➨ ➨㸱❶
3.1. ᗎㄽ
3.2.2 TNF-alpha ࠾ࡼࡧ IL-13 ࡢㄪ〇
⤌࠼≟ TNF-alpha ࠾ࡼࡧ⤌࠼≟ IL-13 ࡣ㸪ࡑࢀࡒࢀ RNase ࣇ࣮ࣜỈ࠾ࡼ
ࡧ0.1%BSAࢆῧຍࡋࡓPBSࢆ⏝࠸࡚⁐ゎ࠾ࡼࡧᕼ㔘ࢆ⾜ࡗࡓࠋ
3.2.3 ୕ḟඖᇵ㣴
୕ḟඖᇵ㣴ࡣ1❶࡛㏙ࡓ᪉ἲྠᵝ⾜࠸㸪ᇵ㣴5᪥┠ࡽᇵ㣴⤊ࡲ࡛㸪 ᇵ㣴ᾮ0.4 μg/mlࡢࣄࢻࣟࢥࣝࢳࢰࣥ㸦Sigma-Aldrich㸧ࢆῧຍࡋࡓࠋᇵ㣴8᪥
┠ࡽࡣࣄࢻࣟࢥࣝࢳࢰࣥຍ࠼㸪ᇵ㣴ᾮᑐࡋ5 ng/mlࡲࡓࡣ50 ng/ml࡞ࡿ
ࡼ࠺ㄪ〇ࡋࡓ⤌࠼≟TNF-alpha࠾ࡼࡧ⤌࠼≟IL-13ࢆῧຍࡋࡓࠋࡲࡓ㸪ᑐ
↷ࢧࣥࣉࣝࡢᇵ㣴ᾮࡣCnT-09ࡶࡋࡃࡣ0.1%ࡢBSAࢆῧຍࡋࡓࠋ
ᇵ㣴 14 ᪥┠㸪ᇵᆅࡢධࡗࡓእഃࡢᇵ㣴─ࡽᇵ㣴⣽⬊ࡢධࡗࡓෆഃࡢᇵ㣴
─ࢆྲྀࡾฟࡋ㸪᭰ล࣓ࢫ㸦No.11; ࢝ࣥࢲࢫࢺ࣮ࣜࢬ㸧ࢆ⏝࠸࡚㸪ࢥ࣮ࣛࢤ
ࣥࢤࣝ࠾ࡼࡧෆഃࡢᇵ㣴─ࡢᗏ㒊ࡢࣇࣝࢱ࣮ࡈᇵ㣴⣽⬊ࢆ᥇ྲྀࡋࡓࠋ᥇ྲྀ
ࡋࡓࢧࣥࣉࣝࡣ㸪10%୰ᛶ⦆⾪࣐࣍ࣝࣜࣥᾮ࡛ᅛᐃࡋࡓࠋ࣐࣍ࣝࣜࣥᅛᐃᚋ㸪
ࣃࣛࣇࣥໟᇙࢆ⾜ࡗࡓ⓶࠾ࡼࡧᇵ㣴⣽⬊ࢆ3 μm࡛ⷧษࡋ㸪࣐࣊ࢺ࢟ࢩࣜࣥ
࢚࢜ࢪࣥᰁⰍ࠾ࡼࡧච⤌⧊Ꮫ౪ࡋࡓࠋ
3.2.4 ච⤌⧊Ꮫ
ච⤌⧊Ꮫࡣ㸰❶࡛㏙ࡓ᪉ἲྠᵝ⾜ࡗࡓࠋ⏝࠸ࡓ୍ḟᢠయࡣ㸪㸰❶ࡢ
⤖ᯝᇶ࡙ࡁ㸪ZO-1࠾ࡼࡧclaudin-1ඹ1 μg/ml࡛⏝ࡋࡓࠋᐇ㦂ࡣ␗࡞ࡿࢧ
ࣥࣉࣝࢆ⏝࠸࡚3ᅇ⾜ࡗࡓࠋ
3.3 ⤖ᯝ
3.3.1 ᇵ㣴⣽⬊ࡢᙧែ࠾ࡅࡿTNF-alpha࠾ࡼࡧIL-13ࡢᙳ㡪
TNF-alphaࡲࡓࡣIL-13ࡢᏑᅾୗ࠾࠸࡚ࡶ㸪ᇵ㣴⣽⬊ࡣゅᒙᵝࡢᒙࢆᙧᡂࡋ
ࡓࠋ᭷Ჲᒙᵝࡢᒙࡽᇶᗏᒙᵝࡢᒙ࠾࠸࡚ᾏ⥥≧ኚ࠾ࡼࡧ␗ᖖゅࢆㄆࡵ
ࡓ㸦ᅗ3-1B, C, E, F㸧ࠋ
3.3.2 ࢥࣥࢺ࣮ࣟࣝ࠾ࡅࡿZO-1࠾ࡼࡧ claudin-1ࡢⓎ⌧
ࢿ࢞ࢸࣈࢥࣥࢺ࣮ࣟࣝࡋ࡚⏝࠸ࡓṇᖖ≟⓶࠾ࡼࡧᇵ㣴⣽⬊࠾࠸࡚ࡣ㸪
ࡕࡽࡶ㝧ᛶᡤぢࡣㄆࡵࡽࢀ࡞ࡗࡓࠋ
3.3.2 ZO-1࠾ࡼࡧclaudin-1ࡢⓎ⌧࠾ࡅࡿTNF-alphaࡢᙳ㡪
ZO-1ࡢⓎ⌧ࢥࣥࢺ࣮ࣟࣝࡢᕪࡣㄆࡵࡽࢀ࡞ࡗࡓ㸦ᅗ3-2B, C㸧ࠋ୍᪉㸪
claudin-1ࡢⓎ⌧ࡣ㸪5 ng/mlࡢTNF-alphaῧຍࡼࡾ㸪ᰁⰍᛶࡢ㒊ศⓗ࡞ᾘኻࡀ
ㄆࡵࡽࢀࡓ㸦ᅗ3-2E㸧ࠋࡲࡓ㸪ࡑࢀࡣ50 ng/mlࡢῧຍ࠾࠸࡚ࡼࡾ㢧ⴭ࡛࠶ࡗ
ࡓ㸦ᅗ3-3F㸧ࠋ
3.3.3 ZO-1࠾ࡼࡧclaudin-1ࡢⓎ⌧࠾ࡅࡿIL-13ࡢᙳ㡪
ZO-1ࡢⓎ⌧ࢥࣥࢺ࣮ࣟࣝࡢᕪࡣㄆࡵࡽࢀ࡞ࡗࡓ㸦ᅗ3-3B, C㸧ࠋ୍᪉㸪
claudin-1ࡢⓎ⌧ࡣ㸪5 ng/mlࡢIL-13ῧຍࡼࡾ㸪ᰁⰍᛶࡢ㒊ศⓗ࡞ᾘኻࡀㄆࡵ
ࡽࢀࡓ㸦ᅗ3-3E㸧ࠋIL-13ࡢ⃰ᗘࡼࡿᕪࡣㄆࡵࡽࢀ࡞ࡗࡓ㸦ᅗ3-4E, F㸧ࠋ
3.4. ⪃ᐹ
ᮏ❶࡛ࡣ㸪ZO-1࠾ࡼࡧclaudin-1࠾ࡅࡿ TNF-alpha࠾ࡼࡧIL-13ࡢཬࡰࡍ ᙳ㡪ࡘ࠸࡚㸪≟୕ḟඖᇵ㣴⾲⓶ࣔࢹࣝࢆ⏝࠸࡚ホ౯ࡋࡓࠋTNF-alpha ࡣ㸪 ZO-1ࡢⓎ⌧ᙳ㡪ࢆ࠼࡞ࡗࡓࠋࡲࡓ㸪claudin-1࠾࠸࡚ࡣ㸪⏝㔞౫ᏑᛶᰁⰍ ᛶࡢ㒊ศⓗ࡞ᾘኻࡀㄆࡵࡽࢀࡓࠋ
ࡇࢀࡲ࡛㸪ࣄࢺ⭠⟶⒴⣽⬊ᰴ㸦T84࠾ࡼࡧCaco-2㸧࠾࠸࡚㸪TNF-alphaࡣ㸪 ZO-1ࡢᒁᅾኚࢆ⏕ࡌࡉࡏ࡞ࡗࡓࡇࡀ♧ࡉࢀ࡚࠾ࡾ㸪୍᪉࡛claudin-1
࠾࠸࡚ࡣ TNF-alpha ࡼࡾⓎ⌧ศᕸኚࡀㄆࡵࡽࢀ࡚࠸ࡿࠋࡉࡽࡑࢀࡽࡢ
ኚకࡗ࡚㸪⣽⬊㛫࠾ࡅࡿ≀㉁㏱㐣ᛶࡢቑຍࡀㄆࡵࡽࢀ࡚࠸ࡿ[35]ࠋࡲࡓ㸪
≟⭈⮚ᒀ⣽⟶ୖ⓶⏤᮶⣽⬊ᰴ (MDCK⣽⬊) ࠾࠸࡚㸪TNF-alphaࡣZO-1 ࡢⓎ
⌧㔞ᙳ㡪ࢆ࠼ࡎ㸪claudin-1ࡢⓎ⌧㔞ࢆపୗࡉࡏࡓ[73]ࠋࡉࡽච⺯ගᰁⰍ
ീ࠾࠸࡚ࢱࢺࢪࣕࣥࢡࢩࣙࣥࡢᙧែࡣ TNF-alpha ࡢῧຍࡼࡾ◚ቯࡉࢀ࡚
࠾ࡾ㸪ࢱࢺࢪࣕࣥࢡࢩࣙࣥࡢᙧᡂࡀ㞀ᐖࡉࢀࡓࡇࡀ♧၀ࡉࢀࡓ[73]ࠋࡇࢀࡽ
ࡢ⤖ᯝࡣ㸪ᮏ◊✲࠾ࡅࡿ⤖ᯝࢆᨭᣢࡍࡿࡶࡢ࡛࠶ࡿࠋ
ADᝈ⪅ࡢኚ㒊⓶࠾࠸࡚㸪ZO-1 ࡢⓎ⌧㔞ࡀపୗࡋ࡚࠾ࡾ[102]㸪ࡲࡓ㸪
Ⓞᝈ⪅ࡢ⓶࠾࠸࡚ ZO-1 ࡢᒁᅾࡢኚ࠾ࡼࡧ㌿㔞ࡢቑຍࡀㄆࡵࡽࢀࡿ
ࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿ[40]ࡇࡽ㸪ZO-1ࡢⓎ⌧ㄪ⠇ࡣ㸪TNF-alpha௨እࡢᅉ Ꮚࡀ㛵ࡋ࡚࠸ࡿᛮࢃࢀࡿࠋ
୍᪉㸪ADᝈ⪅ࡢኚ㒊⓶࠾࠸࡚claudin-1ࡢⓎ⌧㔞ࡀపୗࡋ࡚࠾ࡾ[102]㸪
ࡲࡓ㸪Ⓞᝈ⪅ࡢ⓶࠾࠸࡚㸪claudin-1 ࠾ࡅࡿ㌿㔞࠾ࡼࡧච⤌⧊Ꮫ
ࡼࡿᰁⰍᙉᗘࡀపୗࡋ࡚࠸ࡿࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿ[40]ࠋࡋࡓࡀࡗ࡚㸪ᮏ◊✲
ࡢ⤖ᯝࡼࡾ㸪CAD ࡢࡼ࠺࡞⅖ᛶ⓶ᝈࡢኚ㒊࠾࠸࡚㸪TNF-alpha ࡣ
claudin-1ࡢⓎ⌧ㄪ⠇┤᥋㛵ࡋ࡚࠸ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡓࠋ
IL-13ࡣ㸪ZO-1ࡢⓎ⌧ᙳ㡪ࢆ࠼࡞ࡗࡓࠋࡲࡓ㸪claudin-1࠾࠸࡚ࡣ㸪ᰁ
Ⰽᛶࡢ㒊ศⓗ࡞ᾘኻࡀㄆࡵࡽࢀࡓࠋ
ࡇࢀࡲ࡛㸪࢝ࣝࢩ࣒࢘ࡼࡾศㄏᑟࡋࡓࣄࢺࢣࣛࢳࣀࢧࢺ࠾࠸࡚㸪
IL-13ࡢ่⃭ࡼࡾ㸪ZO-1ࡢⓎ⌧㔞ࡣኚࡋ࡞ࡗࡓࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿ[18]ࠋ
ࡲࡓ㸪CADࣔࢹࣝ≟ࡢ㠀ኚ㒊⓶࠾࠸࡚㸪ZO-1ࡢⓎ⌧ࡣᖖ≟ẚ㍑ࡋ࡚
ኚࡀㄆࡵࡽࢀ࡞ࡗࡓ[79]ࠋࡉࡽ㸪AD ᝈ⪅࠾ࡼࡧ CAD ࣔࢹࣝ≟ࡢ㠀ኚ 㒊⓶࠾࠸࡚㸪ᖖ⓶ẚ㍑ࡋ㸪ච⤌⧊Ꮫࡼࡿ claudin-1ࡢᰁⰍᙉᗘ ࡢపୗࡀㄆࡵࡽࢀ࡚࠸ࡿ[18, 79]ࠋࡇࢀࡽࡢᐇࢆ㚷ࡳࡿ㸪ᮏ◊✲࡛ᚓࡽࢀࡓ
⤖ᯝࡼࡾ㸪IL-13ࡣ㸪ZO-1ࡢⓎ⌧ㄪ⠇┤᥋ⓗ࡞㛵ࢆࡋ࡚࠸࡞࠸୍᪉㸪 claudin-1ࡢⓎ⌧ㄪ⠇㛵ࡋ࡚࠸ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡿࠋ
ࡋࡋ㸪࢝ࣝࢩ࣒࢘ࡼࡾศㄏᑟࡋࡓࣄࢺࢣࣛࢳࣀࢧࢺ࠾࠸࡚㸪IL-13 ࡢῧຍࡼࡾ㸪 claudin-1 ࡢⓎ⌧㔞ࡀቑຍࡍࡿࡇࡀ♧ࡉࢀ࡚࠸ࡿ[18]ࠋࡲࡓ㸪
ࣄࢺࢣࣛࢳࣀࢧࢺࢆ⏝࠸ࡓ୕ḟඖᇵ㣴⓶ࣔࢹࣝ࠾࠸࡚㸪IL-13ࡼࡿ่⃭
ᑐࡋ㸪claudin-1ࡢ㌿㔞࠾ࡼࡧⓎ⌧㔞ࡣኚࢆ♧ࡉ࡞ࡗࡓ[30]ࠋࡇࢀࡽࡢ▩
┪ࡍࡿᐇࡣ㸪⏝࠸ࡓ⣽⬊ࡸᇵ㣴᮲௳㸪࡞ࡽࡧ่⃭᮲௳㸦⃰ᗘ࠾ࡼࡧ่⃭㛫㸧
࡞㉳ᅉࡍࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀ㸪ゎ㔘ࡣὀពࢆせࡍࡿᛮࢃࢀࡿࠋࡲࡓ㸪
TNF-alphaࡲࡓࡣIL-13ࡢῧຍࡼࡾ㸪ᮏࣔࢹ࡛ࣝࡣ୍㒊ࡢᇵ㣴⣽⬊ኚᛶࡀㄆ
ࡵࡽࢀࡓࠋࡋࡓࡀࡗ࡚㸪ᮏ◊✲࡛⏝࠸ࡓᐇ㦂᮲௳ࡘ࠸࡚ࡶ㸪ᚋࢱࣥࣃࢡ㔞ࡢ ᐃ㔞ࡸ่⃭᮲௳ࡢ᳨ウࡀᚲせ⪃࠼ࡽࢀࡓࠋ
ᮏ◊✲࡛ࡣ㸪TNF-alpha࠾ࡼࡧIL-13ࡑࢀࡒࢀࡘ࠸࡚㸪ࢱࢺࢪࣕࣥࢡࢩࣙ
ࣥ࠾ࡅࡿᙳ㡪ࢆホ౯ࡋࡓࠋ⤌⧊ᇵ㣴ࡋࡓࣄࢺࡢ⓶࠾࠸࡚㸪Th2ࢧࢺ࢝
ࣥ (IL-4, IL-5, IL-13) ࠾ࡼࡧTNF-alphaࡼࡿ TSLPࡢ⏘⏕ࡣ㸪Th2ࢧࢺ࢝
ࣥ (IL-4ࡶࡋࡃࡣ IL-13 ࡲࡓࡣ㸪IL-4࠾ࡼࡧ IL-13) ࠾ࡼࡧTNF-alpha ࢆΰྜࡋ
่࡚⃭ࡋࡓሙྜ࠾࠸࡚ࡢࡳㄆࡵࡽࢀࡓ[9]ࠋࡘࡲࡾ㸪Th2 ࢧࢺ࢝ࣥ࠾ࡼࡧ
TNF-alphaࡣCAD ࠾ࡅࡿ⓶චែ㸪┦ຍⓗ࡞స⏝ࢆ᭷ࡍࡿྍ⬟ᛶࡀ⪃
࠼ࡽࢀࡿࠋࡋࡓࡀࡗ࡚㸪ᚋࡢin vitro࠾ࡅࡿ⓶ࣂࣜᶵ⬟◊✲ࡣ㸪่⃭
᮲௳ࡢࡉࡽ࡞ࡿ᳨ウࡀᚲせᛮࢃࢀࡿࠋ
ᮏ◊✲ࡢ⤖ᯝࡽ㸪TNF-alpha࠾ࡼࡧIL-13 ࡣclaudin-1ࡢⓎ⌧ㄪ⠇㛵ࡋ㸪 CAD࠾ࡅࡿࢱࢺࢪࣕࣥࢡࢩࣙࣥࡢࣂࣜᶵ⬟ᙳ㡪ࢆ࠼࡚࠸ࡿྍ⬟ᛶࡀ 㧗ࡲࡗࡓࠋZO-1࠾ࡼࡧclaudin-1CADࡢែࡢ㛵ಀࢆ᫂ࡽࡍࡿࡣ㸪
ࡼࡾ⏕య࠾ࡅࡿኚࢆ࡛ᫎࡁࡿᵝ࡞in vitroࣔࢹࣝࡢ㛤Ⓨࢆྵࡵ㸪ࡉࡽ࡞ࡿ
◊✲ࡀᚲせᛮࢃࢀࡿࠋ
3.5 ᅗ
ᅗ3-1 TNF-alpha࠾ࡼࡧIL-13ࡼࡿᇵ㣴⣽⬊ࡢᙧែኚ
(A) ᇵ ᆅ ࡢ ࡳ 㸪(B) TNF-alpha 5 ng/ml㸪(C) TNF-alpha 50 ng/ml㸪(D) ᇵ ᆅ +0.1%BSA㸪(E) IL-13 5 ng/ml㸪(F) IL-13 50 ng/mlࠋ࣐࣊ࢺ࢟ࢩ࢚ࣜࣥ࢜ࢪࣥᰁⰍࠋ ࢫࢣ࣮ࣝࣂ࣮ࡣ50 μmࢆ♧ࡍࠋ
ᅗ
ᅗ3-2 ᇵ㣴⣽⬊ࡢZO-1࠾ࡼࡧclaudin-1ࡢⓎ⌧࠾ࡅࡿTNF-alphaࡢᙳ㡪 (A, B, C) ZO-1㸪(D, E, F) claudin-1㸪(B, E) TNF-alpha 5 ng/ml㸪(C, F) TNF-alpha
50 ng/mlࠋࢫࢣ࣮ࣝࣂ࣮ࡣ50 μmࢆ♧ࡍࠋ
ᅗ
ᅗ3-3 ᇵ㣴⣽⬊ࡢZO-1࠾ࡼࡧclaudin-1ࡢⓎ⌧࠾ࡅࡿIL-13ࡢᙳ㡪
(A, B, C) ZO-1㸪(D, E, F) claudin-1㸪(B, E) IL-13 5 ng/ml㸪(C, F) IL-13 50 ng/mlࠋ ࢫࢣ࣮ࣝࣂ࣮ࡣ50 μmࢆ♧ࡍࠋ
⥲ ⥲ᣓ
CADࡣ㸪ࣄࢺADྠᵝ㸪Th2⣽⬊ࡑࢀࡼࡾ⏘⏕ࡉࢀࡿTh2ᆺࢧࢺ࢝ࣥᏑᅾୗ࡛㸪⎔ቃࣞࣝࢤࣥᑐࡋ≉␗ⓗ⏘⏕ࡉࢀࡓ IgE ᢠయࡀ⫧‶⣽⬊
⤖ྜࡋ㸪⬺㢛⢏ࢆ㉳ࡇࡍࡇ࡛Ⓨ⮳ࡿ⪃࠼ࡽࢀ࡚࠸ࡿ[53]ࠋTh2⣽⬊ࡢ ศ㐣⛬࠾࠸࡚㸪ࢣࣛࢳࣀࢧࢺࡢ⏘⏕ࡍࡿᾮᛶᅉᏊ࡞ࡽࡧ㸪ゅᒙ࠾ࡼࡧࢱ
ࢺࢪࣕࣥࢡࢩࣙࣥࡽ࡞ࡿ⓶ࣂࣜࡣ㸪㔜せ࡞ᙺࢆᯝࡓࡋ࡚࠸ࡿ⪃࠼
ࡽࢀ࡚࠸ࡿࡀ㸪ヲ⣽ࡘ࠸࡚ࡣ᫂࡞Ⅼࡶከ࠸[3, 50]ࠋࡑࡢࡓࡵ㸪CADࡢែ
࠾ࡅࡿ⓶චࣂࣜᶵ⬟ࡢࡉࡽ࡞ࡿゎ᫂ྥࡅࡓin vitroࢶ࣮ࣝࡋ࡚㸪ᮏ◊
✲࡛ࡣ≟ࢣࣛࢳࣀࢧࢺ⣽⬊ᰴࡼࡾస〇ࡉࢀࡓ୕ḟඖᇵ㣴⾲⓶ࣔࢹࣝὀ┠ࡋ ࡓࠋ
➨㸯❶࡛ࡣ㸪 ≟୕ḟඖᇵ㣴⾲⓶ࣔࢹࣝࢆస〇ࡋ㸪TNF-alpha, TGF-beta, CCL2
࠾ࡼࡧCCL20ࡘ࠸࡚㑇ఏᏊ㌿ゎᯒࢆ⾜࠸㸪≟ࡢṇᖖ⓶ࡢ㢮ఝᛶࢆ༢ᒙ
ᇵ㣴ẚ㍑ࡋࡓࠋ୕ḟඖᇵ㣴࠾ࡼࡧ⓶࠾࠸࡚ࡣ㸪࡚ࡢࢧࢺ࢝ࣥ㑇ఏᏊ ࡢ㌿ࡀㄆࡵࡽࢀࡓࠋࡲࡓ㸪TNF-alpha, CCL2࠾ࡼࡧCCL20ࡣ㸪࠸ࡎࢀࡶ༢ᒙᇵ 㣴ẚ㸪⓶㢮ఝࡋࡓ㌿ࣃࢱ࣮ࣥࢆ♧ࡋࡓࠋࡇࢀࡼࡾ㸪ᮏࣔࢹࣝࢆ⏝࠸
ࡓࢧࢺ࢝ࣥࡢ㌿ゎᯒࡣ㸪༢ᒙᇵ㣴ᑐࡋඃᛶࢆᣢࡘࡇࡀ♧၀ࡉࢀࡓࠋ ➨㸰❶࡛ࡣ㸪ᮏࣔࢹࣝ࠾ࡅࡿ ZO-1 ࠾ࡼࡧ claudin-1 ࡢⓎ⌧ࡘ࠸࡚㸪ච
⤌⧊Ꮫࢆ⾜࠸㸪≟ࡢṇᖖ⓶ࡢẚ㍑ࢆ⾜ࡗࡓࠋᮏࣔࢹࣝ࠾࠸࡚ ZO-1 ࡣ㸪
⓶㢮ఝࡋࡓᰁⰍࣃࢱ࣮ࣥ࠾ࡼࡧᒁᅾࢆ♧ࡋ㸪⣽⬊㉁ࢆ୰ᚰࡋࡓⓎ⌧㸪ゅ ᒙᵝᒙࢆ㝖ࡃ࡚ࡢᒙ࠾ࡅࡿⓎ⌧ࡀㄆࡵࡽࢀࡓࠋclaudin-1 ࡣ㸪⓶㢮ఝࡋ ࡓ⻏ࡢᕢ≧ࡢᰁⰍࣃࢱ࣮ࣥࢆ♧ࡋࡓࠋࡲࡓ㸪⓶࠾࠸࡚ゅᒙࢆ㝖ࡃ࡚ࡢᒙ࡛
Ⓨ⌧ࡀㄆࡵࡽࢀࡓࡢᑐࡋ㸪ᮏࣔࢹ࡛ࣝࡣ㢛⢏ᒙᵝᒙࡽ᭷Ჲᒙᵝᒙࡢୖᒙ
㝈ᒁࡋ࡚Ⓨ⌧ࡀㄆࡵࡽࢀࡓࠋࡇࢀࡽࡢ⤖ᯝࡼࡾ㸪㢛⢏ᒙ࠾ࡅࡿࢱࢺࢪࣕࣥࢡ ࢩࣙࣥ◊✲࠾࠸࡚㸪ᮏࣔࢹࣝࡀ᭷⏝࡞ࢶ࣮ࣝ࡞ࡿྍ⬟ᛶࡀ♧ࡉࢀࡓࠋ ➨㸱❶࡛ࡣ㸪ᮏࣔࢹࣝࢆ⏝࠸࡚ ZO-1 ࠾ࡼࡧ claudin-1 ࠾ࡅࡿ TNF-alpha ࠾
ࡼࡧ IL-13 ࡢཬࡰࡍᙳ㡪ࢆホ౯ࡋࡓࠋTNF-alpha ࡲࡓࡣ IL-13 ࡢ่⃭ࡼࡾ㸪
claudin-1ࡢⓎ⌧ᙉᗘࡢపୗࡀㄆࡵࡽࢀࡓࠋ୍᪉㸪ZO-1ࡢⓎ⌧ኚࡣㄆࡵࡽࢀ
࡞ࡗࡓࠋࡋࡓࡀࡗ࡚㸪TNF-alpha࠾ࡼࡧIL-13ࡣ㸪claudin-1ࡢⓎ⌧ㄪ⠇㛵
ࡋ㸪ࢱࢺࢪࣕࣥࢡࢩࣙࣥࡢࣂࣜᶵ⬟ᙳ㡪ࢆ࠼࡚࠸ࡿࡇࡀ♧၀ࡉࢀࡓࠋ ᮏ◊✲ࡢ⤖ᯝࡽ㸪≟ࢣࣛࢳࣀࢧࢺ⣽⬊ᰴࢆ⏝࠸࡚స〇ࡋࡓ୕ḟඖᇵ㣴⾲
⓶ࣔࢹࣝࡢᣢࡘචࣂࣜᶵ⬟ࡣ㸪⓶㢮ఝࡋࡓᛶ㉁ࢆ᭷ࡋ࡚࠸ࡿࡇࡀ᫂
ࡽ࡞ࡗࡓࠋࡋࡓࡀࡗ࡚㸪ᮏࣔࢹࣝࡣ≟ࢣࣛࢳࣀࢧࢺ࠾ࡅࡿ㸪⿕㦂ᑐ㇟ࡢ
⏕⌮Ꮫⓗᶵ⬟◊✲ࡸࢱࢺࢪࣕࣥࢡࢩࣙࣥࡢᙳ㡪ホ౯㸪᭷⏝࡞ࢶ࣮ࣝ࡞
ࡿྍ⬟ᛶࢆᣢࡘ⪃࠼ࡽࢀࡿࠋࡲࡓ㸪CAD࠾ࡅࡿ⓶ࣂࣜᶵ⬟㞀ᐖࡘ࡞
ࡀࡿཎᅉࡋ࡚㸪TNF-alpha࠾ࡼࡧIL-13ࡼࡿclaudin-1ࡢⓎ⌧ㄪ⠇ࡀ㛵ࡋ࡚
࠸ࡿࡇࡀ♧၀ࡉࢀࡓࠋᚋࡣ㸪㛵㐃ศᏊࡘ࠸࡚ࡉࡽᗈ⠊࡞ከゅⓗ◊✲ࡀᚲ せᛮࢃࢀࡿࠋࡲࡓ㸪⋓ᚓචᛂࡢึᮇ࠾࠸࡚ࡣ㸪ࢣࣛࢳࣀࢧࢺᢠཎᥦ
♧⣽⬊ࡢ┦స⏝ࡀ㔜せ࡛࠶ࡿ⪃࠼ࡽࢀࡿࠋࡋࡓࡀࡗ࡚㸪ᵝࠎ࡞ᾮᛶᅉᏊࢆ
ࡋ࡚」㞧ែ㛵ࡋ࡚࠸ࡿࢣࣛࢳࣀࢧࢺᢠཎᥦ♧⣽⬊ࡢࢡࣟࢫࢺ
࣮ࢡࢆ┤᥋ホ౯࡛ࡁࡿࣔࢹࣝࡋ࡚㸪ᮏࣔࢹࣝࡣᑗ᮶ⓗ㸪ᢠཎᥦ♧⣽⬊ࡢඹ ᇵ㣴ࡼࡿ⾲⓶ࣔࢹࣝࡢⓎᒎࡀᮇᚅࡉࢀࡿࠋ
ㅰ ㅰ㎡
ᮏ◊✲ࢆ⾜࠺㝿ࡋ࡚㸪⤊ጞ᠓⠜࡞ࡿᚚᣦᑟࢆཷࡅ㈷ࡾࡲࡋࡓᒱ㜧Ꮫᛂ⏝⏕≀⛉Ꮫ㒊⋇་⮫ᗋᨺᑕ⥺Ꮫ◊✲ᐊࡢ๓⏣㈆ಇᩍᤵ㸪⚄ᚿ㑣ᘯ᫂ᩍᤵ㸪す⏣ⱥ 㧗ຓᩍ㸦⌧ 㜰ᗓ❧Ꮫ⏕⎔ቃᏛ◊✲⛉ᩍᤵ㸧῝⏒࡞ࡿឤㅰࢆ⏦ࡋୖࡆ
ࡲࡍࠋ
ᮏ✏ࡢసᡂ㝿ࡋ࡚㸪ࡈ⢭ㄞ࠸ࡓࡔࡁ㸪ࡈᣦᑟࡈ㠴᧡ࢆ㈷ࡾࡲࡋࡓᰝࡢᒱ㜧
Ꮫ ᰘ⏣᪩ⱑᩍᤵ㸪ᰝࡢᖏᗈ␆⏘Ꮫ ⊦⇃ኖᩍᤵ㸪ᒾᡭᏛ ᒣ㷂┿ᩍᤵ
࠾ࡼࡧᮾி㎰ᕤᏛ す⸨බྖᩍᤵᚰࡼࡾឤㅰࢆ⏦ࡋୖࡆࡲࡍࠋ
ᮏ◊✲㐙⾜࠶ࡓࡾ㸪ᐇ㦂ჾලࢆᛌࡃ⏝ࡉࡏ࡚㡬ࡁࡲࡋࡓ⋇་⌮Ꮫ◊✲
ᐊࡢᰡᚨ☻ᩍᤵ㸪㓇ὒᶞᩍᤵ࡞ࡽࡧྠ◊✲ᐊࡢⓙᵝ῝ㅰ࠸ࡓࡋࡲࡍࠋ ᪥㡭ࡼࡾ᭷┈࡞ࡿᚚຓゝከ࡞ࡿᚚ༠ຊࢆ㡬ࡁࡲࡋࡓ⋇་⮫ᗋᨺᑕ⥺Ꮫ◊
✲ᐊࡢᢏ⾡⿵బဨࡢⓙᵝ࠾ࡼࡧᏛ⏕ࡢⓙᵝᚰࡼࡾឤㅰ࠸ࡓࡋࡲࡍࠋ
Ꮫ㝔࡛ࡢ◊✲ᑐࡋ࡚㸪ࡈ⌮ゎ᪥ࠎࡢᴗົ࠾࠸࡚ከ࡞ࡿࡈ༠ຊࢆ㈷
ࡾࡲࡋࡓᑎᮏື≀㝔ࡢࢫࢱࢵࣇࡢⓙᵝ㸪㐍Ꮫᑐࡋ࡚ࡈ⌮ゎ㸪ᚚຓゝ࠾ࡼࡧᝰ ࡋࡳ࡞࠸ᚚᨭࢆ㈷ࡾࡲࡋࡓ୧ぶ࠾ࡼࡧᐙ᪘ᚰࡼࡾ῝ㅰ࠸ࡓࡋࡲࡍࠋ
ཧ ཧ⪃ᩥ⊩
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