0 17 Immunosuppressant Immunosuppressant NNP 18 23 PG490 PG490 NNP 24 25 ( ( ( 25 35 triptolide triptolide NN 35 36 ) ) ) 37 45 inhibits inhibit VBZ 46 52 T-cell t-cell NN 53 66 interleukin-2 interleukin-2 NN 67 77 expression expression NN 78 80 at at IN 81 84 the the DT 85 90 level level NN 91 93 of of IN 94 112 purine-box/nuclear purine-box/nuclear JJ 113 119 factor factor NN 120 122 of of IN 123 132 activated activate VBN 133 140 T-cells T-cell NNP 141 144 and and CC 145 154 NF-kappaB NF-kappaB NNP 155 170 transcriptional transcriptional JJ 171 181 activation activation NN 181 182 . . . 184 189 PG490 PG490 NNP 190 191 ( ( ( 191 201 triptolide triptolide NN 201 202 ) ) ) 203 205 is be VBZ 206 207 a a DT 208 217 diterpene diterpene NN 218 228 triepoxide triepoxide NN 229 233 with with IN 234 240 potent potent JJ 241 258 immunosuppressive immunosuppressive JJ 259 262 and and CC 263 279 antiinflammatory antiinflammatory JJ 280 290 properties property NNS 290 291 . . . 292 297 PG490 PG490 NNP 298 306 inhibits inhibit VBZ 307 324 interleukin(IL)-2 interleukin(il)-2 NN 325 335 expression expression NN 336 338 by by IN 339 345 normal normal JJ 346 351 human human JJ 352 362 peripheral peripheral JJ 363 368 blood blood NN 369 380 lymphocytes lymphocyte NNS 381 391 stimulated stimulate VBN 392 396 with with IN 397 404 phorbol phorbol NN 405 417 12-myristate 12-myristate NN 418 428 13-acetate 13-acetate NN 429 430 ( ( ( 430 433 PMA PMA NNP 433 434 ) ) ) 435 438 and and CC 439 447 antibody antibody NN 448 450 to to TO 451 454 CD3 CD3 NNP 455 456 ( ( ( 456 460 IC50 IC50 NNP 461 463 of of IN 464 466 10 10 CD 467 472 ng/ml ng/ml NN 472 473 ) ) ) 473 474 , , , 475 478 and and CC 479 483 with with IN 484 487 PMA PMA NNP 488 491 and and CC 492 501 ionomycin ionomycin NN 502 503 ( ( ( 503 507 Iono Iono NNP 507 508 , , , 509 513 IC50 ic50 NN 514 516 of of IN 517 519 40 40 CD 520 525 ng/ml ng/ml NN 525 526 ) ) ) 526 527 . . . 528 530 In in IN 531 537 Jurkat Jurkat NNP 538 545 T-cells T-cell NNP 545 546 , , , 547 552 PG490 PG490 NNP 553 561 inhibits inhibit VBZ 562 581 PMA/Iono-stimulated pma/iono-stimulated JJ 582 586 IL-2 il-2 NN 587 600 transcription transcription NN 600 601 . . . 602 607 PG490 PG490 NNP 608 616 inhibits inhibit VBZ 617 620 the the DT 621 630 induction induction NN 631 633 of of IN 634 637 DNA DNA NNP 638 645 binding binding NN 646 654 activity activity NN 655 657 at at IN 658 661 the the DT 662 680 purine-box/antigen purine-box/antigen NN 681 689 receptor receptor NN 690 698 response response NN 699 706 element element NN 707 708 ( ( ( 708 721 ARRE)/nuclear arre)/nuclear JJ 722 728 factor factor NN 729 731 of of IN 732 741 activated activate VBN 742 749 T-cells t-cell NNS 750 751 ( ( ( 751 756 NF-AT NF-AT NNP 756 757 ) ) ) 758 764 target target NN 765 773 sequence sequence NN 774 777 but but CC 778 781 not not RB 782 784 at at IN 785 788 the the DT 789 798 NF-kappaB NF-kappaB NNP 799 803 site site NN 803 804 . . . 805 810 PG490 PG490 NNP 811 814 can can MD 815 825 completely completely RB 826 833 inhibit inhibit VB 834 849 transcriptional transcriptional JJ 850 860 activation activation NN 861 863 at at IN 864 867 the the DT 868 889 purine-box/ARRE/NF-AT purine-box/arre/nf-at NN 890 893 and and CC 894 903 NF-kappaB NF-kappaB NNP 904 910 target target NN 911 914 DNA dna NN 915 924 sequences sequence NNS 925 934 triggered trigger VBN 935 937 by by IN 938 941 all all DT 942 949 stimuli stimulus NNS 950 958 examined examine VBN 959 960 ( ( ( 960 963 PMA PMA NNP 963 964 , , , 965 973 PMA/Iono PMA/Iono NNP 973 974 , , , 975 980 tumor tumor NN 981 989 necrosis necrosis NN 990 1002 factor-alpha factor-alpha NN 1002 1003 ) ) ) 1003 1004 . . . 1005 1010 PG490 PG490 NNP 1011 1015 also also RB 1016 1024 inhibits inhibit VBZ 1025 1039 PMA-stimulated pma-stimulated JJ 1040 1050 activation activation NN 1051 1053 of of IN 1054 1055 a a DT 1056 1064 chimeric chimeric JJ 1065 1078 transcription transcription NN 1079 1085 factor factor NN 1086 1088 in in IN 1089 1094 which which WDT 1095 1098 the the DT 1099 1109 C-terminal c-terminal JJ 1110 1113 TA1 TA1 NNP 1114 1129 transactivation transactivation NN 1130 1136 domain domain NN 1137 1139 of of IN 1140 1149 NF-kappaB NF-kappaB NNP 1150 1153 p65 p65 NN 1154 1156 is be VBZ 1157 1162 fused fuse VBN 1163 1165 to to TO 1166 1169 the the DT 1170 1173 DNA dna NN 1174 1181 binding binding NN 1182 1188 domain domain NN 1189 1191 of of IN 1192 1196 GAL4 gal4 NN 1196 1197 . . . 1198 1200 In in IN 1201 1206 16HBE 16hbe NN 1207 1212 human human JJ 1213 1222 bronchial bronchial JJ 1223 1233 epithelial epithelial JJ 1234 1239 cells cell NNS 1239 1240 , , , 1241 1245 IL-8 il-8 NN 1246 1256 expression expression NN 1257 1259 is be VBZ 1260 1269 regulated regulate VBN 1270 1283 predominantly predominantly RB 1284 1286 by by IN 1287 1296 NF-kappaB NF-kappaB NNP 1296 1297 , , , 1298 1301 and and CC 1302 1307 PG490 PG490 NNP 1308 1311 but but CC 1312 1315 not not RB 1316 1327 cyclosporin cyclosporin NN 1328 1329 A a NN 1330 1333 can can MD 1334 1344 completely completely RB 1345 1352 inhibit inhibit VB 1353 1363 expression expression NN 1364 1366 of of IN 1367 1371 IL-8 il-8 NN 1371 1372 . . . 1373 1376 The the DT 1377 1386 mechanism mechanism NN 1387 1389 of of IN 1390 1395 PG490 pg490 NN 1396 1406 inhibition inhibition NN 1407 1409 of of IN 1410 1418 cytokine cytokine NN 1419 1423 gene gene NN 1424 1434 expression expression NN 1435 1442 differs differ VBZ 1443 1447 from from IN 1448 1459 cyclosporin cyclosporin NN 1460 1461 A a NN 1462 1465 and and CC 1466 1474 involves involve VBZ 1475 1482 nuclear nuclear JJ 1483 1493 inhibition inhibition NN 1494 1496 of of IN 1497 1512 transcriptional transcriptional JJ 1513 1523 activation activation NN 1524 1526 of of IN 1527 1536 NF-kappaB NF-kappaB NNP 1537 1540 and and CC 1541 1544 the the DT 1545 1555 purine-box purine-box NN 1556 1565 regulator regulator NN 1566 1575 operating operate VBG 1576 1578 at at IN 1579 1582 the the DT 1583 1593 ARRE/NF-AT arre/nf-at NN 1594 1598 site site NN 1599 1601 at at IN 1602 1603 a a DT 1604 1608 step step NN 1609 1614 after after IN 1615 1623 specific specific JJ 1624 1627 DNA dna NN 1628 1635 binding binding NN 1635 1636 . . .