炎症・再生
Online ISSN : 1880-5795
Print ISSN : 1346-8022
ISSN-L : 1346-8022
21 巻 , 3 号
選択された号の論文の11件中1~11を表示しています
  • 室田 誠逸
    2001 年 21 巻 3 号 p. 167-169
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
  • 水島 裕, 坪田 一男, 高橋 政代, 八木 透
    2001 年 21 巻 3 号 p. 171-184
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
  • 小竹 茂, 鎌谷 直之
    2001 年 21 巻 3 号 p. 185-192
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
    Interleukin (IL) -17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of co-cultures of mouse hemopoietic cells and primary osteoblastic cells with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts such as tartrate-resistant acid phosphatase (TRAP) activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for osteoclastogenesis induced by IL-17, which was completely inhibited by adding indomethacin or NS 398, a selective inhibitor of cyclooxgenase-2 (COX-2) . Adding IL-17 increased prostaglandin E2 (PGE2) synthesis both in co-cultures of bone marrow cells and osteoblastic cells and in single cultures of osteoblastic cells, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblastic cells. ODF is a membrane-associated protein, which transduces an essential signal (s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the co-cultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients (p<0.0001) . Anti-IL-17 antibody significantly inhibited OCL formation in the co-cultures with culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblastic cells, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts. IL-17 may be involved in osteoclastic bone resorption in RA patients. It has been reported that IL-17 also produce many factors inducing degradation cartilage in RA. Therefore, IL-17 may play a pivotal role in joint destruction in RA.
  • 山岡 淳一, 佐々木 稔, 宮地 良樹
    2001 年 21 巻 3 号 p. 193-197
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
    UV radiation causes inflammation characterized by erythema and swelling, immunosuppression, apoptosis, melanogenesis, photoaging, and photocarcinogenesis, whereas it also exhibits anti-inflammatory or therapeutic effects as seen in the treatment of psoriasis and atopic dermatitis. Nitric oxide (NO), a reactive gaseous molecule with multiple cellular functions, has been speculated to play pathogenic or protective roles in inflammatory dermatoses. Therefore, it is important to elucidate how UVB radiation regulates or modifies NO production and nitric oxide synthase (NOS) expression in skin. To examine this issue, we used murine cultured keratinocyte Pam 212 cells and found that low doses of UVB radiation significantly suppressed NO production and inducible NOS (iNOS) expression in keratinocytes stimulated by IFN-γ or TNF-α. Taking pathogenic roles of excessive NO produced through iNOS induction into consideration, UVB-induced suppression of NO production may explain in part the anti-inflammatory or therapeutic effects of UVB radiation in inflammatory dermatoses. However, in keratinocytes under nonstimulated condition, UVB radiation increased NO production, where brain NOS (bNOS) mRNA and protein expressions were enhanced and iNOS mRNA expression was suppressed. These results suggest that NO thus produced after UVB radiation in non-inflammatory skin may explain in part the subsequent erythema formation, melanogenesis and other UVB-induced skin reactions.
  • 豊田 淑江, 山口 照英, 押澤 正, 内田 恵理子, 早川 堯夫
    2001 年 21 巻 3 号 p. 199-207
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
    To examine the regulatory mechanisms of proliferation and maturation in neutrophilic lineage cells, we have found the existence of transferrin receptor (Trf-R) positive (Trf-R+) and negative (Trf-R-) cells in DMSO-treated HL-60 cells and successfully sorted into Trf-R+ and Trf-R- cells. Differentiated Trf-R- cells exhibited much more maturation of neutrophilic cells as compared with Trf-R+ cells, and G-CSF accelerated differentiation of Trf-R- cells. On the other hand, Trf-R+ cells had a tendency to proliferate rather than differentiate, and proliferation has enhanced by G-CSF. These resullts indicate that Trf-R expression coincides with the commitment to proliferate or differentiate of HL-60 cells, and G-CSF accelerates these commitments. On the basis from the results of G-CSF-induced signal transduction in Trf-R+ and Trf-R- cells, STAT 3 promoted the differentiation of HL-60 cells into neutrophils, while p 70 S6 kinase promotes proliferation and negatively regulate neutrophilic differentiation.
    We also examined cross talk of G-CSF and GM-CSF on the differentiation of HL-60 cells into nuetrophils. While G-CSF accelerate the neutrophilic differentiation of DMSO-treated HL-60 cells, GM-CSF markedly inhibited the G-CSF induced enhancement of neutrophilic differentiation. Furthermore, GM-CSF did not alter the G-CSF induced tyrosine phosphorylation of STAT 3, but GM-CSF inhibited the nuclear translocation of tyrosine-phosphorylated STAT 3. Therefore, we concluded that G-CSF-dependent nuclear translocation of STAT 3 coordinates with the promotion of neutrophilic differentiation in DMSO-treated HL-60 cells.
  • 松村 潔, 小林 茂夫
    2001 年 21 巻 3 号 p. 209-217
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
    Prostaglandins play various roles in the brain under physiological as well as pathological conditions. This review summarizes our present knowledge about brain localization of two isoforms of cyclooxygenase, enzymes responsible for prostaglandin biosynthesis, and their possible functions. Cyclooxygenase-1 (COX-1) is con-stitutively expressed in microglia throughout the brain. Little is known about COX-1 function there. COX-1 is also abundantly expressed in the primary sensory neurons both at their cell bodies and at the central terminals in the medulla and spinal cord suggesting its involvement in sensory signal transmissions. COX-2 is constitutively expressed in telencephalic neurons in an activity-dependent manner. This neuronal expression of COX-2 was reported to be involved in the regulation of regional cerebral blood flow. On the other hand, some studies have reported that COX-2 might exert adverse actions after brain ischemia and in Alzheimer's disease. Under various infectious as well as inflammatory conditions, COX-2 is expressed in brain endothelial cells. We presented a large body of evidence that elevation of prostaglandin EZ in the brain and occurrence of fever during infection/inflammation are the consequences of this endothelial expression of COX-2. Thus, brain endothelial cells seem to transmit blood borne cytokine signals to brain by producing prostaglandin E2.
  • 石井 (堤) 裕子, 矢口 均, 長岡 功
    2001 年 21 巻 3 号 p. 219-226
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
    Defensins constitute a family of cationic antimicrobial peptides found in various animals, and act as key elements in the innate host defense. Mammalian defensins are deviled into α- and β-defensin subfamilies. In human, β-defensins (hBDs) are expressed in many epithelial tissues including trachea, skin, and intestine. Interestingly, expression of hBD1 is constitutive, while hBD2 expression is strongly induced in response to bacteria infection and proinflammatory cytokines. The promoter region of hBD2 gene contains several consensus binding sites for NFκB (nuclear factor κB), C/EBPβ (CCAAT/enhancer-binding protein β) and IFN-γ, suggesting inflammatory signaling may elicit the induction of hBD2 expression. However, the regulation mechanism of hBD expressions is little known.
    To clarify the transcriptional regulation of hBD genes, we investigated their promoter activities in response to LPS using CD 14+ macrophage-like RAW 264.7 cells. The hBD1 promoter was not responsible to LPS, although the region from -162 to -70 was essential for its constitutive transcription. In contrast, the transcriptional activity of hBD2 promoter, which contained 3 potent NFκB binding sites at -2270, -576, and -208, was increased in response to LPS. Mutation or deletion of the NFκB site at -576 caused a 90% decrease in LPS response. Furthermore, gel mobility shift assay indicated that LPS increased NFκB binding activity with the -576 site on the hBD2 promoter. These observations suggest that the interaction between NFκB and the -576 site is important for LPS response of hBD2 promoter. Macrophages and epithelial cells express Toll-like receptors (TLRs) which induce activation of NFκB. Taken together, the TLR-NFκB pathway is likely involved in the LPS-induced transcription of hBD2 gene.
  • 花城 和彦, 中村 真理子, 仲宗根 敏幸, 渡慶次 賀博, 小杉 忠誠
    2001 年 21 巻 3 号 p. 227-233
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
    Falcon Cell culture insertを用いて, ラット内皮細胞のIgE透過性に対する抗アレルギー剤の効果を検討した.内皮細胞を通過するIgEの透過係数は, クリアランス速度を基本として算出した.ヒスタミン (1×10-10M) に24時間暴露した内皮細胞のIgE透過係数は, ヒスタミン非存在下に比して著しく上昇した.ヒスタミンとazelastine hydrochloride (1×10-6M) を同時に暴露したIgEの透過係数は, ヒスタミンのみの暴露に比較して著しく減少した (p<0.05) .ヒスタミンによって亢進したIgE透過性は, suplatast tosilateとketotifen fumarateでは抑制されなかった.しかしながら, azelastine hydrochloride は内皮細胞のヒスタミンによるIgE透過性亢進を抑制する効果を示した.これらの結果から, IgEの血管透過性制御作用を具備した抗アレルギー剤は, アレルギー反応の制禦という観点からは有効な薬剤である.
  • 國上 敏浩, 内田 あおい, 西岡 浩一郎, 平手 謙二, 齋藤 輝信
    2001 年 21 巻 3 号 p. 235-241
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
    Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the production of primary prostanoids by blocking both cyclooxygenase (COX) -1 and COX-2 activities, and in doing so, not only decrease inflammation and pain, but also promote gastrointestinal tract damage and bleeding.
    The inhibitory activities of zaltoprofen (ZP) on the biosynthesis of prostaglandin E2 (PGE2) at the inflammatory site and stomach were compared with those of some NSAIDs (celecoxib : CL, meloxicam : ML, lornoxicam : LR, mofezolac : MF) using the rat carrageenin-air pouch model. At the dose of ZP and CL that inhibited PGE2biosynthesis at the inflammatory site, these hardly inhibited the PGE2release from stomach. In contrast, ML, MF and LR inhibited the biosynthesis of PGE2on both sites at the same dose.
    Furthermore these NSAIDs inhibited the carrageenin-induced paw edema, and produced the ulcer in a dose-dependent manner. The safety index, UD50/ED40ratio, of CL, ZP, ML, LR and MF was >103, 11.3, 0.8, 0.8 and 0.1, respectively. These safety indexes correlated well with the tissue selectivity of NSAIDs on PG biosynthesis inhibition.
    These results suggest that the PG biosynthesis at the inflammatory site and stomach of the same rat is a very useful parameter for evaluating NSAIDs. It seems that these properties of ZP were contributed to the low ulcerogenic activity on clinical uses.
  • 水島 裕, 市川 陽一, 柏崎 禎夫, 菅原 幸子, 長屋 郁郎, 廣畑 和志, 延永 正, 岩崎 由雄
    2001 年 21 巻 3 号 p. 243-272
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
    慢性関節リウマチに対するTS-110の臨床的有用性を評価するため, インドメタシンを対照薬として, TS-1101日12mg分3 (T群) , インドメタシン75mg分3 (I群) で6週間経口投与し, 二重盲検法により比較検討した.
    (1) 総投与例は189例 (T群95例, I群94例) であり, ITT対象症例は有効性, 安全性, 有用性いずれも179例 (T群89例, I群90例) であった.
    (2) 背景因子には「性別」 (p=0.0560) , 「併用薬の有無」 (p=0.0312) 以外, 偏りは認められなかった.
    なお, 本偏りの改善度に及ぼす影響についてMantel-Haenszel法などにて検定を行った結果, 影響は認められなかった.
    (3) 最終全般改善度において, 「改善」以上の改善率は, T群, I群それぞれ29.2% (26/89例) , 16.7% (15/90例) であり, T群の有効性は, I群と同等であった. (4) 副作用発現率は, T群, I群それぞれ20.2% (18/89例) , 26.7% (24/90例) であり, 症状別では消化器症状がT群で13件, I群で17件, 皮疹, そう痒感の過敏症がT群で1件, I群で1件, めまい, 頭痛などの精神・神経系の症状がT群で1件, I群で11件, 臨床検査値の異常変動がT群で11件, I群で7件に認められた.
    (5) 概括安全度において, 「安全である」の安全率はT群, I群それぞれ79.8% (71/89例) , 73.3% (66/90例) であり, T群の安全性は, I群と同等であった.
    (6) 有用度において, 「有用」以上の有用率はT群, I群それぞれ28.1% (25/89例) , 14.4% (13/90例) であり, T群がI群より有意 (p=0.0256) に高かった.
    (7) その他副次評価項目では, 最終評価日における「満足」以上の患者の満足度はT群がI群より有意 (p=0.0164) に高かった.
    以上より, TS-110の12mg/日投与は慢性関節リウマチに対し, インドメタシン75mg/日投与と同等の有効性, 安全性を有し, 患者の満足度を反映した評価では有用性の高い薬剤であると判断された.
  • 水島 裕, 市川 陽一, 柏崎 禎夫, 菅原 幸子, 長屋 郁郎, 廣畑 和志, 延永 正
    2001 年 21 巻 3 号 p. 273-307
    発行日: 2001/05/31
    公開日: 2010/04/12
    ジャーナル フリー
    慢性関節リウマチに対するTS-110長期投与時の臨床的有用性をオーブン試験により検討した.
    (1) 総投与例数は134例であり, 12週以上投与104例 (77.6%) , 24週以上投与78例 (58.2%) , 48週投与27例 (20.1%) であった.
    (2) 各臨床評価項目を各症例の最終評価日において試験開始時と比較し, 疼痛および腫眼関節数, 関節点数, 疼痛点数で有意な改善が認められた.
    (3) 患者の満足度における「満足」以上の割合は, 24週後では17.1% (12/70例) , 32週後以降はいずれも20%以上でほぼ一定であり, 48週後では25.9% (7/27例) であった.
    また, 医師の症状改善度評価における「改善」以上の割合は, 24週後では32.4% (23/71例) , 24週後以降はいずれも30%以上であり, 48週後では34.6% (9/26例) であった.
    (4) 全般改善度における「改善」以上の改善率は, 24週では32.9% (23/70例) , 48週では37.0% (10/27例) であり, 最終評価日では29.8% (34/114例) であった.
    (5) 副作用は, 129例中40例 (31.0%) で63件認められ, いずれも軽度または中等度であった.なお, 治験薬剤との関連性が否定できない臨床検査値の異常変動は, いずれも副作用として扱われた.
    発現率は, 投与期間に伴い高くなることはなく, また, 副作用の種類においても, 投与期間が長くなることに伴い, 特に異なるものは認められなかった.
    (6) 概括安全度における「安全である」の症例の割合 (安全率) は, 24週では85.9% (61/71例) , 48週では88.9% (24/27例) , 最終評価日では69.0% (89/129例) であった.
    (7) 有用度における「有用」以上の有用率は, 24週では35.7% (25/70例) , 48週では40.7% (11/27例) , 最終評価日では26.0% (32/123例) であった.
    これらのことから, TS-110の慢性関節リウマチに対する長期投与における有効性面, 安全性面はいずれも良好であり, 臨床的に有用な薬剤であると考えられる.
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