0 8 Blockade blockade NN 9 11 of of IN 12 18 T-cell t-cell NN 19 29 activation activation NN 30 32 by by IN 33 49 dithiocarbamates dithiocarbamate NNS 50 58 involves involve VBZ 59 64 novel novel JJ 65 75 mechanisms mechanism NNS 76 78 of of IN 79 89 inhibition inhibition NN 90 92 of of IN 93 100 nuclear nuclear JJ 101 107 factor factor NN 108 110 of of IN 111 120 activated activate VBN 121 122 T t NN 123 128 cells cell NNS 128 129 . . . 131 147 Dithiocarbamates dithiocarbamate NNS 148 149 ( ( ( 149 153 DTCs DTC NNP 153 154 ) ) ) 155 159 have have VBP 160 168 recently recently RB 169 173 been be VBN 174 182 reported report VBN 183 185 as as IN 186 194 powerful powerful JJ 195 205 inhibitors inhibitor NNS 206 208 of of IN 209 218 NF-kappaB NF-kappaB NNP 219 229 activation activation NN 230 232 in in IN 233 234 a a DT 235 241 number number NN 242 244 of of IN 245 249 cell cell NN 250 255 types type NNS 255 256 . . . 257 262 Given give VBN 263 266 the the DT 267 271 role role NN 272 274 of of IN 275 279 this this DT 280 293 transcription transcription NN 294 300 factor factor NN 301 303 in in IN 304 307 the the DT 308 318 regulation regulation NN 319 321 of of IN 322 326 gene gene NN 327 337 expression expression NN 338 340 in in IN 341 344 the the DT 345 357 inflammatory inflammatory JJ 358 366 response response NN 366 367 , , , 368 377 NF-kappaB NF-kappaB NNP 378 388 inhibitors inhibitor NNS 389 393 have have VBP 394 398 been be VBN 399 408 suggested suggest VBN 409 411 as as IN 412 421 potential potential JJ 422 433 therapeutic therapeutic JJ 434 439 drugs drug NNS 440 443 for for IN 444 456 inflammatory inflammatory JJ 457 465 diseases disease NNS 465 466 . . . 467 469 We we PRP 470 474 show show VBP 475 479 here here RB 480 484 that that IN 485 489 DTCs DTC NNP 490 499 inhibited inhibit VBD 500 504 both both CC 505 516 interleukin interleukin NN 517 518 2 2 CD 519 520 ( ( ( 520 524 IL-2 il-2 NN 524 525 ) ) ) 526 535 synthesis synthesis NN 536 539 and and CC 540 548 membrane membrane NN 549 559 expression expression NN 560 562 of of IN 563 571 antigens antigen NNS 572 577 which which WDT 578 581 are be VBP 582 589 induced induce VBN 590 596 during during IN 597 603 T-cell t-cell NN 604 614 activation activation NN 614 615 . . . 616 620 This this DT 621 631 inhibition inhibition NN 631 632 , , , 633 638 which which WDT 639 647 occurred occur VBD 648 652 with with IN 653 654 a a DT 655 663 parallel parallel JJ 664 674 activation activation NN 675 677 of of IN 678 683 c-Jun c-jun NN 684 699 transactivating transactivating NN 700 709 functions function NNS 710 713 and and CC 714 724 expression expression NN 724 725 , , , 726 729 was be VBD 730 739 reflected reflect VBN 740 742 by by IN 743 755 transfection transfection NN 756 767 experiments experiment NNS 768 770 at at IN 771 774 the the DT 775 779 IL-2 il-2 NN 780 788 promoter promoter NN 789 794 level level NN 794 795 , , , 796 799 and and CC 800 808 involved involve VBD 809 812 not not RB 813 817 only only RB 818 821 the the DT 822 832 inhibition inhibition NN 833 835 of of IN 836 852 NF-kappaB-driven nf-kappab-driven JJ 853 861 reporter reporter NN 862 872 activation activation NN 873 876 but but CC 877 881 also also RB 882 886 that that DT 887 889 of of IN 890 897 nuclear nuclear JJ 898 904 factor factor NN 905 907 of of IN 908 917 activated activate VBN 918 919 T t NN 920 925 cells cell NNS 926 927 ( ( ( 927 931 NFAT NFAT NNP 931 932 ) ) ) 932 933 . . . 934 945 Accordingly accordingly RB 945 946 , , , 947 962 electrophoretic electrophoretic JJ 963 971 mobility mobility NN 972 977 shift shift NN 978 984 assays assay NNS 985 986 ( ( ( 986 991 EMSAs EMSA NNP 991 992 ) ) ) 993 1002 indicated indicate VBD 1003 1007 that that IN 1008 1019 pyrrolidine pyrrolidine NN 1020 1023 DTC DTC NNP 1024 1025 ( ( ( 1025 1029 PDTC PDTC NNP 1029 1030 ) ) ) 1031 1040 prevented prevent VBD 1041 1050 NF-kappaB NF-kappaB NNP 1050 1051 , , , 1052 1055 and and CC 1056 1060 NFAT NFAT NNP 1061 1072 DNA-binding dna-binding JJ 1073 1081 activity activity NN 1082 1084 in in IN 1085 1086 T t NN 1087 1092 cells cell NNS 1093 1103 stimulated stimulate VBN 1104 1108 with with IN 1109 1115 either either CC 1116 1123 phorbol phorbol NN 1124 1133 myristate myristate NN 1134 1141 acetate acetate NN 1142 1146 plus plus CC 1147 1156 ionophore ionophore NN 1157 1159 or or CC 1160 1170 antibodies antibody NNS 1171 1178 against against IN 1179 1182 the the DT 1183 1193 CD3-T-cell cd3-t-cell NN 1194 1202 receptor receptor NN 1203 1210 complex complex NN 1211 1214 and and CC 1215 1229 simultaneously simultaneously RB 1230 1239 activated activate VBD 1240 1243 the the DT 1244 1251 binding binding NN 1252 1254 of of IN 1255 1259 AP-1 ap-1 NN 1259 1260 . . . 1261 1272 Furthermore furthermore RB 1272 1273 , , , 1274 1278 PDTC PDTC NNP 1279 1293 differentially differentially RB 1294 1302 targeted target VBD 1303 1307 both both CC 1308 1313 NFATp NFATp NNP 1314 1317 and and CC 1318 1323 NFATc NFATc NNP 1324 1330 family family NN 1331 1338 members member NNS 1338 1339 , , , 1340 1350 inhibiting inhibit VBG 1351 1354 the the DT 1355 1370 transactivation transactivation NN 1371 1380 functions function NNS 1381 1383 of of IN 1384 1389 NFATp NFATp NNP 1390 1393 and and CC 1394 1398 mRNA mrna NN 1399 1408 induction induction NN 1409 1411 of of IN 1412 1417 NFATc NFATc NNP 1417 1418 . . . 1419 1429 Strikingly strikingly RB 1429 1430 , , , 1431 1438 Western western JJ 1439 1447 blotting blotting NN 1448 1451 and and CC 1452 1470 immunocytochemical immunocytochemical JJ 1471 1482 experiments experiment NNS 1483 1492 indicated indicate VBD 1493 1497 that that IN 1498 1502 PDTC PDTC NNP 1503 1511 promoted promote VBD 1512 1513 a a DT 1514 1523 transient transient JJ 1524 1527 and and CC 1528 1533 rapid rapid JJ 1534 1543 shuttling shuttling NN 1544 1546 of of IN 1547 1552 NFATp NFATp NNP 1553 1556 and and CC 1557 1562 NFATc NFATc NNP 1562 1563 , , , 1564 1571 leading lead VBG 1572 1574 to to TO 1575 1580 their their PRP$ 1581 1592 accelerated accelerate VBN 1593 1599 export export NN 1600 1604 from from IN 1605 1608 the the DT 1609 1616 nucleus nucleus NN 1617 1619 of of IN 1620 1629 activated activate VBN 1630 1631 T t NN 1632 1637 cells cell NNS 1637 1638 . . . 1639 1641 We we PRP 1642 1649 propose propose VBP 1650 1654 that that IN 1655 1658 the the DT 1659 1669 activation activation NN 1670 1672 of of IN 1673 1675 an an DT 1676 1680 NFAT NFAT NNP 1681 1687 kinase kinase NNP 1688 1690 by by IN 1691 1695 PDTC PDTC NNP 1696 1701 could could MD 1702 1704 be be VB 1705 1716 responsible responsible JJ 1717 1720 for for IN 1721 1724 the the DT 1725 1730 rapid rapid JJ 1731 1740 shuttling shuttling NN 1741 1743 of of IN 1744 1747 the the DT 1748 1752 NFAT NFAT NNP 1752 1753 , , , 1754 1763 therefore therefore RB 1764 1775 transiently transiently RB 1776 1786 converting convert VBG 1787 1790 the the DT 1791 1800 sustained sustained JJ 1801 1816 transactivation transactivation NN 1817 1819 of of IN 1820 1824 this this DT 1825 1838 transcription transcription NN 1839 1845 factor factor NN 1846 1850 that that WDT 1851 1857 occurs occur VBZ 1858 1864 during during IN 1865 1875 lymphocyte lymphocyte NN 1876 1886 activation activation NN 1886 1887 , , , 1888 1891 and and CC 1892 1896 show show VBP 1897 1901 that that IN 1902 1907 c-Jun c-jun NN 1908 1920 NH2-terminal nh2-terminal JJ 1921 1927 kinase kinase NNP 1928 1929 ( ( ( 1929 1932 JNK JNK NNP 1932 1933 ) ) ) 1934 1937 can can MD 1938 1941 act act VB 1942 1944 by by IN 1945 1953 directly directly RB 1954 1969 phosphorylating phosphorylate VBG 1970 1975 NFATp NFATp NNP 1975 1976 . . . 1977 1979 In in IN 1980 1988 addition addition NN 1988 1989 , , , 1990 1993 the the DT 1994 2002 combined combined JJ 2003 2013 inhibitory inhibitory JJ 2014 2021 effects effect NNS 2022 2024 on on IN 2025 2029 NFAT NFAT NNP 2030 2033 and and CC 2034 2039 NF-KB NF-KB NNP 2040 2047 support support VBP 2048 2049 a a DT 2050 2059 potential potential JJ 2060 2063 use use NN 2064 2066 of of IN 2067 2071 DTCs dtc NNS 2072 2074 as as IN 2075 2093 immunosuppressants immunosuppressant NNS 2093 2094 . . .