0 11 LPS-Induced lps-induced JJ 12 21 NF-kappaB NF-kappaB NNP 22 32 activation activation NN 33 36 and and CC 37 46 TNF-alpha TNF-alpha NNP 47 54 release release NN 55 57 in in IN 58 63 human human JJ 64 73 monocytes monocyte NNS 74 77 are be VBP 78 85 protein protein NN 86 94 tyrosine tyrosine NN 95 101 kinase kinase NNP 102 111 dependent dependent JJ 112 115 and and CC 116 123 protein protein NN 124 130 kinase kinase NNP 131 132 C C NNP 133 144 independent independent JJ 144 145 . . . 147 157 BACKGROUND background NN 157 158 : : : 159 164 Tumor tumor NN 165 173 necrosis necrosis NN 174 180 factor factor NN 181 186 alpha alpha NN 187 188 ( ( ( 188 197 TNF-alpha TNF-alpha NNP 197 198 ) ) ) 199 201 is be VBZ 202 204 an an DT 205 214 important important JJ 215 223 mediator mediator NN 224 226 of of IN 227 233 septic septic JJ 234 239 shock shock NN 239 240 . . . 241 250 Endotoxin Endotoxin NNP 251 252 ( ( ( 252 255 LPS LPS NNP 255 256 ) ) ) 257 263 signal signal NN 264 276 transduction transduction NN 277 279 in in IN 280 285 human human JJ 286 295 monocytes monocyte NNS 296 301 leads lead VBZ 302 304 to to TO 305 315 activation activation NN 316 318 of of IN 319 326 nuclear nuclear JJ 327 339 factor-kappa factor-kappa NN 340 341 B B NNP 342 343 ( ( ( 343 352 NF-kappaB NF-kappaB NNP 352 353 ) ) ) 354 357 and and CC 358 367 TNF-alpha TNF-alpha NNP 368 375 release release NN 375 376 . . . 377 385 Previous previous JJ 386 393 studies study NNS 394 398 have have VBP 399 409 implicated implicate VBN 410 420 activation activation NN 421 423 of of IN 424 428 both both CC 429 436 protein protein NN 437 443 kinase kinase NNP 444 445 C C NNP 446 447 ( ( ( 447 450 PKC PKC NNP 450 451 ) ) ) 452 455 and and CC 456 463 protein protein NN 464 472 tyrosine tyrosine NN 473 480 kinases kinase NNS 481 482 ( ( ( 482 485 PTK PTK NNP 485 486 ) ) ) 487 489 in in IN 490 501 LPS-induced lps-induced JJ 502 511 NF-kappaB NF-kappaB NNP 512 522 activation activation NN 523 526 and and CC 527 536 TNF-alpha TNF-alpha NNP 537 547 production production NN 547 548 . . . 549 551 We we PRP 552 564 hypothesized hypothesize VBD 565 569 that that IN 570 580 inhibition inhibition NN 581 583 of of IN 584 590 either either CC 591 594 PKC PKC NNP 595 597 or or CC 598 601 PTK PTK NNP 602 607 would would MD 608 616 decrease decrease VB 617 628 LPS-induced lps-induced JJ 629 638 NF-kappaB NF-kappaB NNP 639 642 DNA DNA NNP 643 650 binding binding NN 651 654 and and CC 655 664 TNF-alpha TNF-alpha NNP 665 672 release release NN 673 675 in in IN 676 681 human human JJ 682 691 monocytes monocyte NNS 691 692 . . . 693 702 MATERIALS MATERIALS NNP 703 706 AND and CC 707 714 METHODS METHODS NNP 714 715 : : : 716 721 Human human JJ 722 731 monocytes monocyte NNS 732 736 were be VBD 737 747 stimulated stimulate VBN 748 752 with with IN 753 756 PMA PMA NNP 757 758 ( ( ( 758 760 50 50 CD 761 766 ng/ml ng/ml NN 766 767 ) ) ) 768 773 alone alone RB 774 776 or or CC 777 780 LPS LPS NNP 781 782 ( ( ( 782 785 100 100 CD 786 791 ng/ml ng/ml NN 791 792 ) ) ) 793 797 with with IN 798 801 and and CC 802 809 without without IN 810 811 a a DT 812 823 nonspecific nonspecific JJ 824 840 serine/threonine serine/threonine NN 841 848 protein protein NN 849 855 kinase kinase NNP 856 865 inhibitor inhibitor NN 866 879 staurosporine staurosporine NN 880 881 ( ( ( 881 887 Stauro Stauro NNP 887 888 ) ) ) 888 889 , , , 890 891 a a DT 892 900 specific specific JJ 901 908 pan-PKC pan-pkc NN 909 918 inhibitor inhibitor NN 919 938 bisindolylmaleimide bisindolylmaleimide NN 939 940 ( ( ( 940 943 Bis Bis NNP 943 944 ) ) ) 944 945 , , , 946 948 or or CC 949 951 an an DT 952 961 inhibitor inhibitor NN 962 964 of of IN 965 968 PTK PTK NNP 969 978 genistein genistein NN 979 980 ( ( ( 980 983 Gen Gen NNP 983 984 ) ) ) 984 985 . . . 986 995 TNF-alpha TNF-alpha NNP 996 1003 release release NN 1004 1006 in in IN 1007 1014 culture culture NN 1015 1027 supernatants supernatant NNS 1028 1031 was be VBD 1032 1040 measured measure VBN 1041 1043 by by IN 1044 1046 an an DT 1047 1052 ELISA ELISA NNP 1052 1053 . . . 1054 1063 NF-kappaB NF-kappaB NNP 1064 1067 DNA DNA NNP 1068 1075 binding binding NN 1076 1079 was be VBD 1080 1089 evaluated evaluate VBN 1090 1092 by by IN 1093 1108 electrophoretic electrophoretic JJ 1109 1117 mobility mobility NN 1118 1123 shift shift NN 1124 1129 assay assay NN 1129 1130 . . . 1131 1138 RESULTS results NNS 1138 1139 : : : 1140 1143 LPS LPS NNP 1144 1153 increased increase VBD 1154 1163 NF-kappaB NF-kappaB NNP 1164 1167 DNA DNA NNP 1168 1175 binding binding NN 1176 1179 and and CC 1180 1189 TNF-alpha TNF-alpha NNP 1190 1197 release release NN 1198 1200 in in IN 1201 1206 human human JJ 1207 1216 monocytes monocyte NNS 1216 1217 . . . 1218 1229 Nonspecific nonspecific JJ 1230 1237 protein protein NN 1238 1244 kinase kinase NNP 1245 1255 inhibition inhibition NN 1256 1265 inhibited inhibit VBD 1266 1275 NF-kappaB NF-kappaB NNP 1276 1286 activation activation NN 1287 1290 and and CC 1291 1300 TNF-alpha TNF-alpha NNP 1301 1308 release release NN 1308 1309 , , , 1310 1315 while while IN 1316 1324 specific specific JJ 1325 1328 PKC PKC NNP 1329 1339 inhibition inhibition NN 1340 1344 with with IN 1345 1348 Bis Bis NNP 1349 1352 had have VBD 1353 1355 no no DT 1356 1362 effect effect NN 1363 1365 on on IN 1366 1377 LPS-induced lps-induced JJ 1378 1387 NF-kappaB NF-kappaB NNP 1388 1391 DNA DNA NNP 1392 1399 binding binding NN 1400 1402 or or CC 1403 1412 TNF-alpha TNF-alpha NNP 1413 1420 release release NN 1420 1421 . . . 1422 1425 PTK PTK NNP 1426 1436 inhibition inhibition NN 1437 1441 with with IN 1442 1445 Gen Gen NNP 1446 1456 attenuated attenuate VBD 1457 1461 both both CC 1462 1473 LPS-induced lps-induced JJ 1474 1483 NF-kappaB NF-kappaB NNP 1484 1487 DNA DNA NNP 1488 1495 binding binding NN 1496 1499 and and CC 1500 1509 TNF-alpha TNF-alpha NNP 1510 1520 production production NN 1521 1523 in in IN 1524 1529 human human JJ 1530 1539 monocytes monocyte NNS 1539 1540 . . . 1541 1547 Direct direct JJ 1548 1558 activation activation NN 1559 1561 of of IN 1562 1565 PKC PKC NNP 1566 1570 with with IN 1571 1574 PMA PMA NNP 1575 1582 induced induce VBD 1583 1587 both both CC 1588 1597 NF-kappaB NF-kappaB NNP 1598 1608 activation activation NN 1609 1612 and and CC 1613 1622 TNF-alpha TNF-alpha NNP 1623 1633 production production NN 1634 1636 by by IN 1637 1642 human human JJ 1643 1652 monocytes monocyte NNS 1652 1653 . . . 1654 1665 CONCLUSIONS conclusions NNS 1665 1666 : : : 1667 1672 These these DT 1673 1680 results result NNS 1681 1688 suggest suggest VBP 1689 1693 that that IN 1694 1705 LPS-induced lps-induced JJ 1706 1715 NF-kappaB NF-kappaB NNP 1716 1726 activation activation NN 1727 1730 and and CC 1731 1740 TNF-alpha TNF-alpha NNP 1741 1748 release release NN 1749 1751 in in IN 1752 1757 human human JJ 1758 1767 monocytes monocyte NNS 1768 1771 are be VBP 1772 1783 independent independent JJ 1784 1786 of of IN 1787 1790 PKC PKC NNP 1791 1799 activity activity NN 1799 1800 . . . 1801 1812 Furthermore furthermore RB 1812 1813 , , , 1814 1817 our our PRP$ 1818 1825 results result NNS 1826 1833 provide provide VBP 1834 1842 evidence evidence NN 1843 1847 that that IN 1848 1851 PTK PTK NNP 1852 1857 plays play VBZ 1858 1859 a a DT 1860 1864 role role NN 1865 1867 in in IN 1868 1879 LPS-induced lps-induced JJ 1880 1889 NF-kappaB NF-kappaB NNP 1890 1900 activation activation NN 1901 1904 and and CC 1905 1914 TNF-alpha TNF-alpha NNP 1915 1922 release release NN 1923 1925 in in IN 1926 1931 human human JJ 1932 1941 monocytes monocyte NNS 1942 1945 and and CC 1946 1950 thus thus RB 1951 1956 could could MD 1957 1959 be be VB 1960 1961 a a DT 1962 1971 potential potential JJ 1972 1983 therapeutic therapeutic JJ 1984 1990 target target NN 1991 1993 in in IN 1994 2006 inflammatory inflammatory JJ 2007 2014 states. states. 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