JP4474163B2 - 免疫調節ペプチド - Google Patents
免疫調節ペプチド Download PDFInfo
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- JP4474163B2 JP4474163B2 JP2003564067A JP2003564067A JP4474163B2 JP 4474163 B2 JP4474163 B2 JP 4474163B2 JP 2003564067 A JP2003564067 A JP 2003564067A JP 2003564067 A JP2003564067 A JP 2003564067A JP 4474163 B2 JP4474163 B2 JP 4474163B2
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- fpr
- peptide
- cells
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- fprl1
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Classifications
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Description
Trp−Lys−Tyr−Met−Gly−D−Met−NH2(WKYMGm;配列番号:2)、
Trp−Lys−Tyr−Met−Val−Gly−NH2(WKYMVG;配列番号:3)、
Trp−Arg−Tyr−Met−Val−D−Met−NH2(WRYMVm;配列番号:4)、
Trp−Glu−Tyr−Met−Val−D−Met−NH2(WEYMVm;配列番号:5)、
Trp−His−Tyr−Met−Val−D−Met−NH2(WHYMVm;配列番号:6)、
Trp−Asp−Tyr−Met−Val−D−Met−NH2(WDYMVm;配列番号:7)、
Trp−Lys−His−Met−Val−D−Met−NH2(WKHMVm;配列番号:8)、
Trp−Lys−Glu−Met−Val−D−Met−NH2(WKEMVm;配列番号:9)、
Trp−Lys−Trp−Met−Val−D−Met−NH2(WKWMVm;配列番号:10)、
Trp−Lys−Arg−Met−Val−D−Met−NH2(WKRMVm;配列番号:11)、
Trp−Lys−Asp−Met−Val−D−Met−NH2(WKDMVm;配列番号:12)、
Trp−Lys−Phe−Met−Val−D−Met−NH2(WKFMVm;配列番号:13)、
Trp−Lys−Tyr−Met−Tyr−D−Met−NH2(WKYMYm;配列番号:14)、
Trp−Lys−Tyr−Met−Phe−D−Met−NH 2 (WKYMFm;配列番号:15)、
Trp−Lys−Tyr−Met−Val−Glu−NH2(WKYMVE;配列番号:16)、
Trp−Lys−Tyr−Met−Val−Val−NH2(WKYMVV;配列番号:17)、
Trp−Lys−Tyr−Met−Val−Arg−NH2(WKYMVR;配列番号:18)、
Trp−Lys−Tyr−Met−Val−Trp−NH2(WKYMVW;配列番号:19)、
Trp−Lys−Tyr−Met−Val−NH2(WKYMV;配列番号:20)、
Lys−Tyr−Met−Val−D−Met−NH2(KYMVm;配列番号:21)、
Lys−Tyr−Met−Val−NH2(KYMV;配列番号:22)、
Tyr−Met−Val−D−Met−NH2(YMVm;配列番号:23)、
Met−Val−D−Met−NH2(MVm;配列番号:24)、
Trp−Lys−Tyr−Met−Trp−D−Met−NH 2 (WKYMWm;配列番号:25)である。
(a)ヒトのモノサイト又は好中球によりスーパーオキシド生成を誘導し、
(b)ヒト末梢血モノサイト又は好中球により細胞内カルシウムの上昇を誘導し、
(c)FPR(ホルミルペプチド受容体)またはFPRL1(ホルミルぺプチド受容体様1)に結合し、
(d)in vivoにおいてヒトのモノサイト又は好中球の走化性移動を誘導し、
(e)FPR(ホルミルペププチド受容体)発現細胞またはFPRL1(ホルミルペプチド受容体様1)発現細胞において脱顆粒を誘導し、
(f)FPR(ホルミルペプチド受容体)またはFPRL1(ホルミルペプチド受容体様1)の活性化を通じて細胞外シグナル制御キナーゼを刺激し、
(g)FPR(ホルミルペプチド受容体)またはFPRL1(ホルミルペプチド受容体様1)の活性化を通じてAktのリン酸化を刺激する特性のうち
少なくとも一つの特性を有する。
Fmocアミノ酸はミリポア社(Millipore)(Bedford,MA)から購入した。Rapidamide樹脂はデュポン社(Dupont)(Boston,MA)から購入した。末梢血単核細胞(PBMC)分離培地(Histopaque−1077)、シトクロムc及びfMLFはシグマ社(Sigma)(St.Louis,MO)から購入した。フラ−2ペンタアセトキシメチルエステル(fura−2/AM)はモレキュラープローブ社(Molecular Probes)(Eugene,OR)から購入した。RPMI1640はライフテクノロジーズ社(Life Technologies)(GrandIsland,NY)から購入した。透析されたウシ胎児血清及び添加されたウシ血清はハイクローンラボラトリーズ社(Hyclone Laboratories Inc)(Logen,UT)から購入した。PTX,GF109203X及びPD98059はカルバイオケム社(Calbiochem)(San Diego,CA)から購入した。LY294002はバイオモルリサーチラボラトリーズ社(BIOMOL reserch laboratories,Inc)(Polymouth Meeting,PA)から購入した。
末梢血白血球濃縮液は蔚山赤十字血液センターから提供された。ヒト好中球は先に記載されているようなデキストラン沈降、赤血球の低浸透圧の溶解(hypotonic lysis)及び溶媒の勾配によるリンパ球分離を標準的な方法に従って分離した(9)。分離されたヒト好中球は直ちに用いられた。
WKYMVm、[配列番号:1]から[配列番号:25]のうち[配列番号:1]のペプチド及びwkymvmのヒト好中球でのスーパーオキシド生成に与えるペプチドの活性を測定した。参考文献に記載されているように、スーパーオキシドアニオン生成をミクロタイタ96穴プレートELISAリーダ(microtiter 96−well plate ELISA reader)(Bio−Tekinstruments,EL312e,Winooski,VT)を使用してシトクロムcの還元を測定し定量を行った(14)。ヒト好中球(96穴プレートの各ウェル当たりに1×106細胞/100μlのRPMI1640培地)は37℃で1分間50μMシトクロムcと共に予め培養し、その後、表示された濃度のペプチドと共に培養した。スーパーオキシド生成は1分間隔で5分にわたって550nmでの光吸収における変化として測定した。少なくとも4回の独立した実験から各位置での活性アミノ酸を有するペプチドを選定した。これらの結果は表1に記載されている。
aスーパーオキシド生成はシトクロムc還元を観測して測定する。
b処理されたペプチドの濃度は100nMであり、WKWM(F/W)m−NH 2 は、WKWMFm−NH 2 とWKWMWm−NH 2 の混合物である。
b処理されたペプチドの濃度は10μMであり、WKWM(F/W)m−NH 2 は、WKWMFm−NH 2 とWKWMWm−NH 2 の混合物である。
FPR発現RBL−2H3細胞で、WKYMVm、[配列番号:1]から[配列番号:25]のうち[配列番号:1]のペプチド及びwkymvmのペプチドが遊離したカルシウムイオンの濃度上昇に与える活性を測定した。FPR発現RBL−2H3細胞を10μMのペプチドで刺激し、遊離したカルシウムイオンの濃度を測定した。遊離したカルシウムイオンの濃度の基準はfura−2/AMを使用してGrynkiewicz方法で蛍光測定して決定した(15)。準備した細胞を新鮮な無血清RPMI1640培地で継続して攪拌しながら50分間37℃で3μMのfura−2/AMで培養した。2×106細胞をカルシウムイオンが存在しないLocke´s溶液(154mMのNaCl、5.6mMのKCl、1.2mMのMgCl2、5mMのHEPES、pH7.3、10mMのグルコース及び0.2mMのEGTA)で各分析に用いられるように分取した。340nm及び380nmでの二重励起波長の蛍光変化及び500nmでの発光波長を測定して、測定された蛍光率を遊離カルシウムイオンの濃度に互換し、上昇した遊離したカルシウムイオンの濃度のピークレベルを測定した。その結果を表3及び図1Aに示した。データは3つの独立した実験の代表値である。
a細胞内カルシウムの増加はfura−2をロードした細胞から測定する。
b WKWM(F/W)m−NH 2 は、WKWMFm−NH 2 とWKWMWm−NH 2 の混合物である。
a細胞内カルシウムの増加はfura−2をロードした細胞から測定する。
b WKWM(F/W)m−NH 2 は、WKWMFm−NH 2 とWKWMWm−NH 2 の混合物である。
いくつかのペプチド(WKGMVm、WKRMVm、6番目のD−Metを置換したペプチド)が細胞質性のカルシウムの上昇を誘導することができないという事実から、前記ペプチドがFPR又はFPRL1に結合できるかどうかについて調べた。ペプチドによりFPR又はFPRL1に対して結合する[125I]が標識されたWKYMVmが置換される程度を測定した。標識されていないWKYMVm又は[配列番号:1]から[配列番号:25]のうち[配列番号:1]のペプチドの非存在下、あるいはペプチドの存在下でこれらのペプチドの量を増加させた状態でFPR発現RBL−2H3細胞を[125I]WKYMVmと共に培養した。
i)ペプチドによる細胞の刺激
培養されたRBL−2H3細胞を2×106細胞分取して示された濃度のWKYMVm及び本発明のペプチドで示された時間刺激した。1μMのWKYMVmでFPR又はFPRL1発現RBL−2H3細胞を多様な時間で刺激した(図3A)。2つの細胞を1μMのWKYMVm処理前にビークル又は100ng/mlのPTX(24時間)、50μMのLY294002(15分)、5μMのGFX(15分)、10μMのBAPTA/AM(60分)、50μMのPD98059(60分)と共に予め培養した(図3B)。FPR又はFPRL1発現RBL−2H3細胞を10μMの本発明のペプチドで2分又は5分間刺激した(図3C)。
各試料(30gペプチド)を10%SDS−PAGEで処理してリン酸化されたERKを抗リン酸化ERK抗体を用いた免疫ブロット法により決定した。タンパク質試料は濃縮された試料バッファーを添加して電気泳動用に準備した。試料のうち一部をLaemmliに記載されたバッファーシステムを使用して10%SDSポリアクリルアミドゲルによって分離した(17)。
FPR又はFPRL1発現RBL−2H3細胞におけるFPR又はFPRL1を通じた細胞シグナリングに対するペプチドの効果を評価して、その結果を図3に示した。図3の結果は3回の独立した実験の代表値を表している。
化学誘引物質受容体の活性化はPI3Kを通じて、Aktの活性化を誘導することはよく知られている(19)。前記ペプチドで細胞の刺激、及び電気泳動、免疫ブロット分析を実施例5と同一の方法で実施した。
顆粒の分泌は肥満細胞で最も重要な作用の一つである(20)。顆粒分泌に与えるWKYMVmの効果を先に記載しているようなβ−ヘキソサミニダーゼ分泌の測定により調べた(18)。簡単に述べると、FPR又はFPRL1発現RBL−2H3細胞(2×105/ウェル)を24ウェル組織培養プレートで一晩培養した。細胞をTyrode’sバッファー(137mM NaCl、12mM NaHCO3、5.6mM グルコース、2.7mM KCl、1mM CaCl2、0.5mM MgCl2、0.4mM NaH2PO4、0.1g/100ml BSA、25mM HEPES、pH7.4)で2回洗浄し、各ペプチドで刺激した。多様な濃度のWKYMVmがFPR又はFPRL1発現RBL−2H3細胞において処置された(図5A)。1μMのWKYMVmを10μMのBAPTA/AMの存在又は非存在下で二つの細胞株を刺激するために使用した(図5B)。刺激してから20分後に氷上にプレートを置くことにより反応を終了させた。β−ヘキソサミニダーゼの培養液中への分泌は50μlの上層液又は細胞溶解液を25μlの5mMのp−ニトロフェニル−N−アセチル−β−D−グルコサミドと共に0.1mMのクエン酸ナトリウム緩衝液(pH3.8)で37℃、2時間培養することにより測定された。培養の最後に50μlの0.4M Na2CO3を添加した。405nmでの吸光度を測定してその結果を図5に示した。データは3点測定を3回実施した実験の平均値±標準誤差(S.E.)である。数値(平均値±標準誤差)は細胞に存在するβ−ヘキソサミニダーゼの全体量に対する百分率で示した。
走化性分析はBoyden Chamberを修正した多重ウェルチャンバー(Neuroprobe Inc.,Gaithersburg,MD)を使用して実施した。簡単に述べると、ポリカーボネートフィルター(8μm孔径)をHEPESが緩衝剤として働くRPMI培地に50μg/mlのラットタイプIコラーゲン(Collaborative Biomedicals)で予めコーティングする。乾燥コーティングされたフィルターを異なる濃度のペプチドを含む96ウェルチャンバー上に置く。FPR又はFPRL1を発現するRBL−2H3細胞は1×106/mlの無血清RPMIの濃度でRPMIに懸濁され、その懸濁液のうち25μlを96ウェル走化性チャンバーの上側ウェル上に載せた。37℃で4時間培養した後、移動しなかった細胞を擦り落として除去し、フィルターを通過して移動した細胞を脱水、固定し、ヘマトキシリン(Sigma,St.Louis,MO)で染色した。染色された細胞を前記ウェル中で無作為に選択された5つの高倍率視野(400倍)で計数した。図7Aは前記走化性分析結果を示している。ビークル、50μMのLY294002(15分)、及び50μMのPD98059(60分)で予め処理された細胞は1μMのWKYMVmと共に走化性分析に使用され、その結果を図7Bに示した。移動した細胞の数を高倍率視野(400倍)で計数して決定した。データは各々2点測定を3回実施した実験の平均値±標準誤差を示している。
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Claims (6)
- [配列番号:1]のアミノ酸配列からなるペプチド。
- 白血球を活性化し、分離され、実質的に純粋な形態で存在することを特徴とする請求項1に記載のペプチド。
- (a)ヒトのモノサイト又は好中球によりスーパーオキシド生成を誘導し、
(b)ヒト末梢血単核球又は好中球により細胞内カルシウムの上昇を誘導し、
(c)FPR又はFPRL1に結合し、
(d)in vitroにおいてヒトのモノサイト又は好中球の走化性による移動を誘導し、
(e)FPR発現細胞又はFPRL1発現細胞において脱顆粒を誘導し、
(f)FPR又はFPRL1の活性化を通じてERKのリン酸化を刺激し、及び、
(g)FPR又はFPRL1の活性化を通じてAktのリン酸化を刺激する特性のうち、少なくとも1つの特性を有することを特徴とする請求項1に記載のペプチド。 - [配列番号:1]のアミノ酸配列のペプチドを含む医薬組成物。
- [配列番号:1]のアミノ酸配列のペプチドをコードするヌクレオチド。
- 請求項5に記載のヌクレオチドを含んでいることを特徴とするベクター。
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CN109679981A (zh) * | 2019-02-21 | 2019-04-26 | 武汉大学 | 一种甲酰基肽定向进化噬菌体及其制备方法与应用 |
KR102067402B1 (ko) | 2019-03-08 | 2020-01-17 | 주식회사 굳티셀 | 조절자 T 세포에 특이적으로 존재하는 새로운 표면단백질 Lrig-1의 용도 |
KR102094747B1 (ko) | 2019-03-08 | 2020-03-30 | 주식회사 굳티셀 | 조절자 T 세포에 특이적으로 존재하는 새로운 표면단백질 Lrig-1의 용도 |
KR102382610B1 (ko) * | 2019-12-24 | 2022-04-05 | 차의과학대학교 산학협력단 | 기능 강화된 중간엽 줄기세포를 포함하는 간질환의 예방 또는 치료용 약학적 조성물 |
KR102317415B1 (ko) | 2020-03-23 | 2021-10-28 | 주식회사 굳티셀 | 조절자 T 세포에 특이적으로 존재하는 새로운 표면단백질 Lrig-1의 용도 |
KR20200035924A (ko) | 2020-03-23 | 2020-04-06 | 주식회사 굳티셀 | 조절자 T 세포에 특이적으로 존재하는 새로운 표면단백질 Lrig-1의 용도 |
KR102429281B1 (ko) * | 2020-05-25 | 2022-08-05 | (주)노바셀테크놀로지 | 신규 안구건조증 치료용 약학적 조성물 |
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CN101709078B (zh) | 2013-04-17 |
KR100839098B1 (ko) | 2008-06-19 |
EP1414849B1 (en) | 2009-04-29 |
CN1533399A (zh) | 2004-09-29 |
KR20070108836A (ko) | 2007-11-13 |
CN101709078A (zh) | 2010-05-19 |
CA2446872C (en) | 2012-03-20 |
JP5232091B2 (ja) | 2013-07-10 |
EP1414849A2 (en) | 2004-05-06 |
KR20060114046A (ko) | 2006-11-03 |
EP2108655A1 (en) | 2009-10-14 |
EP2108655B1 (en) | 2013-11-20 |
CN100569796C (zh) | 2009-12-16 |
KR100803092B1 (ko) | 2008-02-18 |
US7030090B2 (en) | 2006-04-18 |
WO2003064447A2 (en) | 2003-08-07 |
KR100824685B1 (ko) | 2008-04-24 |
DE60327407D1 (de) | 2009-06-10 |
JP2005521388A (ja) | 2005-07-21 |
KR100752756B1 (ko) | 2007-08-29 |
WO2003064447A3 (en) | 2003-11-13 |
KR20040012929A (ko) | 2004-02-11 |
CA2446872A1 (en) | 2003-08-07 |
JP2010000077A (ja) | 2010-01-07 |
US20030224987A1 (en) | 2003-12-04 |
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