0 5 IL-12 il-12 NN 6 13 induces induce VBZ 14 17 IFN ifn NN 18 28 regulating regulate VBG 29 37 factor-1 factor-1 NN 38 39 ( ( ( 39 44 IRF-1 irf-1 NN 44 45 ) ) ) 46 50 gene gene NN 51 61 expression expression NN 62 64 in in IN 65 70 human human JJ 71 73 NK nk NN 74 77 and and CC 78 79 T t NN 80 85 cells cell NNS 85 86 . . . 88 93 IL-12 il-12 NN 94 96 is be VBZ 97 98 a a DT 99 107 critical critical JJ 108 124 immunoregulatory immunoregulatory JJ 125 133 cytokine cytokine NN 134 138 that that WDT 139 147 promotes promote VBZ 148 161 cell-mediated cell-mediated JJ 162 168 immune immune JJ 169 178 responses response NNS 179 182 and and CC 183 186 the the DT 187 202 differentiation differentiation NN 203 205 of of IN 206 211 naive naive JJ 212 216 CD4+ cd4+ JJ 217 222 cells cell NNS 223 225 to to TO 226 229 Th1 th1 NN 230 235 cells cell NNS 235 236 ; ; : 237 244 however however RB 244 245 , , , 246 256 relatively relatively RB 257 260 few few JJ 261 266 IL-12 il-12 NN 267 273 target target NN 274 279 genes gene NNS 280 284 have have VBP 285 289 been be VBN 290 300 identified identify VBN 300 301 . . . 302 304 To to TO 305 311 better well RBR 312 319 clarify clarify VB 320 323 the the DT 324 333 molecular molecular JJ 334 339 basis basis NN 340 342 of of IN 343 348 IL-12 il-12 NN 349 355 action action NN 355 356 , , , 357 359 we we PRP 360 363 set set VBD 364 367 out out RP 368 370 to to TO 371 383 characterize characterize VB 384 389 genes gene NNS 390 402 up-regulated up-regulate VBN 403 405 by by IN 406 411 IL-12 il-12 NN 411 412 , , , 413 418 first first RB 419 421 by by IN 422 433 contrasting contrast VBG 434 440 IL-12- il-12- NN 441 444 and and CC 445 464 IFN-alpha-inducible ifn-alpha-inducible JJ 465 470 genes gene NNS 470 471 . . . 472 474 We we PRP 475 485 identified identify VBD 486 493 several several JJ 494 499 genes gene NNS 500 512 up-regulated up-regulate VBN 513 515 by by IN 516 521 IL-12 il-12 NN 521 522 , , , 523 529 namely namely RB 529 530 , , , 531 541 MIP-1alpha MIP-1alpha NNP 541 542 , , , 543 552 MIP-1beta MIP-1beta NNP 552 553 , , , 554 560 IL-1RA IL-1RA NNP 560 561 , , , 562 565 and and CC 566 569 IFN ifn NN 570 580 regulatory regulatory JJ 581 589 factor-1 factor-1 NN 590 591 ( ( ( 591 596 IRF-1 irf-1 NN 596 597 ) ) ) 597 598 . . . 599 604 IRF-1 IRF-1 NNP 605 607 is be VBZ 608 609 a a DT 610 623 transcription transcription NN 624 630 factor factor NN 631 640 regulated regulate VBN 641 643 by by IN 644 648 IFNs IFN NNP 649 653 that that WDT 654 656 is be VBZ 657 661 also also RB 662 671 essential essential JJ 672 675 for for IN 676 679 Th1 th1 NN 680 689 responses response NNS 689 690 . . . 691 693 We we PRP 694 706 demonstrated demonstrate VBD 707 711 that that IN 712 717 IL-12 il-12 NN 718 726 directly directly RB 727 739 up-regulates up-regulate VBZ 740 745 IRF-1 irf-1 NN 746 748 to to TO 749 752 the the DT 753 757 same same JJ 758 764 extent extent NN 765 767 as as IN 768 777 IFN-alpha IFN-alpha NNP 778 780 in in IN 781 787 normal normal JJ 788 793 human human JJ 794 795 T t NN 796 801 cells cell NNS 802 805 and and CC 806 808 in in IN 809 811 NK NK NNP 812 817 cells cell NNS 817 818 . . . 819 821 We we PRP 822 828 showed show VBD 829 833 that that IN 834 839 IL-12 il-12 NN 840 843 had have VBD 844 845 a a DT 846 852 direct direct JJ 853 859 effect effect NN 860 862 on on IN 863 868 IRF-1 IRF-1 NNP 868 869 , , , 870 872 an an DT 873 879 effect effect NN 880 883 not not RB 884 892 mediated mediate VBN 893 903 indirectly indirectly RB 904 906 by by IN 907 910 the the DT 911 920 induction induction NN 921 923 of of IN 924 933 IFN-gamma IFN-gamma NNP 934 944 production production NN 944 945 . . . 946 957 Furthermore furthermore RB 957 958 , , , 959 963 IL-2 il-2 NN 964 967 and and CC 968 973 IL-12 il-12 NN 974 989 synergistically synergistically RB 990 997 induced induce VBD 998 1003 IRF-1 irf-1 NN 1003 1004 , , , 1005 1012 whereas whereas IN 1013 1022 IFN-alpha IFN-alpha NNP 1023 1026 and and CC 1027 1032 IL-12 il-12 NN 1033 1036 did do VBD 1037 1040 not not RB 1040 1041 . . . 1042 1045 The the DT 1046 1059 participation participation NN 1060 1062 of of IN 1063 1068 STAT4 stat4 NN 1069 1071 in in IN 1072 1075 the the DT 1076 1086 regulation regulation NN 1087 1089 of of IN 1090 1095 IRF-1 IRF-1 NNP 1096 1099 was be VBD 1100 1112 demonstrated demonstrate VBN 1113 1115 in in IN 1116 1119 two two CD 1120 1124 ways way NNS 1124 1125 . . . 1126 1131 First first RB 1131 1132 , , , 1133 1138 STAT4 STAT4 NNP 1139 1142 was be VBD 1143 1151 required require VBN 1152 1155 for for IN 1156 1159 the the DT 1160 1175 IL-12-dependent il-12-dependent JJ 1176 1191 transactivation transactivation NN 1192 1194 of of IN 1195 1197 an an DT 1198 1203 IRF-1 irf-1 NN 1204 1212 reporter reporter NN 1213 1222 construct construct NN 1222 1223 , , , 1224 1227 and and CC 1228 1234 second second RB 1234 1235 , , , 1236 1241 STAT4 stat4 NN 1242 1249 binding bind VBG 1250 1252 to to TO 1253 1256 the the DT 1257 1262 IRF-1 irf-1 NN 1263 1271 promoter promoter NN 1272 1275 was be VBD 1276 1281 shown show VBN 1282 1287 using use VBG 1288 1292 EMSA EMSA NNP 1292 1293 . . . 1294 1296 In in IN 1297 1305 contrast contrast NN 1306 1308 to to TO 1309 1314 IL-12 il-12 NN 1314 1315 , , , 1316 1318 no no DT 1319 1332 up-regulation up-regulation NN 1333 1335 of of IN 1336 1341 IRF-1 IRF-1 NNP 1342 1345 was be VBD 1346 1351 found find VBN 1352 1354 in in IN 1355 1370 IL-4-stimulated il-4-stimulated JJ 1371 1376 cells cell NNS 1376 1377 , , , 1378 1381 and and CC 1382 1386 IL-4 il-4 NN 1387 1390 did do VBD 1391 1394 not not RB 1395 1400 block block VB 1401 1416 IL-12-dependent il-12-dependent JJ 1417 1430 up-regulation up-regulation NN 1431 1433 of of IN 1434 1439 IRF-1 irf-1 NN 1439 1440 . . . 1441 1450 Therefore therefore RB 1450 1451 , , , 1452 1457 IRF-1 IRF-1 NNP 1458 1461 may may MD 1462 1464 be be VB 1465 1467 an an DT 1468 1477 important important JJ 1478 1489 contributor contributor NN 1490 1492 to to TO 1493 1498 IL-12 il-12 NN 1499 1508 signaling signaling NN 1508 1509 , , , 1510 1513 and and CC 1514 1516 we we PRP 1517 1526 speculate speculate VBP 1527 1531 that that IN 1532 1535 the the DT 1536 1545 defective defective JJ 1546 1551 IL-12 il-12 NN 1552 1561 responses response NNS 1562 1566 seen see VBN 1567 1569 in in IN 1570 1578 IRF-1-/- irf-1-/- JJ 1579 1583 mice mouse NNS 1584 1589 might might MD 1590 1592 be be VB 1593 1605 attributable attributable JJ 1605 1606 , , , 1607 1609 in in IN 1610 1614 part part NN 1614 1615 , , , 1616 1618 to to TO 1619 1622 the the DT 1623 1630 absence absence NN 1631 1633 of of IN 1634 1638 this this DT 1639 1652 transcription transcription NN 1653 1659 factor factor NN 1659 1660 . . .