0 8 CNI-1493 CNI-1493 NNP 9 17 inhibits inhibit VBZ 18 37 monocyte/macrophage monocyte/macrophage NN 38 43 tumor tumor NN 44 52 necrosis necrosis NN 53 59 factor factor NN 60 62 by by IN 63 74 suppression suppression NN 75 77 of of IN 78 89 translation translation NN 90 100 efficiency efficiency NN 100 101 . . . 103 108 Tumor tumor NN 109 117 necrosis necrosis NN 118 124 factor factor NN 125 126 ( ( ( 126 129 TNF TNF NNP 129 130 ) ) ) 131 139 mediates mediate VBZ 140 141 a a DT 142 146 wide wide JJ 147 154 variety variety NN 155 157 of of IN 158 165 disease disease NN 166 172 states state NNS 173 182 including include VBG 183 189 septic septic JJ 190 195 shock shock NN 195 196 , , , 197 202 acute acute JJ 203 206 and and CC 207 214 chronic chronic JJ 215 227 inflammation inflammation NN 227 228 , , , 229 232 and and CC 233 241 cachexia cachexia NN 241 242 . . . 243 251 Recently recently RB 251 252 , , , 253 254 a a DT 255 266 multivalent multivalent JJ 267 282 guanylhydrazone guanylhydrazone NN 283 284 ( ( ( 284 292 CNI-1493 CNI-1493 NNP 292 293 ) ) ) 294 303 developed develop VBN 304 306 as as IN 307 309 an an DT 310 319 inhibitor inhibitor NN 320 322 of of IN 323 333 macrophage macrophage NN 334 344 activation activation NN 345 348 was be VBD 349 354 shown show VBN 355 357 to to TO 358 366 suppress suppress VB 367 370 TNF TNF NNP 371 381 production production NN 382 385 and and CC 386 393 protect protect NN 394 401 against against IN 402 408 tissue tissue NN 409 421 inflammation inflammation NN 422 425 and and CC 426 435 endotoxin endotoxin NN 436 445 lethality lethality NN 446 447 [ [ ( 447 454 Bianchi Bianchi NNP 454 455 , , , 456 458 M. M. NNP 458 459 , , , 460 466 Ulrich Ulrich NNP 466 467 , , , 468 470 P. P. NNP 470 471 , , , 472 477 Bloom Bloom NNP 477 478 , , , 479 481 O. O. NNP 481 482 , , , 483 492 Meistrell Meistrell NNP 492 493 , , , 494 496 M. M. NNP 496 497 , , , 498 507 Zimmerman Zimmerman NNP 507 508 , , , 509 513 G.A. G.A. NNP 513 514 , , , 515 530 Schmidtmayerova Schmidtmayerova NNP 530 531 , , , 532 534 H. H. NNP 534 535 , , , 536 545 Bukrinsky Bukrinsky NNP 545 546 , , , 547 549 M. M. NNP 549 550 , , , 551 560 Donnelley Donnelley NNP 560 561 , , , 562 564 T. T. NNP 564 565 , , , 566 572 Bucala Bucala NNP 572 573 , , , 574 576 R. R. NNP 576 577 , , , 578 584 Sherry Sherry NNP 584 585 , , , 586 588 B. B. NNP 588 589 , , , 590 597 Manogue Manogue NNP 597 598 , , , 599 603 K.R. K.R. NNP 603 604 , , , 605 614 Tortolani Tortolani NNP 614 615 , , , 616 620 A.J. A.J. NNP 620 621 , , , 622 628 Cerami Cerami NNP 628 629 , , , 630 632 A. A. NNP 632 633 & & CC 634 640 Tracey Tracey NNP 640 641 , , , 642 652 K.J.(1995) K.J.(1995) NNP 653 662 Mol.Med.1 Mol.Med.1 NNP 662 663 , , , 664 671 254-266 254-266 CD 671 672 , , , 673 676 and and CC 677 684 Bianchi Bianchi NNP 684 685 , , , 686 688 M. M. NNP 688 689 , , , 690 695 Bloom Bloom NNP 695 696 , , , 697 699 O. O. NNP 699 700 , , , 701 706 Raabe Raabe NNP 706 707 , , , 708 710 T. T. NNP 710 711 , , , 712 717 Cohen Cohen NNP 717 718 , , , 719 721 P. P. NNP 722 724 S. S. NNP 724 725 , , , 726 733 Chesney Chesney NNP 733 734 , , , 735 737 J. J. NNP 737 738 , , , 739 745 Sherry Sherry NNP 745 746 , , , 747 749 B. B. NNP 749 750 , , , 751 766 Schmidtmayerova Schmidtmayerova NNP 766 767 , , , 768 770 H. H. NNP 770 771 , , , 772 777 Zhang Zhang NNP 777 778 , , , 779 781 X. X. NNP 781 782 , , , 783 792 Bukrinsky Bukrinsky NNP 792 793 , , , 794 796 M. M. NNP 796 797 , , , 798 804 Ulrich Ulrich NNP 804 805 , , , 806 808 P. P. NNP 808 809 , , , 810 816 Cerami Cerami NNP 816 817 , , , 818 820 A. A. NNP 820 821 & & CC 822 828 Tracey Tracey NNP 828 829 , , , 830 838 J.(1996) J.(1996) NNP 839 849 J.Exp.Med. J.Exp.Med. NNP 849 850 , , , 851 853 in in IN 854 859 press press NN 859 860 ] ] ) 860 861 . . . 862 864 We we PRP 865 869 have have VBP 870 873 now now RB 874 884 elucidated elucidate VBN 885 888 the the DT 889 898 mechanism mechanism NN 899 901 by by IN 902 907 which which WDT 908 916 CNI-1493 CNI-1493 NNP 917 925 inhibits inhibit VBZ 926 936 macrophage macrophage NN 937 940 TNF TNF NNP 941 950 synthesis synthesis NN 951 954 and and CC 955 959 show show VBP 960 964 here here RB 965 969 that that IN 970 972 it it PRP 973 977 acts act VBZ 978 985 through through IN 986 997 suppression suppression NN 998 1000 of of IN 1001 1004 TNF TNF NNP 1005 1016 translation translation NN 1017 1027 efficiency efficiency NN 1027 1028 . . . 1029 1037 CNI-1493 CNI-1493 NNP 1038 1045 blocked block VBD 1046 1053 neither neither CC 1054 1057 the the DT 1058 1076 lipopolysaccharide lipopolysaccharide NN 1077 1078 ( ( ( 1078 1090 LPS)-induced lps)-induced JJ 1091 1100 increases increase NNS 1101 1103 in in IN 1104 1107 the the DT 1108 1118 expression expression NN 1119 1121 of of IN 1122 1125 TNF TNF NNP 1126 1130 mRNA mRNA NNP 1131 1134 nor nor CC 1135 1138 the the DT 1139 1152 translocation translocation NN 1153 1155 of of IN 1156 1163 nuclear nuclear JJ 1164 1170 factor factor NN 1171 1179 NF-kappa NF-kappa NNP 1180 1181 B B NNP 1182 1184 to to TO 1185 1188 the the DT 1189 1196 nucleus nucleus NN 1197 1199 in in IN 1200 1211 macrophages macrophage NNS 1212 1221 activated activate VBN 1222 1224 by by IN 1225 1227 15 15 CD 1228 1231 min min NN 1232 1234 of of IN 1235 1238 LPS LPS NNP 1239 1250 stimulation stimulation NN 1250 1251 , , , 1252 1262 indicating indicate VBG 1263 1267 that that IN 1268 1276 CNI-1493 cni-1493 NN 1277 1281 does do VBZ 1282 1285 not not RB 1286 1295 interfere interfere VB 1296 1300 with with IN 1301 1306 early early JJ 1307 1315 NF-kappa NF-kappa NNP 1316 1326 B-mediated b-mediated JJ 1327 1342 transcriptional transcriptional JJ 1343 1353 regulation regulation NN 1354 1356 of of IN 1357 1360 TNF TNF NNP 1360 1361 . . . 1362 1369 However however RB 1369 1370 , , , 1371 1380 synthesis synthesis NN 1381 1383 of of IN 1384 1387 the the DT 1388 1394 26-kDa 26-kda JJ 1395 1403 membrane membrane NN 1404 1408 form form NN 1409 1411 of of IN 1412 1415 TNF TNF NNP 1416 1419 was be VBD 1420 1431 effectively effectively RB 1432 1439 blocked block VBN 1440 1442 by by IN 1443 1451 CNI-1493 CNI-1493 NNP 1451 1452 . . . 1453 1460 Further further JJ 1461 1469 evidence evidence NN 1470 1473 for for IN 1474 1477 the the DT 1478 1491 translational translational JJ 1492 1503 suppression suppression NN 1504 1506 of of IN 1507 1510 TNF TNF NNP 1511 1513 is be VBZ 1514 1519 given give VBN 1520 1522 by by IN 1523 1534 experiments experiment NNS 1535 1540 using use VBG 1541 1557 chloram-phenicol chloram-phenicol NN 1558 1575 acetyltransferase acetyltransferase NN 1576 1577 ( ( ( 1577 1580 CAT CAT NNP 1580 1581 ) ) ) 1582 1592 constructs construct NNS 1593 1603 containing contain VBG 1604 1612 elements element NNS 1613 1615 of of IN 1616 1619 the the DT 1620 1623 TNF TNF NNP 1624 1628 gene gene NN 1629 1633 that that WDT 1634 1637 are be VBP 1638 1646 involved involve VBN 1647 1649 in in IN 1650 1653 TNF TNF NNP 1654 1667 translational translational JJ 1668 1678 regulation regulation NN 1678 1679 . . . 1680 1684 Both both CC 1685 1688 the the DT 1689 1690 5 5 CD 1690 1691 ’ ' SYM 1692 1695 and and CC 1696 1697 3 3 CD 1697 1698 ’ ' SYM 1699 1711 untranslated untranslated JJ 1712 1719 regions region NNS 1720 1722 of of IN 1723 1726 the the DT 1727 1730 TNF TNF NNP 1731 1735 gene gene NN 1736 1740 were be VBD 1741 1749 required require VBN 1750 1752 to to TO 1753 1759 elicit elicit VB 1760 1767 maximal maximal JJ 1768 1781 translational translational JJ 1782 1793 suppression suppression NN 1794 1796 by by IN 1797 1805 CNI-1493 CNI-1493 NNP 1805 1806 . . . 1807 1821 Identification identification NN 1822 1824 of of IN 1825 1828 the the DT 1829 1838 molecular molecular JJ 1839 1845 target target NN 1846 1853 through through IN 1854 1859 which which WDT 1860 1864 CNI- cni- NN 1865 1869 1493 1493 CD 1870 1878 inhibits inhibit VBZ 1879 1882 TNF TNF NNP 1883 1894 translation translation NN 1895 1901 should should MD 1902 1909 provide provide VB 1910 1917 insight insight NN 1918 1922 into into IN 1923 1926 the the DT 1927 1937 regulation regulation NN 1938 1940 of of IN 1941 1951 macrophage macrophage NN 1952 1962 activation activation NN 1963 1966 and and CC 1967 1977 mechanisms mechanism NNS 1978 1980 of of IN 1981 1993 inflammation inflammation NN 1993 1994 . . .