0 10 Activation Activation NNP 11 13 of of IN 14 21 nuclear nuclear JJ 22 35 factor-kappaB factor-kappab NN 36 38 by by IN 39 57 lipopolysaccharide lipopolysaccharide NN 58 60 in in IN 61 72 mononuclear mononuclear JJ 73 83 leukocytes leukocyte NNS 84 86 is be VBZ 87 96 prevented prevent VBN 97 99 by by IN 100 110 inhibitors inhibitor NNS 111 113 of of IN 114 123 cytosolic cytosolic JJ 124 137 phospholipase phospholipase NN 138 140 A2 a2 NN 140 141 . . . 143 145 In in IN 146 155 monocytes monocyte NNS 155 156 , , , 157 175 lipopolysaccharide lipopolysaccharide NN 176 183 induces induce VBZ 184 193 synthesis synthesis NN 194 197 and and CC 198 206 activity activity NN 207 209 of of IN 210 213 the the DT 214 220 85-kDa 85-kda JJ 221 230 cytosolic cytosolic JJ 231 244 phospholipase phospholipase NN 245 247 A2 a2 NN 247 248 . . . 249 253 This this DT 254 260 enzyme enzyme NN 261 269 releases release VBZ 270 281 arachidonic arachidonic JJ 282 286 acid acid NN 287 290 and and CC 291 309 lyso-phospholipids lyso-phospholipid NNS 310 314 from from IN 315 324 membranes membrane NNS 325 330 which which WDT 331 334 are be VBP 335 346 metabolized metabolize VBN 347 349 to to TO 350 361 eicosanoids eicosanoid NNS 362 365 and and CC 366 392 platelet-activating-factor platelet-activating-factor NN 392 393 . . . 394 399 These these DT 400 405 lipid lipid NN 406 415 mediators mediator NNS 416 424 increase increase VBP 425 433 activity activity NN 434 436 of of IN 437 450 transcription transcription NN 451 458 factors factor NNS 459 462 and and CC 463 473 expression expression NN 474 476 of of IN 477 485 cytokine cytokine NN 486 491 genes gene NNS 492 502 indicating indicate VBG 503 504 a a DT 505 513 function function NN 514 517 for for IN 518 527 cytosolic cytosolic JJ 528 541 phospholipase phospholipase NN 542 544 A2 a2 NN 545 547 in in IN 548 554 signal signal NN 555 567 transduction transduction NN 568 571 and and CC 572 584 inflammation inflammation NN 584 585 . . . 586 588 We we PRP 589 593 have have VBP 594 599 shown show VBN 600 610 previously previously RB 611 615 that that IN 616 637 trifluoromethylketone trifluoromethylketone NN 638 648 inhibitors inhibitor NNS 649 651 of of IN 652 661 cytosolic cytosolic JJ 662 675 phospholipase phospholipase NN 676 678 A2 a2 NN 679 689 suppressed suppress VBD 690 707 interleukin-1beta interleukin-1beta NN 708 715 protein protein NN 716 719 and and CC 720 732 steady-state steady-state JJ 733 737 mRNA mrna NN 738 744 levels level NNS 745 747 in in IN 748 753 human human JJ 754 783 lipopolysaccharide-stimulated lipopolysaccharide-stimulated JJ 784 794 peripheral peripheral JJ 795 800 blood blood NN 801 812 mononuclear mononuclear JJ 813 823 leukocytes leukocyte NNS 823 824 . . . 825 827 In in IN 828 832 this this DT 833 838 study study NN 838 839 , , , 840 843 the the DT 844 855 subcellular subcellular JJ 856 866 mechanisms mechanism NNS 867 871 were be VBD 872 880 analyzed analyze VBN 881 883 by by IN 884 889 which which WDT 890 912 trifluoromethylketones trifluoromethylketone NNS 913 922 interfere interfere VBP 923 927 with with IN 928 932 gene gene NN 933 943 expression expression NN 943 944 . . . 945 947 We we PRP 948 953 found find VBD 954 958 that that IN 959 963 they they PRP 964 971 reduced reduce VBD 972 975 the the DT 976 983 initial initial JJ 984 1001 interleukin-1beta interleukin-1beta NN 1002 1006 mRNA mrna NN 1007 1020 transcription transcription NN 1021 1025 rate rate NN 1026 1033 through through IN 1034 1044 prevention prevention NN 1045 1047 of of IN 1048 1059 degradation degradation NN 1060 1062 of of IN 1063 1079 inhibitor-kappaB inhibitor-kappab NN 1080 1085 alpha alpha NN 1085 1086 . . . 1087 1099 Consequently consequently RB 1099 1100 , , , 1101 1110 cytosolic cytosolic JJ 1111 1121 activation activation NN 1121 1122 , , , 1123 1130 nuclear nuclear JJ 1131 1144 translocation translocation NN 1145 1148 and and CC 1149 1160 DNA-binding dna-binding NN 1161 1163 of of IN 1164 1171 nuclear nuclear JJ 1172 1185 factor-kappaB factor-kappab NN 1186 1190 were be VBD 1191 1200 decreased decrease VBN 1200 1201 . . . 1202 1224 Trifluoromethylketones trifluoromethylketone NNS 1225 1235 ameliorate ameliorate VBP 1236 1243 chronic chronic JJ 1244 1256 inflammation inflammation NN 1257 1259 in in FW 1260 1264 vivo vivo FW 1264 1265 . . . 1266 1270 Thus thus RB 1270 1271 , , , 1272 1276 this this DT 1277 1288 therapeutic therapeutic JJ 1289 1296 potency potency NN 1297 1300 may may MD 1301 1307 reside reside VB 1308 1310 in in IN 1311 1320 retention retention NN 1321 1323 of of IN 1324 1332 inactive inactive JJ 1333 1340 nuclear nuclear JJ 1341 1354 factor-kappaB factor-kappab NN 1355 1357 in in IN 1358 1361 the the DT 1362 1369 cytosol cytosol NN 1370 1377 thereby thereby RB 1378 1388 abrogating abrogate VBG 1389 1406 interleukin-1beta interleukin-1beta NN 1407 1411 gene gene NN 1412 1425 transcription transcription NN 1425 1426 . . .