0 8 Defining define VBG 9 20 therapeutic therapeutic JJ 21 28 targets target NNS 29 31 by by IN 32 37 using use VBG 38 48 adenovirus adenovirus NN 48 49 : : : 50 58 blocking block VBG 59 68 NF-kappaB NF-kappaB NNP 69 77 inhibits inhibit VBZ 78 82 both both CC 83 95 inflammatory inflammatory JJ 96 99 and and CC 100 111 destructive destructive JJ 112 122 mechanisms mechanism NNS 123 125 in in IN 126 136 rheumatoid rheumatoid JJ 137 145 synovium synovium NN 146 149 but but CC 150 156 spares spar VBZ 157 174 anti-inflammatory anti-inflammatory JJ 175 184 mediators mediator NNS 184 185 . . . 187 190 The the DT 191 195 role role NN 196 198 of of IN 199 202 the the DT 203 216 transcription transcription NN 217 223 factor factor NN 224 233 NF-kappaB nf-kappab NN 234 236 in in IN 237 240 the the DT 241 253 pathogenesis pathogenesis NN 254 256 of of IN 257 267 rheumatoid rheumatoid JJ 268 277 arthritis arthritis NN 278 281 has have VBZ 282 286 long long RB 287 291 been be VBN 292 293 a a DT 294 301 subject subject NN 302 304 of of IN 305 316 controversy controversy NN 316 317 . . . 318 320 We we PRP 321 325 used use VBD 326 328 an an DT 329 339 adenoviral adenoviral JJ 340 349 technique technique NN 350 352 of of IN 353 361 blocking block VBG 362 371 NF-kappaB nf-kappab NN 372 379 through through IN 380 394 overexpression overexpression NN 395 397 of of IN 398 401 the the DT 402 412 inhibitory inhibitory JJ 413 420 subunit subunit NN 421 433 IkappaBalpha IkappaBalpha NNP 433 434 , , , 435 440 which which WDT 441 444 has have VBZ 445 448 the the DT 449 458 advantage advantage NN 459 463 that that IN 464 466 it it PRP 467 470 can can MD 471 473 be be VB 474 478 used use VBN 479 481 in in IN 482 485 the the DT 486 494 diseased diseased JJ 495 501 tissue tissue NN 502 508 itself itself PRP 508 509 , , , 510 514 with with IN 515 518 >90 >90 CD 518 519 % % NN 520 522 of of IN 523 526 the the DT 527 535 synovial synovial JJ 536 547 macrophages macrophage NNS 547 548 , , , 549 560 fibroblasts fibroblast NNS 560 561 , , , 562 565 and and CC 566 567 T t NN 568 573 cells cell NNS 574 582 infected infect VBN 582 583 . . . 584 586 We we PRP 587 592 found find VBD 593 597 that that IN 598 601 the the DT 602 613 spontaneous spontaneous JJ 614 624 production production NN 625 627 of of IN 628 633 tumor tumor NN 634 642 necrosis necrosis NN 643 649 factor factor NN 650 655 alpha alpha NN 656 659 and and CC 660 665 other other JJ 666 682 pro-inflammatory pro-inflammatory JJ 683 692 cytokines cytokine NNS 693 695 is be VBZ 696 715 NF-kappaB-dependent nf-kappab-dependent JJ 716 718 in in IN 719 729 rheumatoid rheumatoid JJ 730 738 synovial synovial JJ 739 745 tissue tissue NN 745 746 , , , 747 749 in in IN 750 758 contrast contrast NN 759 761 to to TO 762 765 the the DT 766 770 main main JJ 771 788 anti-inflammatory anti-inflammatory JJ 789 798 mediators mediator NNS 798 799 , , , 800 804 like like IN 805 810 IL-10 IL-10 NNP 811 814 and and CC 815 818 -11 -11 NN 818 819 , , , 820 823 and and CC 824 827 the the DT 828 832 IL-1 il-1 NN 833 841 receptor receptor NN 842 852 antagonist antagonist NN 852 853 . . . 854 856 Of of IN 857 861 even even RB 862 866 more more JJR 867 875 interest interest NN 875 876 , , , 877 889 IkappaBalpha IkappaBalpha NNP 890 904 overexpression overexpression NN 905 914 inhibited inhibit VBD 915 918 the the DT 919 929 production production NN 930 932 of of IN 933 939 matrix matrix NN 940 958 metalloproteinases metalloproteinas NNS 959 960 1 1 CD 961 964 and and CC 965 966 3 3 CD 967 972 while while IN 973 976 not not RB 977 986 affecting affect VBG 987 992 their their PRP$ 993 999 tissue tissue NN 1000 1009 inhibitor inhibitor NN 1009 1010 . . . 1011 1019 Blocking block VBG 1020 1029 NF-kappaB nf-kappab NN 1030 1032 in in IN 1033 1036 the the DT 1037 1047 rheumatoid rheumatoid JJ 1048 1053 joint joint NN 1054 1058 thus thus RB 1059 1062 has have VBZ 1063 1064 a a DT 1065 1069 very very RB 1070 1080 beneficial beneficial JJ 1081 1088 profile profile NN 1088 1089 , , , 1090 1098 reducing reduce VBG 1099 1103 both both CC 1104 1107 the the DT 1108 1120 inflammatory inflammatory JJ 1121 1129 response response NN 1130 1133 and and CC 1134 1137 the the DT 1138 1144 tissue tissue NN 1145 1156 destruction destruction NN 1156 1157 . . . 1158 1161 The the DT 1162 1172 adenoviral adenoviral JJ 1173 1182 technique technique NN 1183 1192 described describe VBN 1193 1197 here here RB 1198 1201 has have VBZ 1202 1212 widespread widespread JJ 1213 1226 applicability applicability NN 1226 1227 , , , 1228 1236 allowing allow VBG 1237 1242 rapid rapid JJ 1243 1250 testing testing NN 1251 1253 of of IN 1254 1257 the the DT 1258 1265 effects effect NNS 1266 1268 of of IN 1269 1277 blocking block VBG 1278 1279 a a DT 1280 1289 potential potential JJ 1290 1301 therapeutic therapeutic JJ 1302 1308 target target NN 1309 1311 in in IN 1312 1318 either either DT 1319 1327 cultures culture NNS 1328 1330 of of IN 1331 1337 normal normal JJ 1338 1343 cells cell NNS 1344 1346 or or CC 1347 1349 in in IN 1350 1353 the the DT 1354 1362 diseased diseased JJ 1363 1369 tissue tissue NN 1370 1376 itself itself PRP 1376 1377 . . .