0 12 Differential differential JJ 13 20 effects effect NNS 21 23 of of IN 24 42 lipopolysaccharide lipopolysaccharide NN 43 46 and and CC 47 52 tumor tumor NN 53 61 necrosis necrosis NN 62 68 factor factor NN 69 71 on on IN 72 81 monocytic monocytic JJ 82 89 IkappaB IkappaB NNP 90 96 kinase kinase NNP 97 107 signalsome signalsome JJ 108 118 activation activation NN 119 122 and and CC 123 130 IkappaB ikappab NN 131 142 proteolysis proteolysis NN 142 143 . . . 145 148 The the DT 149 161 inflammatory inflammatory JJ 162 171 mediators mediator NNS 172 190 lipopolysaccharide lipopolysaccharide NN 191 192 ( ( ( 192 195 LPS LPS NNP 195 196 ) ) ) 197 200 and and CC 201 206 tumor tumor NN 207 215 necrosis necrosis NN 216 222 factor factor NN 223 224 ( ( ( 224 227 TNF TNF NNP 227 228 ) ) ) 229 232 are be VBP 233 239 potent potent JJ 240 250 activators activator NNS 251 253 of of IN 254 263 NF-kappaB NF-kappaB NNP 263 264 . . . 265 269 This this DT 270 275 study study NN 276 284 compared compare VBD 285 288 the the DT 289 295 effect effect NN 296 298 of of IN 299 304 these these DT 305 312 stimuli stimulus NNS 313 315 on on IN 316 326 endogenous endogenous JJ 327 334 IkappaB IkappaB NNP 335 341 kinase kinase NNP 342 343 ( ( ( 343 346 IKK IKK NNP 346 347 ) ) ) 348 358 signalsome signalsome JJ 359 369 activation activation NN 370 373 and and CC 374 381 IkappaB ikappab NN 382 409 phosphorylation/proteolysis phosphorylation/proteolysis NN 410 412 in in IN 413 418 human human JJ 419 428 monocytic monocytic JJ 429 434 cells cell NNS 435 438 and and CC 439 451 investigated investigate VBD 452 455 the the DT 456 460 role role NN 461 463 of of IN 464 467 the the DT 468 478 signalsome signalsome JJ 479 487 proteins protein NNS 488 497 IKK-alpha IKK-alpha NNP 497 498 , , , 499 507 IKK-beta IKK-beta NNP 507 508 , , , 509 527 NF-kappaB-inducing NF-kappaB-inducing NNP 528 534 kinase kinase NNP 535 536 ( ( ( 536 539 NIK NIK NNP 539 540 ) ) ) 540 541 , , , 542 551 IKK-gamma IKK-gamma NNP 552 553 ( ( ( 553 562 NF-kappaB NF-kappaB NNP 563 572 essential essential JJ 573 582 modulator modulator NN 582 583 ) ) ) 583 584 , , , 585 588 and and CC 589 592 IKK IKK NNP 593 611 complex-associated complex-associated JJ 612 619 protein protein NN 619 620 . . . 621 627 Kinase Kinase NNP 628 634 assays assay NNS 635 641 showed show VBD 642 646 that that IN 647 650 TNF TNF NNP 651 659 elicited elicit VBD 660 661 a a DT 662 667 rapid rapid JJ 668 671 but but CC 672 683 short-lived short-lived JJ 684 693 induction induction NN 694 696 of of IN 697 700 IKK IKK NNP 701 709 activity activity NN 710 714 with with IN 715 716 a a DT 717 723 3-fold 3-fold JJ 724 731 greater great JJR 732 738 effect effect NN 739 741 on on IN 742 751 IKK-alpha IKK-alpha NNP 752 756 than than IN 757 759 on on IN 760 768 IKK-beta IKK-beta NNP 768 769 , , , 770 777 peaking peak VBG 778 780 at at IN 781 782 5 5 CD 783 786 min min NN 786 787 . . . 788 790 In in IN 791 799 contrast contrast NN 799 800 , , , 801 804 LPS lps NN 805 818 predominantly predominantly RB 819 829 stimulated stimulate VBD 830 838 IKK-beta IKK-beta NNP 839 847 activity activity NN 847 848 , , , 849 854 which which WDT 855 861 slowly slowly RB 862 871 increased increase VBD 871 872 , , , 873 880 peaking peak VBG 881 883 at at IN 884 886 30 30 CD 887 890 min min NN 890 891 . . . 892 893 A a DT 894 900 second second JJ 901 905 peak peak NN 906 909 was be VBD 910 918 observed observe VBN 919 921 at at IN 922 923 a a DT 924 929 later later JJ 930 934 time time NN 935 940 point point NN 941 950 following follow VBG 951 954 LPS LPS NNP 955 966 stimulation stimulation NN 966 967 , , , 968 973 which which WDT 974 983 consisted consist VBD 984 986 of of IN 987 991 both both CC 992 1001 IKK-alpha IKK-alpha NNP 1002 1005 and and CC 1006 1011 -beta -beta NN 1012 1020 activity activity NN 1020 1021 . . . 1022 1025 The the DT 1026 1036 endogenous endogenous JJ 1037 1043 levels level NNS 1044 1046 of of IN 1047 1050 the the DT 1051 1061 signalsome signalsome JJ 1062 1072 components component NNS 1073 1077 were be VBD 1078 1088 unaffected unaffected JJ 1089 1091 by by IN 1092 1103 stimulation stimulation NN 1103 1104 . . . 1105 1116 Furthermore furthermore RB 1116 1117 , , , 1118 1121 our our PRP$ 1122 1129 studies study NNS 1130 1136 showed show VBD 1137 1148 association association NN 1149 1151 of of IN 1152 1155 the the DT 1156 1170 IKK-alpha/beta IKK-alpha/beta NNP 1171 1182 heterodimer heterodimer NN 1183 1187 with with IN 1188 1191 NIK NIK NNP 1191 1192 , , , 1193 1206 IkappaB-alpha IkappaB-alpha NNP 1207 1210 and and CC 1211 1219 -epsilon -epsilon NN 1220 1222 in in IN 1223 1235 unstimulated unstimulated JJ 1236 1241 cells cell NNS 1241 1242 . . . 1243 1251 Exposure exposure NN 1252 1254 to to TO 1255 1258 LPS LPS NNP 1259 1261 or or CC 1262 1265 TNF TNF NNP 1266 1269 led lead VBD 1270 1272 to to TO 1273 1285 differential differential JJ 1286 1294 patterns pattern NNS 1295 1297 of of IN 1298 1311 IkappaB-alpha IkappaB-alpha NNP 1312 1315 and and CC 1316 1331 IkappaB-epsilon IkappaB-epsilon NNP 1332 1345 disappearance disappearance NN 1346 1350 from from IN 1351 1354 and and CC 1355 1365 reassembly reassembly NN 1366 1370 with with IN 1371 1374 the the DT 1375 1385 signalsome signalsome NN 1385 1386 , , , 1387 1394 whereas whereas IN 1395 1404 IKK-alpha IKK-alpha NNP 1404 1405 , , , 1406 1414 IKK-beta IKK-beta NNP 1414 1415 , , , 1416 1419 and and CC 1420 1423 NIK NIK NNP 1424 1432 remained remain VBD 1433 1451 complex-associated complex-associated JJ 1451 1452 . . . 1453 1456 NIK NIK NNP 1457 1463 cannot cannot MD 1464 1477 phosphorylate phosphorylate VB 1478 1491 IkappaB-alpha IkappaB-alpha NNP 1492 1500 directly directly RB 1500 1501 , , , 1502 1505 but but CC 1506 1508 it it PRP 1509 1516 appears appear VBZ 1517 1519 to to TO 1520 1522 be be VB 1523 1524 a a DT 1525 1537 functionally functionally RB 1538 1547 important important JJ 1548 1555 subunit subunit NN 1555 1556 , , , 1557 1564 because because IN 1565 1572 mutated mutate VBN 1573 1576 NIK NIK NNP 1577 1586 inhibited inhibit VBD 1587 1603 stimulus-induced stimulus-induced JJ 1604 1620 kappaB-dependent kappab-dependent JJ 1621 1634 transcription transcription NN 1635 1639 more more RBR 1640 1651 effectively effectively RB 1652 1656 than than IN 1657 1664 mutated mutate VBN 1665 1674 IKK-alpha IKK-alpha NNP 1675 1677 or or CC 1678 1683 -beta -beta NN 1683 1684 . . . 1685 1699 Overexpression Overexpression NNP 1700 1702 of of IN 1703 1706 IKK IKK NNP 1707 1725 complex-associated complex-associated JJ 1726 1733 protein protein NN 1734 1743 inhibited inhibit VBD 1744 1761 stimulus-mediated stimulus-mediated JJ 1762 1775 transcription transcription NN 1775 1776 , , , 1777 1784 whereas whereas IN 1785 1794 NF-kappaB NF-kappaB NNP 1795 1804 essential essential JJ 1805 1814 modulator modulator NN 1815 1823 enhanced enhance VBD 1824 1826 it it PRP 1826 1827 . . . 1828 1831 The the DT 1832 1845 understanding understanding NN 1846 1848 of of IN 1849 1853 LPS- LPS- NNP 1854 1857 and and CC 1858 1869 TNF-induced tnf-induced JJ 1870 1879 signaling signaling NN 1880 1883 may may MD 1884 1889 allow allow VB 1890 1893 the the DT 1894 1905 development development NN 1906 1908 of of IN 1909 1917 specific specific JJ 1918 1928 strategies strategy NNS 1929 1931 to to TO 1932 1937 treat treat VB 1938 1955 sepsis-associated sepsis-associated JJ 1956 1963 disease disease NN 1963 1964 . . .