますか?(分担) (2004)
  • Author(s): 笠山宗正
  • Total Pages: 23
  • Publisher: メディカルレビュー社
  • Description: 「研究成果報告書概要(和文)」より