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IRF-1-mediated IFN-γ enhancement of TRAIL-induced apoptosis

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(1)³¤¥“Èó. * F* a. (2004) 44 2 Korea J Vet Res(2004) 44(2) : 195~200. 53"*-Fê^Ҟö®ÚB*'/γö~‚Ã&V*’ *3'"~&NW. ;ç *ÁJÒöÁšFêÁ;Cê Áfž Á;;S Áj&C Á–«ê . . . . . . *§&v >~"&, Ún;W’², »ÖVF’² (²Òߞ: 2004j 4ú 17¢) 1. 2. IRF-1-mediated IFN-γ enhancement of TRAIL-induced apoptosis Sang-Youel Park1*, Jae-Won Seol, You-Jin Lee, Seog-Jin Kang2, In-shik Kim1, Hyung-sub Kang1, Joon-seok Chae1, and Jong-Hoo Cho1 College of Veterinary Medicine, 1Bio-Safty Research Institute, Chonbuk National University, Jeonju 561-756, Korea 2 National Livestock Research Institute, Cheonan 330-801, Korea (Accepteda April 17, 2004) Abstract : Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family and potent inducer of apoptosis. TRAIL has been shown to effectively limit tumor growth in vivo without detectable cytotoxic side effects. Interferon (IFN)-γ often modulates the anti-cancer activities of TNF family members including TRAIL. We previously reported that IFN-γ enhanced TRAIL-induced Apoptosis in HeLa cells without the unknown mechanism. In this study, we investigated whether IRF-1 involves in IFN-γ-enhanced TRAIL-induced apoptosis. We exposed HeLa cells to IFN-γ for 12 hours and then treated with recombinant TRAIL protein. No apoptosis was induced in cells pretreated with IFN-γ, and TRAIL only induced 30% apoptosis after 3 hours treatment. In HeLa cells pretreated with IFN-γ, TRAIL induced cell death to more than 75% at 3 hours, showed that IFN-γ-pretreatment enhanced HeLa cell death to TRAILinduced apoptosis. To investigate the functional role of IRF-1 in IFN-γ-enhanced TRAIL-induced apoptosis, IRF-1 was overexpressed by using an adenoviral vector AdIRF-1. IRF-1 overexpression increased apoptotic cell death and significantly enhanced apoptotic cell death induced by TRAIL when infected cells were treated with TRAIL. Our findings show that IFN-γ enhances TRAIL-induced apoptosis by IRF-1 in HeLa cells. Key words : IFN-γ, TRAIL, IRF-1, HeLa. B †. ~ £Ú‚Ž 7ö ‚ ª~>– ~ ^Ҟj Fê~º Wîj ~‚. f ^ ‚šö šÒ~ º &N >ÏÚ ¯  Ò f ֏Žb‚Ž ^Ò ž ^ *ê¢ –. 5 ‚WzB ^Ҟj Fê inducing ligand Tumor Necrosis Factor (TNF) family type II transmembrane cytokine molecule , ligand-type [1, 7, 18, 30]. TRAIL TRAIL , Death Receptor-4 (DR-4), Death Receptor-5 (DR-5), Decoy Receptor-1 (DcR-1) Decoy Recepter-2 (DcR-2) ,. ^Ҟ)¦ ^¶ö ~š –.>Úæ – Ö Ëÿ'ž ^ #r ";~ ~¾‚ rJ^ ®. 6‚ š ";f ·‚ ^ ‚ šÚê V& ~ " z  “çWj Fæ~ WË" ªz  B ";ö ®ÚB Ö 7º‚ †j ~º ©b‚ ¾ rJ^ ® [12]. TRAILf TNF-related apoptosisApoptosis( , .. š ¢^f 2003jê vò‚“ 21Òëö ~~ æö>îr š ¢^f 2002jê *§&v æö ’jö ~~ ’>îr *Corresponding author: Sang-Youel Park College of Veterinary Medicine, Chonbuk National University, Jeonju 561-756, Korea [Tel: 82-63-270-3886, Fax: 82-63-270-3780, E-mail: sypark@chonbuk.ac.kr]. 195.

(2) ;çÁJÒöÁšFêÁ;CêÁfžÁ;;SÁj&CÁ–«ê. 196. ~º ©b‚ rJ^ ® . TRAILf ß® z^öò ß š'b‚ ·Ï~ ^Ҟj Fê~º ©b‚ > Ú ®b–, ;ç^öBº jZ ëWš ìº ©b‚ ¾æ¾, î‚Ú «· ~òB‚B ôf ’& ê¯7 š . Interferon-gamma (žV¾† 6î, IFN-γ)º T ^¾ NK ^‚¦V ªj>Úæ–, :šÊ~ B ÛB¾ & &N ^ ~ Ãj ÛB~º  ·‚ VËj &æ ®º ©b‚ 6Ò rJ^ ® [8, 13, 14]. 6‚ žV¾† 6îº Fas j Ž‚ ·‚ ^ҞFê ž¶ ö &‚ ^~ 6>Wj Ã&Úb‚Ž, ž¶. ö ~‚ ^Ҟj Ã;ʺ †j ~º ©b‚ >î [22]. ‚" ’¶ ~  [2, 17, 19, 31] ö ~~š, žV¾† 6îº TNF¾ TRAIL" 7K~ «·^ö &‚ ^ҞËj Ã&ʺ ©b‚  >Ú «· &N ’¶ ~ &š –> ®b¾,  «{‚ V*f jçræ j*® C&ææ p ®º. ;š . ‚Þ, *Җ.ž¶, interferon regulatory factor (IRF)1f žV¾† 6îö &‚ ^ ^ *êöB · ‚ F*¶~ *Ò¢ –.~º ž¶‚B ¾ rJ^ ®b –, «· ÛBVËj &æ ®º ©b‚ ‚"~ ’. ö ~š C&æ ® [3-5, 23, 24, 32]. Tamura  [27, 28]~ ’ö ~~š T lymphocyteöB DNA ¶çö ~ ‚ ^ҞöBº IRF-1š jº~–, Ö ~š'š¢  >î . V¢B  ’¶ f š® ’¢ Û~ HeLa ^ ö &‚ žV¾† 6î~ ^ҞË~ Ã;j {ž ~,  V*" IRF-1"~ &NWj –Ò~¶ ~&. . ß®, IRF-1 Wîj "B* Ò > ®º adenovirus ÇV¢ šÏ~ žV¾† 6î& TRAIL ^Ҟ à ; Î"f ?f Î"¢ šºæ –Ò~& .. Òò 5 O». ^" 5 ^V·  þöB ÒÏB HeLa, CRE Ò 293 ^" ¢ ATCC‚¦V / Aj ÒÏ~& . ^~ WË F æ¢ *šB 100 µg/ml gentamicin" 100 µg/ml penicillinstreptomycinš ŽB “Bf 10%(V/V) fetal bovine serumš Î&B Væö 5% CO ¢ /~šB 37 C‚ V·V . ^~ šË G; z^~ šËj G;~V *šB ^¢ 12-well plateö 1.0Ü10 š >² ' wellö If r 5% CO , 2. 4. o. 2. çöB 24* V·~& . 12-well plateöB à ‚ ^ö IFN-γ (100 U/ml) (Roche, Germany)¢ * ¾Ò~ 12* êö Җ TRAIL [20] Wîj ¾ ҂ r 3* ÿn z V·~& . ^~ šË G ;f crystal violet "ï O» [16]ö ~š ¦Ò~& , ^~ ;¢ *ã ~öB &V‚ ê Òêb ‚ R'~& . ^~ šË G;O»f ^¢ 30% ethanol" 3% formaldehyde& Ú ®º 0.5% crystal violetb‚ NöB 10ª* "ï~ všº böB 4² ^¿‚ ê š–V . š–B êö ^¢ 1% SDS χb‚ ϚBB 550 nmöB ‡7ê¢ G; ~& . 37oC. 8FTUFSO #MPUUJOH. B* Wîj {ž~V *~ Western blottingj. ~& [15, 21]. þÏ'ö ² ¾ÒB ^¢ scraper¢ šÏ~ Îj, PBS‚ ^¿‚ ê Îjê ^ ö ^Ϛ‡(25 mM HEPES, pH 7.4, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl , 0.1 mM DTT, and protease inhibitor mixture)j IÚ ¦FÎ ê ârö 30ª* O ~~ .r2 ªê~& . Wî~ ª¶ïö ² 12~15% SDS-PAGE¢ šÏ~ Wîj ªÒ~ nitrocellulose membraneö transfer ~& . TransferB membranej blocking, primary antibody, secondary antibody BB‚ '' 1* ÿn V·‚ ê, super-signal kit (Pierce, USA)¢ šÏ~ ¦ï~& .  þö Òς FADD, IAP-1, IAP-2, Bcl-2, BclXL 5IRF-1(sc-497) ~ antibodyº Santa Cruz (Santa Cruz, USA)öB ’«~&, DR-4, DR-5º Stressgen (Victoria, Canada)öB ’«~ ÒÏ~& . 2. "EFOPWSJBM WFDUPS. j–ž:šÊ~ Ã" ?"^~ š &N ¦* ž E1 F*¶ ¦*f E3 F*¶ ¦*¢ B–Î AdIRF1f Hardy  [6]~ O»ö &~ Cre-lox Җj Û ~ ò Úr . º£~š, CMV promoter‚ ·šB SV40 polyA signal‚ ƒ¾º IRF-1š¾ enhanced green fluorescence protein (EGFP)¢ òº cDNAö pAdloxIRF-1š¾ pAdlox-EGFP¢ ò V *š shuttle vectorž pAdlox¢ ã«~& . ҖB adenovirusº '.~² – ·B pAdlox-IRF-1š¾ pAdlox-EGFPf Cre recombinase ~ B*ö ~š Ad packing cell linež CRE8~ ψ5 helper virus DNA¢ cotransfection ~ B·~& . ҖB adenovirusº 293 ^"öB ÃV, cesium chloride ¢ šÏ‚ &ê ’V öªÒö ~š ªÒ~ ;B~ & ..

(3) TRAIL. Fê ^Ҟö ®ÚB IFN-γ ö ~‚ Ã& V* ’: IRF-1"~ &NW. 197. "EFOPWJSJBM *OGFDUJPO. ^¢ ö ª"‚ rÆ ¢ 6"V. 6"f ö~º ö ² free OptiVæö b~ ^ö 4* ÿ n ¾Ò~& 6" Î ^¢ ‚ ² aÚ ".  & Î&B VæöB V·~& . 6" B ^¢ *ÿn j ¾Ò‚ ê crystal "ï O» b‚ ^ šË ¦Ò¢ ~&. ^~ ;º *ã ~öB ¦Ò~šB R'~&. j ¾Ò‚ ^öB Wî~ B*f j šÏ~ –Ò~&. HeLa 6~12 well plate adenovirus . Adenovirus multiplicity of infection (MOI 0-40) MEM I (Gibco, USA) . PBS 3 FBS F-12K HeLa 3 TRAIL violet [17] . . AdIRF-1 IRF-1 Western blotting .. Ö" 5 V *'/  γ. JODSFBTFE. 53"*-. BDUJWJUZ. GPS. )F-B. DFMM. BQPQUPTJT. žV¾† 6îº T ^¾ NK ^‚¦V ªj>Ú æ–, :šÊ~ B ÛB¾ & &N ^ ~ à j ÛB~º  ·‚ VËj &æ ® [8-11]. ž V¾† 6îö ~‚ TRAIL Fê ^Ҟ Ã;·Ïj {ž~V *‚ Ñ® þj ~& . HeLa ^ö žV¾† 6î¢ 100 U/ml~ ³ê‚ 12* ÿn *¾ Ò ‚ ê, ¢>'ž TRAIL 'Ï ³êž 100 ng/ml~ ³ ê‚ ¾Ò~  3* ÿn V·~ ^ šË j G;~& (Fig. 1A, B). žV¾† 6î¢ ¾Ò‚ ^ öBº ^ Ҟö &š jZ 'Ëj ~æ pj šË ¦ÒöBê &––" jZ Nš¢ šæ p ~ . ¾ TRAILj ëb‚ ¾Ò‚ ^öBº £ 80%~ ^ šËj &b–, žV¾† 6î¢ *¾ Ò~ TRAILj ¾Ò‚ ^öBº 60%~ šËj &æº ©b‚ G;>î .  þj Û~ HeLa ^ öB žV¾† 6îö ~š TRAIL Fê ^Ҟš 2V šç Ã&>îrj r > ®î . *'/  γ. TUJNVMBUFE. )F-B DFMM. *3'. QSPUFJO. FYQSFTTJPO. JO. žV¾† 6î~ TRAIL ‚W Ã&ö ®ÚB IRF-1~ †ö &š –Ò~V *~ žV¾† 6îf TRAIL j ¾Ò‚ ê IRF-1 Wî~ B* ;ê¢ –Ò~& . V·B HeLa ^ö žV¾† 6î(100 U/ml)¢ 12 * *¾Ò~, TRAIL(100 ng/ml)j 1* ¾Ò‚ ê HeLa ^öB~ IRF-1 Wî æzçj Western blotting j ~ –Ò~& (Fig. 2). Fig. 2öBf ?š žV ¾† 6î¢ ¾Ò‚ HeLa ^öB IRF-1~ B*ïf žV¾† 6î¢ ¾Ò~æ pf ^öB  *&‚. Fig. 1. Effect of IFN-γ on TRAIL-induced apoptosis. (A) HeLa cells plated in 12-well were pretreated with IFN-γ (100 U/ml) for 12 hours, and then coincubated with or without recombinant TRAIL protein (100 ng/ml) for additional 3 hours. Cell viability was determined by crystal violet staining method. Viability of control cells was set at 100%, and viability relative to the control was presented. The experiments were performed at triplicate, at least twice. The bar indicates standard error. (B) Cell morphology under the conditions as described in (A) was photographed (×200).. Ã&¢ {ž† > ®îb–, TRAILö ~‚ IRF-1~ B *ï~ æzº "æ p~ .  þ~ Ö" žV¾ † 6îö ~‚ TRAIL~ ^Ҟ Ã; V*ö ®ÚB IRF-1 Wîš 7º‚ †j ~º ©b‚ 6>î. . 6‚ DR-4, DR-5, FADD, IAP-1, IAP-2, Bcl-2, BclXL , TRAILö ~‚ ^Ҟö ç7 &N>Ú TRAIL ~ ^Ҟ ‚Wj –.~º Wî ~ B*ï æz ¢ –Ò~&b¾ IRF-1j Bž~º žV¾† 6î¢ ¾Ò‚ ^f ¾Ò~æ pf ^Қö F~W ®º æz¢ &V~æ á~& (Data not shown). V¢B žV¾† 6îö ~‚ TRAIL~ ^ Ҟ à ; V*ö IRF-1 Wîš "º –.¶‚B †j ~ º ©b‚ ê . 0WFSFYQSFTTJPO PG *3' QSPUFJO CZ "EFOPWJSBM 7FDUPST. ö ~‚ “z Î" " &NB ’ Ö" [24-28,. IRF-1.

(4) 198. ;çÁJÒöÁšFêÁ;CêÁfžÁ;;SÁj&CÁ–«ê. Fig. 2. Expression of IRF-1 protein. HeLa cells were pretreated with IFN-γ (100 U/ml) for 12 hours, and then coincubated with or without recombinant TRAIL protein (100 ng/ml) for 1 hour. Whole cell lysates were prepared as described in experimental procedures and subjected to Western blotting analysis.. š B‚>Úæ ® . Tanaka  [27, 28]f *Ò –.ž¶ž IRF-1š c-mycš¾ fosBö ~‚ ^~ ; î*~j ÛB‚  ~&b–, DNA ¶çö &‚ >wb‚ ‚Wz >º p53 Wî" «· ÛBž¶‚B IRF-1"~ 7K·Ïö &š ~, IRF-1ö &‚ “ z ~òB‚B~ &ËWj "î [3, 5, 24, 26, 29].  ’¶ f IRF-1~ "B* O»j wÏ~ IRF1" TRAIL"~ &NWj ;ã~¶ ~& . b& IRF1 Wîj "B* Ò > ®º ÇV¢ adenovirusö ã «~&b–, &––b‚B EGFP B* ÇV¢ 㫂 AdEGFPf AdIRF-1j HeLa ^ö 6"B ^  šË ¦Ò¢ ~& .  Ö" AdIRF-1 ¾Ò–öB º MOI~ æzö Ö ~š'ž ^Ҟ Î"¢ & b–, &––ž AdEGFP ¾Ò–öBº F~W ®º æ z¢ " > ìî (Fig. 3A). ¯, AdIRF-1j 5, 10, 20, 40 MOI ê‚ ¾Ò~&jr, '' 5%, 12%, 18%, 25% ~ ^Ҟ Î"¢ "î . ¾ ‚& AdEGFP ¾Ò–ž 40 MOIöBº B> &––ö jš F~W ® º ^Ҟ~ æzê "æ p~ . 6‚ AdIRF-1 ~ TRAILö &‚ Î"¢ ¦Ã~V *š AdIRF-1j ¾ ҂ ^ö  TRAILj ¾Ò~ šË ¦Ò¢. ~& (Fig. 3A). TRAILj ëb‚ ¾Ò‚ ^f AdEGFP¢ ¾Ò‚ ^öBº £ 20% ;ê~ ^Ò žš ¢ÚÒb¾, TRAIL" AdIRF-1j  ¾Ò‚ ^ öBº AdIRF-1~ MOIö Ö ~š'b‚ ^Ҟ š ¢ÚÒrj {ž† > ®î . AdIRF-1 ‚& ¾Ò MOIž 40 MOIöBº AdIRF-1 ë ¾Ò 25%&~ ^Ҟš TRAIL"~ ¾ÒöBº 52%‚ 2V š ç~ ^Ҟj & (Fig. 3A). AdIRF-1ö ~‚ IRF1 Wî~ B*f Western blottingj šÏ~ {ž~ & (Fig. 3B).  Ö" AdIRF-1j 5, 10, 20, 40 MOI ê ‚ ¾Ò‚ ^öB IRF-1 Wîf MOI ~š'b‚ "B*š ¢ÚÒrj {ž† > ®î (Fig. 3B). « 32]. Fig. 3. Effect of IRF-1 overexpression on TRAIL-induced apoptosis. (A) HeLa cells were infected with AdEGFP or AdIRF-1 for 4 hours, washed, and further cultured. 24 hours later, recombinant TRAIL protein (100 ng/ml) was added to culture medium and incubated for 3 hours. Cell viability was determined by crystal violet staining method. Viability of control cells was set at 100%, and viability relative to the control was presented. The experiments were performed at triplicate, at least twice The bar indicates standard error. (B) HeLa cells were infected with AdEGFP or AdIRF-1 for 4 hours, washed, and further cultured. 24 hours later, whole cell lysates were prepared and subjected to Western blotting analysis for IRF-1 expression. The loading indicates a nonspecific protein band that was used to ensure equal protein loading.. ~š, HeLa ^öB IRF-1 Wî B* Ã&º IRF-1 ö ~‚ ç7'ž ^Ҟj Ã&Vj öò jî¢, TRAILö ~‚ ^Ҟö –.¶‚B ·Ï~ TRAIL ö ~‚ ^Ҟj *&~² Ã&V . šº Suk  [23]š ‚ žV¾† 6îf TNF-αö ~‚ “ê·Ï ö IRF-1 ã‚& "º †j ‚ º ’ Ö"fê ¢ ~~º ÚϚ .  ’ Ö"¢ º£~¶š, HeLa ^öB žV¾† 6îº TRAIL Fê ^Ҟj *&~² Ã&Vb –, žV¾† 6î¢ ¾Ò‚ ^öB *Җ.ž¶ž IRF-1 Wî~ *&‚ Ã&¢ {ž~& . IRF-1 W î~ †j ç7 {ž~V *~, HeLa ^ö IRF-.

(5) TRAIL. Fê ^Ҟö ®ÚB IFN-γ ö ~‚ Ã& V* ’: IRF-1"~ &NW. Wîj "B* Vb–,  TRAILj ¾Ò~&. .  Ö" žV¾† 6î¢ ¾Ò~&j rf FÒ~² TRAIL Fê ^Ҟš *&~² Ã&>îrj {ž~ & . š‚ ’ Ö"º žV¾† 6îö ~‚ TRAIL ~ ^Ҟ Ã&ö &‚ IRF-1~ pf &NWj B ~&b–, Ëê IRF-1ö ~‚ “z ~òB~ BBö V . ¶ò¢ B† > ®j ©b‚ 'B . ß® IRF1 Wîj šÏ‚ F*¶ ~ò ª¢f IRF-1 Wî" TRAILj šÏ‚ ~ò~ &ËWj B† > ®j ©b‚ ÒòB .. 1. ^^ò. 1. Cha, S. S., Kim, M. S., Choi, Y. H., Sung, B. J., Shin, N. K., Shin, H. C., Sung, Y. C. and Oh, B. H. 2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity. Immunity. 1999, 11, 253-261. 2. Fish, S. M., Proujansky, R. and Reenstra, W. W. Synergistic effects of interferon gamma and tumour necrosis factor alpha on T84 cell function. Gut. 1999, 45, 191-198. 3. Fujita, T., Kimura, Y., Miyamoto, M., Barsoumian, E. L. and Taniguchi, T. Induction of endogenous IFNalpha and IFN-beta genes by a regulatory transcription factor, IRF-1. Nature. 1989, 337, 270-272. 4. Fujita, T., Sakakibara, J., Sudo, Y., Miyamoto, M., Kimura, Y. and Taniguchi, T. Evidence for a nuclear factor(s), IRF-1, mediating induction and silencing properties to human IFN-beta gene regulatory elements. EMBO J. 1988, 7, 3397-3405. 5. Harada, H., Kitagawa, M., Tanaka, N., Yamamoto, H., Harada, K., Ishihara, M. and Taniguchi, T. Antioncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science. 1993, 259, 971974. 6. Hardy, S., Kitamura, M., Harris-Stansil, T., Dai, Y. and Phipps, M. L. Construction of adenovirus vectors through Cre-lox recombination. J. Virol. 1997, 71, 1842-1849. 7. Hymowitz, S. G., Christinger, H. W., Fuh, G., Ultsch, M., O’Connell, M., Kelley, R. F., Ashkenazi, A. and de Vos, A. M. Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol. Cell. 1999, 4, 563-571. 8. Kakimi, K., Guidotti, L. G., Koezuka, Y. and Chisari, F. V. Natural killer T cell activation inhibits. 9.. 10.. 11.. 12. 13.. 14.. 15.. 16.. 17.. 18.. 19.. 199. hepatitis B virus replication in vivo. J. Exp. Med. 2000, 192, 921-930. Kim, K. B., Choi, Y. H., Kim, I. K., Chung, C. W., Kim, B. J., Park, Y. M. and Jung, Y. K. Potentiation of Fas- and TRAIL-mediated apoptosis by IFN-gamma in A549 lung epithelial cells: enhancement of caspase8 expression through IFN-response element. Cytokine. 2002, 20, 283-288. Kirkwood, J. M. and Ernstoff, M. S. Role of interferons in the therapy of melanoma. J. Invest. Dermatol. 1990, 95, 180S-184S. Kirkwood, J. M., Ernstoff, M. S., Trautman, T., Hebert, G., Nishida, Y., Davis, C. A., Balzer, J., Reich, S., Schindler, J. and Rudnick, S. A. In vivo biological response to recombinant interferon-gamma during a phase I dose-response trial in patients with metastatic melanoma. J. Clin. Oncol. 1990, 8, 10701082. Nagata, S. Apoptosis by death factor. Cell. 1997, 88, 355-365. Nunokawa, Y. and Tanaka, S. Interferon-gamma inhibits proliferation of rat vascular smooth muscle cells by nitric oxide generation. Biochem. Biophys. Res. Commun. 1992, 188, 409-415. Orange, J. S., Wolf, S. F. and Biron, C. A. Effects of IL-12 on the response and susceptibility to experimental viral infections. J. Immunol. 1994, 152, 1253-1264. Park, S. Y. and Seol, D. W. Regulation of Akt by EGF-R inhibitors, a possible mechanism of EGF-R inhibitor-enhanced TRAIL-induced apoptosis. Biochem Biophys. Res. Commun. 2002, 295, 515-518. Park, S. Y., Billiar, T. R. and Seol, D. W. Hypoxia Inhibition of Apoptosis Induced by Tumor Necrosis Factor- Related Apoptosis-Inducing Ligand (TRAIL). Biochem. Biophys. Res. Commun. 2002, 291, 150-153. Park, S. Y., Billiar, T. R. and Seol, D. W. IFN-γ Inhibition of TRAIL-Induced IAP-2 Upregulation, a Possible Mechanism of IFN- γ-Enhanced TRAILInduced Apoptosis. Biochem. Biophys. Res. Commun. 2002, 291, 233-236. Pitti, R. M., Marsters, S. A., Ruppert, S., Donahue, C. J., Moore, A. and Ashkenazi, A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J. Biol. Chem. 1996, 271, 12687-12690. Sasagawa, T., Hlaing, M. and Akaike, T. Synergistic.

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Taken together, these results suggested that latex containing the ficin inhibited the cell growth and induced apoptosis by caspase and Bcl-2 family signaling pathway in

iMSC‑EVs decreased itching, which was supported by reduced inflammatory cell infiltration and mast cells in AD mouse skin; reduced IgE receptor expression and

□ The least-upper-bound property (sometimes called completeness or supremum property) is a fundamental property of the real number system. The least-upper-bound

□ The least-upper-bound property (sometimes called completeness or supremum property) is a fundamental property of the real number system. The least-upper-bound

이것은 가 위로 유계가 아니라는 문제의 가정에 모순이다... 유리수의

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하지만 여기서는 항번호가 자연수인 경우만 증명 하였다... 그러므로