JPWO2006003927A1 - 非炎症性ストレス応答の指標剤およびその利用 - Google Patents
非炎症性ストレス応答の指標剤およびその利用 Download PDFInfo
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Abstract
Description
[1]スーパーオキシドが介在する非炎症性ストレス応答の指標剤であって、非炎症性ストレスカスケードに関与する成分を含有してなる指標剤、
[2]前記非炎症性ストレスカスケードに関与する成分が、IL−18、活性型IL−18、P38MAPキナーゼ、リン酸化P38MAPキナーゼ、カスパーゼ11、カスパーゼ1、活性化カスパーゼ1からなる群から選択される1または2以上のタンパク質を含有することを特徴とする上記[1]記載の指標剤、
[3]前記非炎症性ストレスカスケードに関与する成分が、IL−18である上記[1]記載の指標剤、
[4]前記IL−18が血中に存在する活性型IL−18である上記[3]に記載の指標剤、
[5]さらにP38MAPキナーゼを含有してなる上記[3]または[4]に記載の指標剤、
[6]前記P38MAPキナーゼがリン酸化されたものである上記[5]に記載の指標剤、
[7]前記P38MAPキナーゼがマウス由来であり、当該キナーゼのリン酸化部位がThr180またはTyr182である上記[6]に記載の指標剤、
[8]前記P38MAPキナーゼがヒト由来であり、当該キナーゼのリン酸化部位がThr185またはTyr187である上記[6]に記載の指標剤、
[9]さらにカスパーゼ−11を含有してなる上記[3]〜[8]いずれかに記載の指標剤、
[10]さらにカスパーゼ−1を含有してなる上記[3]〜[9]いずれかに記載の指標剤、
[11]前記カスパーゼ−1が活性化カスパーゼ−1である上記[10]に記載の指標剤、
[12]前記非炎症性ストレスが精神的ストレスである上記[3]〜[11]いずれかに記載の指標剤、
[13]前記精神的ストレスが拘束ストレスである上記[12]に記載の指標剤、
[14]上記[1]〜[13]いずれかに記載の指標剤を検出するための非炎症性ストレス応答の可視化剤、
[15]IL−18抗体を含有する上記[14]に記載の可視化剤、
[16]前記IL−18抗体が活性型IL−18を特異的に認識するものである、上記[15]に記載の可視化剤、
[17]さらにP38MAPキナーゼ抗体を含有する上記[15]または[16]に記載の可視化剤、
[18]前記P38MAPキナーゼ抗体が抗リン酸化P38MAPキナーゼ抗体である上記[17]に記載の可視化剤、
[19]前記抗リン酸化P38MAPキナーゼ抗体がリン酸化Thr180もしくはTyr182を有するP38MAPキナーゼ、またはリン酸化Thr185もしくはTyr187を有するP38MAPキナーゼを認識するものである上記[18]に記載の可視化剤、
[20]さらにカスパーゼ−11抗体を含有する上記[15]〜[19]いずれかに記載の可視化剤、
[21]さらにカスパーゼ−1抗体またはカスパーゼー1の基質を含有する上記[15]〜[20]いずれかに記載の可視化剤、
[22]前記カスパーゼ−1抗体が活性化カスパーゼ−1を特異的に認識するものである、上記[21]に記載の可視化剤、
[23]上記[1]〜[13]いずれかに記載の指標剤の量または活性を測定することを特徴とする非炎症性ストレスの程度を測定する方法、
[24]指標剤が、IL−18または活性型IL−18である上記[23]記載の方法。
[25]上記[14]〜[22]いずれかに記載の可視化剤を用いることを特徴とする上記[23]または[24]に記載の方法、
[26]前記非炎症性ストレスが精神的ストレスである上記[23]〜[25]のいずれかに記載の方法、
[27]前記精神的ストレスが拘束ストレスである上記[26]に記載の方法、
[28]上記[14]〜[22]いずれかに記載の可視化剤を含む非炎症性ストレスの測定キット。
[29]前記可視化剤がIL−18抗体を含有する上記[28]記載のキット、
[30]前記IL−18抗体が活性型IL−18を認識するものである上記[29]記載のキット、
[31]上記[14]〜[22]いずれかに記載の可視化剤を動物に適用することを特徴とする、非炎症性ストレス応答に基づく免疫状態の変動を予防、改善または予想する方法、
[32]前記動物がヒトを除く脊椎動物である上記[31]に記載の予防、改善または予想方法、
[33]上記[1]〜[13]いずれかに記載の指標剤の量または活性を低減させるための非炎症性ストレス応答に基づく免疫状態変動の治療剤、
[34]前記治療剤の有効成分がIL−18抗体または抗IL−18受容体抗体である上記[33]に記載の治療剤、
[35]前記有効成分がIL−18抗体であり、当該IL−18抗体が活性型IL−18に特異的に結合するものである[34]に記載の治療剤、
[36]前記治療剤の有効成分がスーパーオキシドジムスターゼまたはビタミンEである上記[33]記載の治療剤、
[37]上記[1]〜[13]いずれかに記載の指標剤の量または活性を測定することを特徴とする、非炎症性ストレスにより発症、悪化若しくは再発する疾患に対する治療効果、改善効果若しくは予防効果を有する物質をスクリーニングする方法、
[38]前記指標剤が、IL−18または活性型IL−18である上記[37]記載の方法。
[39]前記疾患が、全身性エリテマトーデス、ループス腎炎、アトピー性皮膚炎、多発性硬化症、気管支喘息、乾癬、脳虚血、脳変性、脳炎、関節リウマチ、月経異常、子宮内膜症または性欲低下である上記[37]または[38]記載の方法、
[40]上記[1]〜[13]いずれかに記載の指標剤の量または活性を測定することを特徴とする、酸化ストレスに対する抑制効果若しくは防止効果を有する物質をスクリーニングする方法、
に関する。
坐剤の場合は直腸内投与される。
1)培養細胞を被検物質存在条件下で培養する、または、動物を被検物質投与条件下で飼育する工程、
2)前記培養細胞または前記動物から調製した検体中の指標剤を定量する工程、および、
3)被検物質存在条件下または被検物質投与条件下における指標剤の量を被検物質非存在条件下または被検物質非投与条件下における指標剤の量と比較し、有意に指標剤の量を減少または増加させた前記被検物質を、非炎症性ストレスにより発症、悪化若しくは再発する疾患に対する治療効果、改善効果若しくは予防効果を有する物質と判定する工程、または酸化ストレスに対する抑制効果若しくは防止効果を有する物質と判定する工程、を含む。
雄性C57B6マウスは、Seac Yoshitomiより購入した。IL−18ノックアウト(KO)マウス(C57/B6バックグランド、Immunity. 8, 383−390 (1998))およびカスパーゼ−1ノックアウト(KO)マウス(Balb/Cバックグランド、Science. 267, 2000−2003 (1995))は、それぞれ竹田博士および杭田博士より供与された。MRL/MpJUmmCrj−lpr/lpr(MRL/lpr)マウスは、日本チャールスリバー株式会社より購入した。マウスは、20℃でケージ当たり1匹格納された。マウスを用いる実験は、10時に開始した。
抗ACTH抗血清はProgen Biotechnik(ドイツ)製、抗マウスIL−18モノクローナル抗体はMBL(日本)製、抗マウスカスパーゼ−1抗体(sc−515)はSanta Cruz(米国)製、抗マウス/ラットカスパーゼ−11抗体はBIOMOL(米国)製、および抗リン酸化(Thr180/Tyr182)P38 MAPキナーゼ抗体はCell Signaling Technology(米国)製を使用した。抗マウスIL−6ポリクローナル抗体は、ケミコン社製を使用した。抗マウスIL−18受容体抗体は、常法にしたがって、マウスIL−18受容体の膜貫通領域直近の親水性領域の部分ペプチド(20アミノ酸)を合成し、ウサギに免疫し、得られた抗血清を使用した。
拘束ストレスとして、マウスを拘束器(27mmの直径の丸型プラスチックチューブ)中に1、3または6時間置き、IL−18レベルを測定した。IL−6の分析に関しては、マウスを前述のように拘束し、次いで元のケージに6時間収容した後に測定した。
拘束後、マウスをジエチルエーテルで麻酔し、血液をEDTA含有チューブに採血した。血漿は、4℃、10000×gで10分間遠心分離により分離し、−80℃で保存した。IL−18およびIL−6は、それぞれQuantikineTMイムノアッセイキット(R&Dシステムズ)およびOptEIATM (BD−Pharmingen)を用いるELISAで分析した。
すべての実験データは、3回以上の独立した実験の平均±S.D.として示した。異なる処理間の統計学的比較は、GraphPad Prism プログラム(GraphPad Software Inc.)を用いるStudentのt検定により行った。0.05未満のP値を統計学的に有意であると見なした。図に表された符号は、以下の通りである。
*;対照に対してP<0.05
**;対照に対してP<0.01
***;対照に対してP<0.001
#;ストレス負荷に対してP<0.01(n=4−9)
ストレス負荷に対してP<0.05(n=4−9)(図4の場合)
野生型に対してP<0.05(図5の場合)
##;ストレス負荷に対してP<0.001(n=4−9)
ストレス負荷に対してP<0.01(n=4−9)(図4の場合)
野生型に対してP<0.01(図5の場合)
+;ストレス負荷した野生型に対してP<0.01(n=6)。
拘束ストレスマウスにおける血漿IL−18タンパク質レベルの測定
抗ACTH抗血清(50μl、1:1)、デキサメタゾン(1ng/50μlPBS(−))または抗IL−18抗体(50μl、1:1)をマウスの腹腔内に投与し、10分経過後、拘束チューブ中に6時間置いた。合成ACTH(250μg/50μlPBS(−))を左肢に注入し、6時間経過後マウスを実験に供した。結果を図1に示す。
図1Aより、拘束ストレスに曝されたマウスの血漿中のIL−18レベルは、43±34.3pg/ml(ストレス負荷前)、330±64.3pg/ml(ストレス負荷後3時間)および1059±30.022pg/ml(ストレス負荷後6時間)であった。血漿中のACTHは、IL−18よりも迅速に増加し、ストレス負荷後1時間以内に約500pg/mlに到達したが、3時間で元のレベルに減少した。このことより、血漿中のACTHレベルの上昇は、血漿中のIL−18レベルの増加に先行していることがわかる。なお、血漿中のACTHレベルの上昇は、視床下部−下垂体−副腎(HPA)軸の活性化を表している。
ACTHは、IL−18mRNAの副腎特異的発現を引き起こすことが知られている。よって、ACTHが血漿IL−18のストレス誘導的上昇に関与するかどうかについて調べた。マウスを抗ACTH抗血清またはデキサメタゾンで処置し、血漿中または副腎中のIL−18レベルを分析した。図1Bおよび図1Cより、抗ACTH抗血清およびデキサメタゾンは、血漿中(図1B)および副腎(図1C)においてストレスにより誘導されたIL−18レベルの増加を阻害することがわかった。片方の副腎を摘出したマウスでは、ストレス後のIL−18レベルは擬似操作したマウスよりも低かった。これらの結果から、ストレスにより誘導されたACTHによって血漿および副腎中のIL−18レベルの上昇が引き起こされることが示唆された。
ACTHを投与すると、血漿中のIL−18レベルが上昇するが、ストレス負荷の場合よりも程度が低い(図1D)。副腎中のIL−18レベルは、ストレス負荷の場合と同じ程度に上昇した(図1E)。これらの結果から、ストレス負荷マウスでは、ACTHは主として副腎中のIL−18のストレス誘導性上昇を招くが、血漿IL−18レベルの上昇には他の因子が関与していることが示唆される。
IL−18タンパク質のウエスタンブロッティングによる分析の結果、IL−18は血漿中では18kDの成熟型タンパク質で存在し(図1F、レーン1−3)、一方、副腎中では主として24kDの前駆体型で存在している(図1F、レーン4−6)ことがわかった。これらの結果から、副腎中のIL−18前駆体がプロセッシングされ、血漿中に放出されることが示唆される。
ストレスにおけるカスパーゼ−1の役割
マウスを拘束器中に1時間置き、Ac−YVAD−CHO(200μM /50μlPBS(−))、Z−FA−fmk(100μM /50μlPBS(−))およびSB−203580(マウスあたり100μg/50μlPBS(−))を腹腔内に投与した。拘束開始後1および3時間で、SOD−1(20U)および DPI(30μg)をマウス腹腔内に投与し、ウエスタンブロッティングにより解析した。結果を図2に示す。
ウェスタンブロッティングによるカスパーゼ−11およびMAPキナーゼの解析
副腎組織中のIL−18およびリン酸化P38MAPキナーゼのウェスタンブロット分析は、以下のように行った。副腎組織を、プロテアーゼ阻害剤混合液(ロシュダイアグノスティックス製)を含む免疫沈降(IP)緩衝液(50mM Tris pH7.4、150mM NaCl、0.5%NP−40および0.5%ナトリウムデオキシコレート)中でポリトロンホモジナイザーでホモジナイズした。得られたホモジネート(100μgタンパク質)をプロテインA/Gアガロース(Exalpha Biologicals, Inc.)で前もって清澄化させ、抗マウスIL−18モノクローナル抗体または抗リン酸化(Thr180/Tyr182)P38 MAPキナーゼ抗体とプロテインA/Gアガロース(50μl)とでインキュベートし、遠心分離(13000×gで25分間、4℃)した。沈殿物をボイルして副腎タンパク質を回収し、10−20%SDS−ポリアクリルアミド勾配ゲル中で電気泳動し、Hybond ECL(Amersham製)ニトロセルロース膜に電気的に移した。前記膜を、抗体(IL−18、リン酸化(Thr180/Tyr182)P38 MAPキナーゼ、カスパーゼ−1またはカスパーゼ−11)とともにインキュベートし、反応したタンパク質をECLプラスシステム(Amersham biosciences製)で検出した。プロカスパーゼ−11および活性化P38 MAPキナーゼは、Science Lab 99 イメージアナリシスシステム(Fujifilm製)を用いて定量化した。
LPSによるカスパーゼ−11の誘導はNF−κBの活性化を必要とし、NF−κBの活性化はP38MAPキナーゼにより媒介されることが報告されている。インビトロでは、カスパーゼ−11の誘導がP38MAPキナーゼ阻害剤SB203580で抑制されることが報告されている。本発明においては、インビボで、すなわち、ストレス負荷したマウスでカスパーゼ−11の誘導におけるSB203580の影響を調べた。結果を図3に示す。
免疫組織化学によるIL−18、カスパーゼ−1、カスパーゼ−11およびP38MAPキナーゼの局在
副腎をホルマリン固定し、パラフィンで包埋し、4μmの切片に切断した。前記組織切片を抗体(P38 MAPキナーゼ、カスパーゼ−11、カスパーゼ−1(前三者は200倍希釈)またはIL−18(400倍希釈))とともにインキュベートした。西洋ワサビペルオキシダーゼ結合二次抗体(Santa Cruz製)およびジアミノベンジジン(DBA)を用いて、発色させた。対照として、一次抗体なしの切片およびストレスなしのマウス由来の切片を用いた。結果を図3Eおよび3Fに示す。
カスパーゼ−1活性の分析
副腎中のカスパーゼ−1活性を、カスパーゼアッセイキット(BD−Pharmingen製)を用いて測定した。簡潔に記載すると、副腎組織のホモジェネートをカスパーゼ−1蛍光基質であるAc−YVAD−MCA(acetyl− L−tyrosyl− L−valyl− L−alanyl− L−aspartic acid 4−methyl−coumaryl−7−amide)とインキュベートし、前記基質から遊離したMCAを、蛍光プレートリーダー(励起波長380nm、放射波長420−460nm)を用いて測定した。
P38MAPキナーゼのアップレギュレーションにおけるスーパーオキシドの関与
活性酸素種は、肺の繊維芽細胞、好中球および単球においてP38MAPキナーゼのリン酸化を媒介することが報告されている。ストレスを負荷したマウスにおいて、P38MAPキナーゼのリン酸化に対するSODの影響を調べた。結果を図4に示す。
ストレス負荷したマウスの血漿IL−6レベルの制御におけるIL−18の関与
IL−18欠損マウスを用いて、もうひとつのストレス関連サイトカインであるIL−6と、IL−18との間の関連性を調べた。ストレスなしでは、IL−6はWTおよびIL−18KOで検出不可能であったが、3時間のストレスの後に、IL−6レベルはWTで230pg/mlおよびIL−18KOで25pg/mlであった(図5A)。ストレスから開放された後、WTでは血漿IL−6は約80pg/mlに維持されたが、IL−18KOでは5pg/mlに減少した(図5A)。YVAD−CHO、SODおよび抗IL−18抗体での処理は、WTで血漿IL−6レベルのストレスにより誘導された増加を70%阻害した(図5B)。これらの結果から、ストレスがIL−18依存的に血漿中IL−6を誘導することが示唆される。
IL−18受容体抗体投与によるループス腎炎の治療
10週令のMRL/lprマウスに3時間の拘束ストレスを負荷し、血漿中のIL−6の濃度を調べた。また、前記マウスにストレス負荷10分前に抗IL−18受容体抗体を投与し、IL−6の濃度の変化を調べた。その結果、ストレス負荷6時間後における血漿中IL−18の濃度は、1132、882および793pg/mlまで上昇しており、血漿中IL−6の濃度の上昇は、ストレス負荷後3時間でピークに達した。ストレス負荷後のMRL/lprマウスは、血漿中IL−6の上昇が見られたが、ストレス負荷しないマウスではIL−6は検出されなかった。抗IL−18受容体抗体を投与したマウスにストレスを負荷すると、IL−6の上昇は抑制された。
ヒト初代培養皮膚角化細胞(ケラチノサイト)を、6cm径の細胞培養用ペトリ皿にケラチノサイト用基礎培地中、1.0−2.0×10 6 / dishになるように培養した。これを活性酸素発生剤であるパラコートを1μM 含む同培地中で15分培養した後でパラコート非含有培地に交換し、さらに1時間培養した後で培地を採取し、培地中のIL−18 蛋白の濃度を測定した。また、パラコート処理時に、活性酸素除去剤であるSODもしくは水溶性ビタミンEをSOD (1, 2.5, 5, 10, 20 U / ml), ビタミンE (100 nM, 1, 2.5, 5,10 mM / ml)を含む培地中で細胞を培養し、培地中のIL−18蛋白の濃度を測定した。ケラチノサイトにおいて、活性酸素分子種によるIL−18の活性化と放出が認められた。さらに、これらは活性酸素除去剤であるSOD、あるいは活性酸素を中和するビタミンEによって、用量依存的に抑制された(図7Aおよび7B)。
マウス新生児脳から、Hassanらの方法(Hassan NF, Rifat S, Campbell DE, McCawley LJ, Douglas SD. J. Leukoc Biol. 1991 Jul;50(1):86−92)で単離した脳マイクログリアを1.5−2.0×106/mlになるように培養した。これを活性酸素発生剤であるパラコートを 100 nM含むダルベッコミニマムエッセンシャル培地中で1時間培養した後でパラコート非含有培地に交換。さらに3時間培養した後で培地を採取し、培地中のIL−18 蛋白の濃度を測定した。また、パラコート処理後に活性酸素除去剤であるSODもしくは水溶性ビタミンEをSOD (1, 2.5, 5, 10, 20 U /ml)、ビタミンE (100 nM, 1, 2.5, 5, 10 mM / ml)含む培地中で細胞を培養し、培地中のIL−18蛋白の濃度を測定した。マイクログリアにおいて、活性酸素分子種によるIL−18の活性化と放出が認められた。さらに、これらは活性酸素除去剤であるSOD、あるいは活性酸素を中和するビタミンEによって、用量依存的に抑制された(図8Aおよび8B)。
マウス新生児脳から、Yangらの方法(Yang P, Hernandez MR. Brain Res Brain Res Protoc. 2003 Oct;12(2):67−76)で単離した脳アストロサイトを1.5−2.0 ×10 6 /mlになるように調製した。これを活性酸素発生剤であるパラコートを100 nM含むダルベッコミニマムエッセンシャル培地中で1時間培養した後でパラコート非含有培地に交換。さらに3時間培養した後で培地を採取し、培地中のIL−18 蛋白の濃度を測定した。また、パラコート処理後に、活性酸素除去剤であるSODもしくは水溶性ビタミンEをSOD(1, 2.5, 5, 10, 20 U / ml),ビタミンE(100 nM, 1, 2.5, 5, 10 mM/ml)含む培地中で細胞を培養し、培地中のIL−18蛋白の濃度を測定した。アストロサイトにおいて、活性酸素分子種によるIL−18の活性化と放出が認められた。さらに、これらは活性酸素除去剤であるSOD、あるいは活性酸素を中和するビタミンEによって、用量依存的に抑制された(図9Aおよび9B)。
Hamiltonらの方法(Hamilton TA, Weiel JE, Adams DO. J Immunol. 1984 May; 132(5) :2285−90)でマウスから単離した腹腔マクロファージを1.0−2.0×105 /dishになるようダルベッコミニマムエッセンシャル培地中で培養した。培地を、活性酸素発生剤であるパラコートを100 nM含む同培地に交換して15分培養した後でパラコート非含有培地に交換し、さらに3時間培養した後で培地を採取して、培地中のIL−18 蛋白の濃度を測定した。また、パラコート処理時に、活性酸素除去剤であるSODを (1, 2.5, 5, 10, 20U/ml)含む培地中で細胞を培養し、培地中のIL−18蛋白の濃度を測定した。マクロファージにおいて、活性酸素分子種によるIL−18の活性化と放出が認められた。さらに、これらは活性酸素除去剤であるSOD、あるいは活性酸素を中和するビタミンEによって、用量依存的に抑制された(図10Aおよび10B)。
関節リウマチ患者の病変部位の関節滑膜から採取した滑膜組織をTanakaらの方法(Tanaka M, Harigai M, Kawaguchi Y, Ohta S, Sugiura T, Takagi K, Ohsako−Higami S, Fukasawa C, Hara M, Kamatani N. J Rheumatol. 2001 Aug;28(8):1779−87)でウシ胎児血清10%含有RPMI−1640 培地中で組織培養した。活性酸素発生剤であるパラコートを100 nM含む同培地に交換して15分培養した後、パラコート非含有培地に交換し、さらに1時間培養した後で培地を採取して、培地中のIL−18 蛋白の濃度を測定した。また、パラコート処理時に、活性酸素除去剤であるSOD (1, 2.5, 5, 10, 20 U / ml)を含む培地中で細胞を培養し、培地中のIL−18蛋白の濃度を測定した。滑膜組織において、活性酸素分子種によるIL−18の活性化と放出が認められた。さらに、これらは活性酸素除去剤であるSOD、あるいは活性酸素を中和するビタミンEによって、用量依存的に抑制された(図11Aおよび11B)。
ヒト初代培養腎近位尿細管上皮細胞(CAMBREX 社から購入)を、6 cm 径の細胞培養用ペトリ皿に腎尿細管細胞用基本培地:内容 10 μg/ml hEGF(組換えヒト上皮細胞成長因子) 0.5 ml、 5 mg/ml インシュリン 0.5 ml、 0.5 mg/ml ヒドロコルチゾン 0.5 ml、 FBS(ウシ胎児血清) 2.5 ml、0.5 mg/ml エピネフリン 0.5 ml、6.5μg/ml トリヨードチロニン 0.5 ml、10 mg/ml トランスフェリン 0.5 ml、50 mg/ml ゲンタマイシン、50 μg/ml アンホテリシン−B 0.5 ml)中1.0−2.0 ×106/ dish になるように培養した。これを活性酸素発生剤であるパラコートを100 nM含む同培地中で15分培養し、その後でパラコート非含有同培地に交換した。さらに1時間培養した後で培地を採取し、培地中のIL−18 蛋白の濃度を測定した。また、パラコート処理時に、活性酸素除去剤であるSODもしくは水溶性ビタミンEをSOD (1, 2.5, 5, 10, 20 U / ml), ビタミンE (100 nM, 1, 2.5, 5, 10 mM / ml) を含む培地中で細胞を培養し、培地中のIL−18蛋白の濃度を測定した。腎尿細管細胞において、活性酸素分子種によるIL−18の活性化と放出が認められた。さらに、これらは活性酸素除去剤であるSOD、あるいは活性酸素を中和するビタミンEによって、用量依存的に抑制された(図12Aおよび12B)。
IL−18は、ACTH、FSH、LHの放出を惹き起す
遺伝子組換え技術により作製したIL−18をC57B/6マウスに1.5μg静脈注射し、以後の血中のACTH、FSHおよびLHのレベルを調べた。図13Aに示すように、血中ACTH濃度はIL−18の投与によって上昇した。図13B、13CにIL−18投与1時間後のマウスから採取した血漿中FSHおよびLHのレベルを示す。IL−18の投与により、FSHおよびLHの血漿中濃度が上昇することが示された。このことから、血中にIL−18の上昇が起きることでACTH、FSH、LHの血中レベルに変動が起きることが理解され、ストレスや活性酸素による血中IL−18の上昇が全身状態を大きく左右することがわかる。
Claims (40)
- スーパーオキシドが介在する非炎症性ストレス応答の指標剤であって、非炎症性ストレスカスケードに関与する成分を含有してなる指標剤。
- 前記非炎症性ストレスカスケードに関与する成分が、IL−18、活性型IL−18、P38MAPキナーゼ、リン酸化P38MAPキナーゼ、カスパーゼ11、カスパーゼ1、活性化カスパーゼ1からなる群から選択される1または2以上のタンパク質を含有することを特徴とする請求項1記載の指標剤。
- 前記非炎症性ストレスカスケードに関与する成分が、IL−18である請求項1記載の指標剤。
- 前記IL−18が血中に存在する活性型IL−18である請求項3に記載の指標剤。
- さらにP38MAPキナーゼを含有してなる請求項3または4に記載の指標剤。
- 前記P38MAPキナーゼがリン酸化されたものである請求項5に記載の指標剤。
- 前記P38MAPキナーゼがマウス由来であり、当該キナーゼのリン酸化部位がThr180またはTyr182である請求項6に記載の指標剤。
- 前記P38MAPキナーゼがヒト由来であり、当該キナーゼのリン酸化部位がThr185またはTyr187である請求項6に記載の指標剤。
- さらにカスパーゼ−11を含有してなる請求項3〜8いずれかに記載の指標剤。
- さらにカスパーゼ−1を含有してなる請求項3〜9いずれかに記載の指標剤。
- 前記カスパーゼ−1が活性化カスパーゼ−1である請求項10に記載の指標剤。
- 前記非炎症性ストレスが精神的ストレスである請求項3〜11いずれかに記載の指標剤。
- 前記精神的ストレスが拘束ストレスである請求項12に記載の指標剤。
- 請求項1〜13いずれかに記載の指標剤を検出するための非炎症性ストレス応答の可視化剤。
- IL−18抗体を含有する請求項14に記載の可視化剤。
- 前記IL−18抗体が活性型IL−18を特異的に認識するものである、請求項15に記載の可視化剤。
- さらにP38MAPキナーゼ抗体を含有する請求項15または16に記載の可視化剤。
- 前記P38MAPキナーゼ抗体が抗リン酸化P38MAPキナーゼ抗体である請求項17に記載の可視化剤。
- 前記抗リン酸化P38MAPキナーゼ抗体がリン酸化Thr180もしくはTyr182を有するP38MAPキナーゼ、またはリン酸化Thr185もしくはTyr187を有するP38MAPキナーゼを認識するものである請求項18に記載の可視化剤。
- さらにカスパーゼ−11抗体を含有する請求項15〜19いずれかに記載の可視化剤。
- さらにカスパーゼ−1抗体またはカスパーゼー1の基質を含有する請求項15〜20いずれかに記載の可視化剤。
- 前記カスパーゼ−1抗体が活性化カスパーゼ−1を特異的に認識するものである、請求項21に記載の可視化剤。
- 請求項1〜13いずれかに記載の指標剤の量または活性を測定することを特徴とする非炎症性ストレスの程度を測定する方法。
- 前記指標剤が、IL−18または活性型IL−18である請求項23記載の方法。
- 請求項14〜22いずれかに記載の可視化剤を用いることを特徴とする、請求項23または24に記載の方法。
- 前記非炎症性ストレスが精神的ストレスである請求項23〜25いずれかに記載の方法。
- 前記精神的ストレスが拘束ストレスである請求項26に記載の方法。
- 請求項14〜22いずれかに記載の可視化剤を含む非炎症性ストレスの測定キット。
- 前記可視化剤がIL−18抗体を含有する請求項28記載のキット。
- 前記IL−18抗体が活性型IL−18を認識するものである請求項29記載のキット。
- 請求項14〜22いずれかに記載の可視化剤を動物に適用することを特徴とする、非炎症性ストレス応答に基づく免疫状態の変動を予防、改善または予想する方法。
- 前記動物がヒトを除く脊椎動物である請求項31に記載の予防、改善または予想方法。
- 請求項1〜13いずれかに記載の指標剤の量または活性を低減させるための非炎症性ストレス応答に基づく免疫状態変動の治療剤。
- 前記治療剤の有効成分がIL−18抗体または抗IL−18受容体抗体である請求項33に記載の治療剤。
- 前記有効成分がIL−18抗体であり、当該IL−18抗体が活性型IL−18に特異的に結合するものである請求項34に記載の治療剤。
- 前記治療剤の有効成分がスーパーオキシドジムスターゼまたはビタミンEである請求項33記載の治療剤。
- 請求項1〜13いずれかに記載の指標剤の量または活性を測定することを特徴とする、非炎症性ストレスにより発症、悪化若しくは再発する疾患に対する治療効果、改善効果若しくは予防効果を有する物質をスクリーニングする方法。
- 前記指標剤が、IL−18または活性型IL−18である請求項37記載の方法。
- 前記疾患が、全身性エリテマトーデス、ループス腎炎、アトピー性皮膚炎、多発性硬化症、気管支喘息、乾癬、脳虚血、脳変性、脳炎、関節リウマチ、月経異常、子宮内膜症または性欲低下である請求項37または38記載の方法。
- 請求項1〜13いずれかに記載の指標剤の量または活性を測定することを特徴とする、酸化ストレスに対する抑制効果若しくは防止効果を有する物質をスクリーニングする方法。
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