0 5 Stat6 Stat6 NNP 6 14 inhibits inhibit VBZ 15 20 human human JJ 21 34 interleukin-4 interleukin-4 NN 35 43 promoter promoter NN 44 52 activity activity NN 53 55 in in IN 56 57 T t NN 58 63 cells cell NNS 63 64 . . . 66 69 The the DT 70 85 differentiation differentiation NN 86 88 of of IN 89 94 naive naive JJ 95 103 T-helper T-helper NNP 104 105 ( ( ( 105 107 Th Th NNP 107 108 ) ) ) 109 114 cells cell NNS 115 119 into into IN 120 138 cytokine-secreting cytokine-secreting JJ 139 147 effector effector NN 148 150 Th Th NNP 151 156 cells cell NNS 157 165 requires require VBZ 166 174 exposure exposure NN 175 177 to to TO 178 186 multiple multiple JJ 187 194 signals signal NNS 194 195 , , , 196 205 including include VBG 206 215 exogenous exogenous JJ 216 225 cytokines cytokine NNS 225 226 . . . 227 240 Interleukin-4 interleukin-4 NN 241 242 ( ( ( 242 246 IL-4 il-4 NN 246 247 ) ) ) 248 253 plays play VBZ 254 255 a a DT 256 261 major major JJ 262 266 role role NN 267 269 in in IN 270 274 this this DT 275 282 process process NN 283 285 by by IN 286 295 promoting promote VBG 296 299 the the DT 300 315 differentiation differentiation NN 316 318 of of IN 319 333 IL-4-secreting il-4-secreting NN 334 337 Th2 th2 NN 338 343 cells cell NNS 343 344 . . . 345 347 In in IN 348 351 Th2 th2 NN 352 357 cells cell NNS 357 358 , , , 359 363 IL-4 il-4 NN 364 368 gene gene NN 369 379 expression expression NN 380 382 is be VBZ 383 390 tightly tightly RB 391 401 controlled control VBN 402 404 at at IN 405 408 the the DT 409 414 level level NN 415 417 of of IN 418 431 transcription transcription NN 432 434 by by IN 435 438 the the DT 439 450 coordinated coordinate VBN 451 458 binding binding NN 459 461 of of IN 462 470 multiple multiple JJ 471 484 transcription transcription NN 485 492 factors factor NNS 493 495 to to TO 496 506 regulatory regulatory JJ 507 515 elements element NNS 516 518 in in IN 519 522 the the DT 523 531 proximal proximal JJ 532 540 promoter promoter NN 541 547 region region NN 547 548 . . . 549 556 Nuclear nuclear JJ 557 563 factor factor NN 564 566 of of IN 567 576 activated activate VBN 577 578 T t NN 579 583 cell cell NN 584 585 ( ( ( 585 589 NFAT NFAT NNP 589 590 ) ) ) 591 597 family family NN 598 605 members member NNS 606 610 play play VBP 611 612 a a DT 613 621 critical critical JJ 622 626 role role NN 627 629 in in IN 630 640 regulating regulate VBG 641 645 IL-4 il-4 NN 646 659 transcription transcription NN 660 663 and and CC 664 672 interact interact VBP 673 677 with with IN 678 680 up up RB 681 683 to to TO 684 688 five five CD 689 698 sequences sequence NNS 699 700 ( ( ( 700 706 termed term VBN 707 709 P0 p0 NN 710 717 through through IN 718 720 P4 p4 NN 720 721 ) ) ) 722 724 in in IN 725 728 the the DT 729 733 IL-4 il-4 NN 734 742 promoter promoter NN 742 743 . . . 744 747 The the DT 748 757 molecular molecular JJ 758 768 mechanisms mechanism NNS 769 771 by by IN 772 777 which which WDT 778 782 IL-4 il-4 NN 783 790 induces induce VBZ 791 801 expression expression NN 802 804 of of IN 805 808 the the DT 809 813 IL-4 il-4 NN 814 818 gene gene NN 819 822 are be VBP 823 826 not not RB 827 832 known know VBN 832 833 , , , 834 842 although although IN 843 846 the the DT 847 861 IL-4-activated il-4-activated JJ 862 875 transcription transcription NN 876 882 factor factor NN 883 889 signal signal NN 890 900 transducer transducer NN 901 904 and and CC 905 914 activator activator NN 915 917 of of IN 918 931 transcription transcription NN 932 933 6 6 CD 934 935 ( ( ( 935 940 Stat6 stat6 NN 940 941 ) ) ) 942 944 is be VBZ 945 953 required require VBN 954 957 for for IN 958 962 this this DT 963 969 effect effect NN 969 970 . . . 971 973 We we PRP 974 980 report report VBP 981 985 here here RB 986 990 that that IN 991 996 Stat6 Stat6 NNP 997 1006 interacts interact VBZ 1007 1011 with with IN 1012 1017 three three CD 1018 1025 binding bind VBG 1026 1031 sites site NNS 1032 1034 in in IN 1035 1038 the the DT 1039 1044 human human JJ 1045 1049 IL-4 il-4 NN 1050 1058 promoter promoter NN 1059 1061 by by IN 1062 1077 electrophoretic electrophoretic JJ 1078 1086 mobility mobility NN 1087 1092 shift shift NN 1093 1099 assays assay NNS 1099 1100 . . . 1101 1106 These these DT 1107 1112 sites site NNS 1113 1120 overlap overlap VBP 1121 1124 the the DT 1125 1127 P1 p1 NN 1127 1128 , , , 1129 1131 P2 P2 NNP 1131 1132 , , , 1133 1136 and and CC 1137 1139 P4 P4 NNP 1140 1144 NFAT NFAT NNP 1145 1153 elements element NNS 1153 1154 . . . 1155 1157 To to TO 1158 1169 investigate investigate VB 1170 1173 the the DT 1174 1178 role role NN 1179 1181 of of IN 1182 1187 Stat6 Stat6 NNP 1188 1190 in in IN 1191 1201 regulating regulate VBG 1202 1206 IL-4 il-4 NN 1207 1220 transcription transcription NN 1220 1221 , , , 1222 1224 we we PRP 1225 1229 used use VBD 1230 1245 Stat6-deficient stat6-deficient JJ 1246 1252 Jurkat Jurkat NNP 1253 1254 T t NN 1255 1260 cells cell NNS 1261 1265 with with IN 1266 1275 different different JJ 1276 1282 intact intact JJ 1283 1287 IL-4 il-4 NN 1288 1296 promoter promoter NN 1297 1307 constructs construct NNS 1308 1310 in in IN 1311 1325 cotransfection cotransfection NN 1326 1332 assays assay NNS 1332 1333 . . . 1334 1336 We we PRP 1337 1341 show show VBP 1342 1346 that that IN 1346 1347 , , , 1348 1355 whereas whereas IN 1356 1357 a a DT 1358 1370 multimerized multimerized JJ 1371 1379 response response NN 1380 1387 element element NN 1388 1392 from from IN 1393 1396 the the DT 1397 1405 germline germline NN 1406 1409 IgE ige NN 1410 1418 promoter promoter NN 1419 1422 was be VBD 1423 1429 highly highly RB 1430 1437 induced induce VBN 1438 1440 by by IN 1441 1445 IL-4 il-4 NN 1446 1448 in in IN 1449 1465 Stat6-expressing stat6-expressing JJ 1466 1472 Jurkat Jurkat NNP 1473 1478 cells cell NNS 1478 1479 , , , 1480 1483 the the DT 1484 1490 intact intact JJ 1491 1496 human human JJ 1497 1501 IL-4 il-4 NN 1502 1510 promoter promoter NN 1511 1514 was be VBD 1515 1524 repressed repress VBN 1525 1530 under under IN 1531 1538 similar similar JJ 1539 1549 conditions condition NNS 1549 1550 . . . 1551 1553 We we PRP 1554 1562 conclude conclude VBP 1563 1567 that that IN 1568 1571 the the DT 1572 1580 function function NN 1581 1583 of of IN 1584 1589 Stat6 Stat6 NNP 1590 1592 is be VBZ 1593 1599 highly highly RB 1600 1609 dependent dependent JJ 1610 1612 on on IN 1613 1621 promoter promoter NN 1622 1629 context context NN 1630 1633 and and CC 1634 1638 that that IN 1639 1643 this this DT 1644 1650 factor factor NN 1651 1659 promotes promote VBZ 1660 1664 IL-4 il-4 NN 1665 1669 gene gene NN 1670 1680 expression expression NN 1681 1683 in in IN 1684 1686 an an DT 1687 1695 indirect indirect JJ 1696 1702 manner manner NN 1702 1703 . . .