0 15 Transcriptional transcriptional JJ 16 21 basis basis NN 22 25 for for IN 26 44 hyporesponsiveness hyporesponsiveness NN 45 47 of of IN 48 51 the the DT 52 57 human human JJ 58 67 inducible inducible JJ 68 74 nitric nitric JJ 75 80 oxide oxide NN 81 89 synthase synthase NN 90 94 gene gene NN 95 97 to to TO 98 133 lipopolysaccharide/interferon-gamma lipopolysaccharide/interferon-gamma NN 133 134 . . . 136 139 The the DT 140 144 work work NN 145 153 reported report VBN 154 158 here here RB 159 167 resolves resolve VBZ 167 168 , , , 169 171 at at IN 172 175 the the DT 176 181 level level NN 182 184 of of IN 185 189 gene gene NN 190 200 regulation regulation NN 200 201 , , , 202 205 the the DT 206 217 controversy controversy NN 218 220 as as IN 221 223 to to TO 224 231 whether whether IN 232 234 or or CC 235 238 not not RB 239 244 human human JJ 245 266 monocytes/macrophages monocytes/macrophage NNS 267 270 can can MD 271 278 produce produce VB 279 285 nitric nitric JJ 286 291 oxide oxide NN 292 293 ( ( ( 293 295 NO no NN 295 296 ) ) ) 297 301 when when WRB 302 312 stimulated stimulate VBN 313 317 with with IN 318 336 lipopolysaccharide lipopolysaccharide NN 337 338 ( ( ( 338 341 LPS LPS NNP 341 342 ) ) ) 342 343 , , , 344 348 with with IN 349 351 or or CC 352 359 without without IN 360 374 co-stimulation co-stimulation NN 375 377 by by IN 378 394 interferon-gamma interferon-gamma NN 395 396 ( ( ( 396 405 IFN-gamma IFN-gamma NNP 405 406 ) ) ) 406 407 . . . 408 415 Studies Study NNPS 416 424 included include VBD 425 435 structural structural JJ 436 446 comparison comparison NN 447 449 of of IN 450 453 the the DT 454 463 promoters promoter NNS 464 467 for for IN 468 473 human human JJ 474 477 and and CC 478 483 mouse mouse NN 484 493 inducible inducible JJ 494 496 NO no NN 497 505 synthase synthase NN 506 507 ( ( ( 507 511 iNOS inos NN 511 512 ) ) ) 513 518 genes gene NNS 518 519 , , , 520 532 transfection transfection NN 533 536 and and CC 537 542 assay assay NN 543 545 of of IN 546 551 human human JJ 552 555 and and CC 556 561 mouse mouse NN 562 566 iNOS inos NN 567 575 promoter promoter NN 576 583 regions region NNS 584 586 in in IN 587 595 response response NN 596 598 to to TO 599 602 LPS LPS NNP 603 606 +/- +/- CC 607 616 IFN-gamma IFN-gamma NNP 616 617 , , , 618 621 and and CC 622 637 electrophoretic electrophoretic JJ 638 646 mobility mobility NN 647 652 shift shift NN 653 659 assays assay NNS 660 662 of of IN 663 668 kappa kappa NN 669 670 B B NNP 671 679 response response NN 680 688 elements element NNS 688 689 . . . 690 693 Two two CD 694 706 explanations explanation NNS 707 710 for for IN 711 729 hyporesponsiveness hyporesponsiveness NN 730 732 of of IN 733 736 the the DT 737 742 human human JJ 743 747 iNOS inos NN 748 756 promoter promoter NN 757 759 to to TO 760 763 LPS LPS NNP 764 767 +/- +/- SYM 768 777 IFN-gamma IFN-gamma NNP 778 782 were be VBD 783 788 found find VBN 788 789 : : : 790 791 ( ( ( 791 792 1 1 LS 792 793 ) ) ) 794 802 multiple multiple JJ 803 815 inactivating inactivate VBG 816 826 nucleotide nucleotide NN 827 840 substitutions substitution NNS 841 843 in in IN 844 847 the the DT 848 853 human human JJ 854 865 counterpart counterpart NN 866 868 of of IN 869 872 the the DT 873 881 enhancer enhancer NN 882 889 element element NN 890 894 that that WDT 895 898 has have VBZ 899 903 been be VBN 904 909 shown show VBN 910 912 to to TO 913 921 regulate regulate VB 922 935 LPS/IFN-gamma LPS/IFN-gamma NNP 936 943 induced induced JJ 944 954 expression expression NN 955 957 of of IN 958 961 the the DT 962 967 mouse mouse NN 968 972 iNOS inos NN 973 977 gene gene NN 977 978 ; ; : 979 982 and and CC 983 984 ( ( ( 984 985 2 2 LS 985 986 ) ) ) 987 990 and and CC 991 998 absence absence NN 999 1001 of of IN 1002 1005 one one CD 1006 1008 or or CC 1009 1013 more more JJR 1014 1021 nuclear nuclear JJ 1022 1029 factors factor NNS 1030 1032 in in IN 1033 1038 human human JJ 1039 1050 macrophages macrophage NNS 1051 1052 ( ( ( 1052 1056 e.g. e.g. FW 1056 1057 , , , 1058 1060 an an DT 1061 1074 LPS-inducible lps-inducible JJ 1075 1082 nuclear nuclear JJ 1083 1095 factor-kappa factor-kappa NN 1096 1101 B/Rel B/Rel NNP 1102 1109 complex complex NN 1109 1110 ) ) ) 1110 1111 , , , 1112 1116 that that WDT 1117 1119 is be VBZ 1120 1121 ( ( ( 1121 1124 are be VBP 1124 1125 ) ) ) 1126 1134 required require VBN 1135 1138 for for IN 1139 1146 maximal maximal JJ 1147 1157 expression expression NN 1158 1160 of of IN 1161 1164 the the DT 1165 1169 gene gene NN 1169 1170 . . . 1171 1174 The the DT 1175 1185 importance importance NN 1186 1188 of of IN 1189 1199 resolution resolution NN 1200 1202 of of IN 1203 1207 this this DT 1208 1219 controversy controversy NN 1220 1222 is be VBZ 1223 1227 that that IN 1228 1234 future future JJ 1235 1243 research research NN 1244 1246 in in IN 1247 1251 this this DT 1252 1256 area area NN 1257 1263 should should MD 1264 1266 be be VB 1267 1275 directed direct VBN 1276 1282 toward toward IN 1283 1286 the the DT 1287 1300 understanding understanding NN 1301 1303 of of IN 1304 1315 alternative alternative JJ 1316 1326 mechanisms mechanism NNS 1327 1331 that that WDT 1332 1335 can can MD 1336 1342 result result VB 1343 1345 in in IN 1346 1349 the the DT 1350 1360 successful successful JJ 1361 1371 production production NN 1372 1374 of of IN 1375 1377 NO no NN 1377 1378 . . .