JP6610860B2 - Il−6産生抑制作用を有する非下痢原性分散接着性大腸菌及びその利用 - Google Patents
Il−6産生抑制作用を有する非下痢原性分散接着性大腸菌及びその利用 Download PDFInfo
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- JP6610860B2 JP6610860B2 JP2015121127A JP2015121127A JP6610860B2 JP 6610860 B2 JP6610860 B2 JP 6610860B2 JP 2015121127 A JP2015121127 A JP 2015121127A JP 2015121127 A JP2015121127 A JP 2015121127A JP 6610860 B2 JP6610860 B2 JP 6610860B2
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Description
実施例1では、上皮細胞において各種の刺激により誘導されるIL-6産生に対する、健常者由来の分散接着性大腸菌(DAEC)株(SK1144)及び散発下痢症患者由来のDAEC株(V64)の効果を検討した。
(1-1)供試菌
DAECとして、本発明者により単離された健常者由来株(SK1144:受託番号NITE P-02049)及び散発下痢症患者由来株(V64)を用いた(Fujihara S.ら, Jpn J. Infect. Dis., vol.62, p.318-323, 2009参照)。実施例1では、これらの株をLB培地にて37℃で16時間培養し、OD600が0.20〜0.27(3×108〜4×108 CFU/ml相当)となったことを確認した。そして、これらの培養物(1 ml)を、10,000 rpmで5分間遠心して上清を除いた。得られた沈殿物(菌体)を、メチルα-D-マンノピラノシド(MαDM:和光純薬株式会社)を0.5%の濃度で含有するイーグルMEM培地(日水製薬株式会社)(以下、「0.5%MαDM含有EMEM」という)で懸濁して、菌液(約1×109 CFU/ml)を得た。
上皮細胞として、ヒト上皮細胞株HEp-2(大日本製薬より入手した)を用いた。実施例1では、HEp-2細胞を、ウシ胎仔血清(FBS:NICHIREI社)を10%含有するダルベッコ変法イーグル培地(DMEM:日水製薬株式会社)を用いて、24ウェルプレートにて約70〜90%コンフルエントとなるまで37℃、5%CO2雰囲気下で培養した。
HEp-2細胞のIL-6産生を誘導するために、刺激物質として、Toll様受容体(TLR)5のリガンドであるフラジェリン、プロテインキナーゼ活性化剤であるPMA、炎症性サイトカインのTNF-α、及び細胞に炎症を引き起こす細菌であるサルモネラを用いた。以下に、各刺激物質を含む試薬の調製について説明する。
サルモネラの精製べん毛タンパクであるflagellin(Novus Biologicals社)を、0.5% MαDM含有EMEMに溶解して、フラジェリン溶液(2μg/ml)を調製した。
PMA溶液は、次のようにして調製した。ホルボール12-ミリステート13-アセテート(SIGMA社)をDMSOに10μg/mlとなるように溶解し、得られた溶液を濾過フィルターMillex-LG (0.20 μm)(EMD Millipore社)により滅菌した。滅菌した溶液を0.5%MαDM含有EMEMで100倍に希釈して、PMA溶液(100 ng/ml)を調製した。
TNF-α(SIGMA社)を50%グリセロールに溶解し、得られた溶液を濾過フィルターMinisart(0.45μm)(Sartorius Stedim社)により滅菌して、TNF-α溶液(5μg/ml)を調製した。
サルモネラ(Salmonella Enteritidis)は、大阪市立環境科学研究所より入手した。サルモネラの菌液は、次のようにして調製した。サルモネラを、LB培地にて37℃で16時間培養した。そして、この培養物(1 ml)を、10,000 rpmで5分間遠心して上清を除き、得られた沈殿物(菌体)を0.5%MαDM含有EMEMに懸濁して、菌液(約1×109 CFU/ml)を得た。
HEp-2細胞を培養した24ウェルプレートから培地を除き、各ウェルに0.5% MαDM含有EMEMを1 mlずつ添加した。そして、上記のSK1144株又はV64株の菌液を1ウェル当たり5μlずつ添加して、HEp-2細胞とSK1144株又はV64株とを接触させた。菌体数と細胞数との比は約25:1とした。また、対照として、別のウェルに、菌液に代えて0.5%MαDM含有EMEMを5μl添加した。3時間後、IL-6誘導刺激をするウェルにフラジェリン溶液、PMA溶液、TNF-α溶液又はサルモネラ菌液を添加して、37℃、5%CO2雰囲気下で19時間インキュベートした。各刺激物質の終濃度は、フラジェリンが50 ng/ml、PMAが2.5 ng/ml、TNF-αが100 ng/ml、サルモネラ菌が5×106 CFU/mlであった。IL-6誘導刺激をしないウェルには、各刺激物質に代えて、0.5%MαDM含有EMEMを添加した。インキュベーション後、各ウェルから上清を回収した。回収した上清をサンプルとして、Human Interleukin-6 (Hu IL-6) ELISAキット(Life Technologies社、Cat.No. KHC0061)を用いて、上清中のIL-6濃度を定量した。なお、具体的な操作は、当該キットに添付されたマニュアルに従って行った。
IL-6濃度の定量結果を、図1〜4に示す。図中、「+」は、刺激物質を添加したことを示し、「−」は、刺激物質を添加しなかったことを示す。これらの図に示されるように、分散接着性大腸菌と接触させていないHEp-2細胞(対照)は、フラジェリン、PMA、TNF-α及びサルモネラ菌による刺激によりIL-6産生が誘導されていた。また、患者由来のV64株と接触させたHEp-2細胞では、未刺激の場合及びいずれの刺激物質を添加した場合も、IL-6産生が誘導されていた。一方、健常者由来のSK1144株と接触させたHEp-2細胞では、未刺激の場合及びいずれの刺激物質を添加した場合も、IL-6産生が抑制されていた。これらのことから、SK1144株は、上皮細胞の刺激誘導性のIL-6産生を抑制することが示された。本発明者は、今回の実験に先立ち、供試した分散接着性大腸菌が上皮細胞における炎症性サイトカインIL-8濃度の上昇を抑制することを発見し、既に報告している。今回、いずれの刺激物質によるIL-6産生も抑制されたことから、SK1144株は、IL-8のみならず炎症反応を包括的に抑制していることが示唆される。
本参考例では、上皮細胞においてフラジェリン刺激により誘導されるIL-8産生に対する、健常者由来のDAEC株(SK1144)及び散発下痢症患者由来のDAEC株(V64)の効果を示した。
(1-1)供試菌
実施例1と同様にして、SK1144株及びV64株のそれぞれの菌液(約1×109 CFU/ml)を調製した。
上皮細胞として、TLR5を安定発現するHEK293形質転換体(TLR5, NF-κB/SEAP Stably Transfected HEK293 cell line、IMGENEX社)を用いた。本参考例では、この細胞を、ウシ胎仔血清(FBS:NICHIREI社)を10%含有するダルベッコ変法イーグル培地(DMEM:日水製薬株式会社)を用いて、96ウェルプレートにて約70〜90%コンフルエントとなるまで37℃、5%CO2雰囲気下で培養した。
実施例1と同様にして、flagellin(Novus Biologicals社)を0.5% MαDM含有EMEMに溶解して、フラジェリン溶液(2μg/ml)を調製した。
HEK293形質転換体を培養した96ウェルプレートから培地を除き、各ウェルに0.5% MαDM含有EMEMを200μlずつ添加した。そして、上記のSK1144株又はV64株の菌液を1ウェル当たり5μlずつ添加して、HEp-2細胞とSK1144株又はV64株とを接触させた。菌体数と細胞数との比は約100:1とした。また、対照として、別のウェルに、菌液に代えて0.5%MαDM含有EMEMを5μl添加した。3時間後、IL-8誘導刺激をするウェルにフラジェリン溶液を添加して、37℃、5%CO2雰囲気下で19時間インキュベートした。フラジェリンの終濃度は50 ng/mlであった。IL-8誘導刺激をしないウェルには、フラジェリン溶液に代えて、0.5%MαDM含有EMEMを添加した。インキュベーション後、各ウェルから上清を回収した。回収した上清をサンプルとして、Human CXCL8/IL-8 Quantikine ELISAキット(R&D SYSTEMS社、Cat.No. D8000C)を用いて、上清中のIL-8濃度を定量した。なお、具体的な操作は、当該キットに添付されたマニュアルに従って行った。
IL-8濃度の定量結果を、図5に示す。図中、「+」は、刺激物質を添加したことを示し、「−」は、刺激物質を添加しなかったことを示す。図5に示されるように、分散接着性大腸菌と接触させていない細胞(対照)は、フラジェリンによる刺激によりIL-8産生が誘導されていた。また、患者由来のV64株と接触させた細胞では、未刺激の場合及びいずれの刺激物質を添加した場合も、IL-8産生が誘導されていた。一方、健常者由来のSK1144株と接触させた細胞では、未刺激の場合及びいずれの刺激物質を添加した場合も、IL-8産生が抑制されていた。これらのことから、SK1144株は、上皮細胞の刺激誘導性のIL-8産生を抑制することが示された。
Claims (9)
- 上皮細胞のインターロイキン6(IL-6)産生を抑制する作用を有し、非線毛性接着因子(Afa)遺伝子を有する、非下痢原性分散接着性大腸菌。
- 上皮細胞のインターロイキン8(IL-8)産生を抑制する作用をさらに有する、請求項1に記載の非下痢原性分散接着性大腸菌。
- べん毛を有し、運動性のある、請求項1又は2に記載の非下痢原性分散接着性大腸菌。
- 上皮細胞のIL-6産生が、細菌、菌体成分、炎症性サイトカイン及び起炎性化学物質の少なくとも1種による上皮細胞の刺激によって生じるものである、請求項1〜3のいずれか1項に記載の非下痢原性分散接着性大腸菌。
- 独立行政法人製品評価技術基盤機構 特許微生物寄託センターに受託番号NITE P-02049で受託された大腸菌SK1144である、請求項1〜4のいずれか1項に記載の非下痢原性分散接着性大腸菌。
- 請求項1〜5のいずれか1項に記載の非下痢原性分散接着性大腸菌を有効成分とする、上皮細胞のIL-6産生抑制剤。
- 上皮細胞が、腸管上皮細胞である、請求項6に記載のIL-6産生抑制剤。
- 上皮細胞のIL-8産生を抑制する作用をさらに有する、請求項6又は7に記載のIL-6産生抑制剤。
- 請求項1〜5のいずれか1項に記載の非下痢原性分散接着性大腸菌を有効成分とする、炎症性腸疾患の予防又は治療剤。
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