0 11 Interferons interferon NNS 12 19 inhibit inhibit VBP 20 30 activation activation NN 31 33 of of IN 34 39 STAT6 stat6 NN 40 42 by by IN 43 54 interleukin interleukin NN 55 56 4 4 CD 57 59 in in IN 60 65 human human JJ 66 75 monocytes monocyte NNS 76 78 by by IN 79 87 inducing induce VBG 88 94 SOCS-1 socs-1 NN 95 99 gene gene NN 100 110 expression expression NN 110 111 . . . 113 124 Interferons Interferon NNP 125 126 ( ( ( 126 130 IFNs IFN NNP 130 131 ) ) ) 132 139 inhibit inhibit VBP 140 149 induction induction NN 150 152 by by IN 153 157 IL-4 il-4 NN 158 160 of of IN 161 169 multiple multiple JJ 170 175 genes gene NNS 176 178 in in IN 179 184 human human JJ 185 194 monocytes monocyte NNS 194 195 . . . 196 203 However however RB 203 204 , , , 205 208 the the DT 209 218 mechanism mechanism NN 219 221 by by IN 222 227 which which WDT 228 232 IFNs ifn NNS 233 240 mediate mediate VBP 241 245 this this DT 246 256 inhibition inhibition NN 257 260 has have VBZ 261 264 not not RB 265 269 been be VBN 270 277 defined define VBN 277 278 . . . 279 283 IL-4 il-4 NN 284 293 activates activate VBZ 294 298 gene gene NN 299 309 expression expression NN 310 312 by by IN 313 321 inducing induce VBG 322 330 tyrosine tyrosine NN 331 346 phosphorylation phosphorylation NN 346 347 , , , 348 364 homodimerization homodimerization NN 364 365 , , , 366 369 and and CC 370 377 nuclear nuclear JJ 378 391 translocation translocation NN 392 394 of of IN 395 398 the the DT 399 405 latent latent JJ 406 419 transcription transcription NN 420 426 factor factor NN 426 427 , , , 428 433 STAT6 STAT6 NNP 434 435 ( ( ( 435 441 signal signal NN 442 452 transducer transducer NN 453 456 and and CC 457 466 activator activator NN 467 469 of of IN 470 485 transcription-6 transcription-6 NN 485 486 ) ) ) 486 487 . . . 488 504 STAT6-responsive stat6-responsive JJ 505 513 elements element NNS 514 517 are be VBP 518 536 characteristically characteristically RB 537 544 present present JJ 545 547 in in IN 548 551 the the DT 552 561 promoters promoter NNS 562 564 of of IN 565 579 IL-4-inducible il-4-inducible JJ 580 585 genes gene NNS 585 586 . . . 587 594 Because because IN 595 600 STAT6 STAT6 NNP 601 611 activation activation NN 612 614 is be VBZ 615 624 essential essential JJ 625 628 for for IN 629 641 IL-4-induced il-4-induced JJ 642 646 gene gene NN 647 657 expression expression NN 657 658 , , , 659 661 we we PRP 662 670 examined examine VBD 671 674 the the DT 675 682 ability ability NN 683 685 of of IN 686 690 type type NN 691 692 I i CD 693 696 and and CC 697 701 type type NN 702 704 II ii CD 705 709 IFNs IFN NNP 710 712 to to TO 713 721 regulate regulate VB 722 732 activation activation NN 733 735 of of IN 736 741 STAT6 stat6 NN 742 744 by by IN 745 749 IL-4 il-4 NN 750 752 in in IN 753 760 primary primary JJ 761 766 human human JJ 767 776 monocytes monocyte NNS 776 777 . . . 778 790 Pretreatment Pretreatment NNP 791 793 of of IN 794 803 monocytes monocyte NNS 804 808 with with IN 809 817 IFN-beta IFN-beta NNP 818 820 or or CC 821 830 IFN-gamma IFN-gamma NNP 830 831 , , , 832 835 but but CC 836 839 not not RB 840 844 IL-1 il-1 NN 844 845 , , , 846 850 IL-2 il-2 NN 850 851 , , , 852 862 macrophage macrophage NN 863 881 colony-stimulating colony-stimulating JJ 882 888 factor factor NN 888 889 , , , 890 912 granulocyte/macrophage granulocyte/macrophage JJ 913 931 colony-stimulating colony-stimulating JJ 932 938 factor factor NN 938 939 , , , 940 944 IL-6 IL-6 NNP 944 945 , , , 946 948 or or CC 949 961 transforming transform VBG 962 968 growth growth NN 969 975 factor factor NN 976 980 beta beta SYM 981 991 suppressed suppress VBD 992 1002 activation activation NN 1003 1005 of of IN 1006 1011 STAT6 stat6 NN 1012 1014 by by IN 1015 1019 IL-4 il-4 NN 1019 1020 . . . 1021 1025 This this DT 1026 1036 inhibition inhibition NN 1037 1040 was be VBD 1041 1051 associated associate VBN 1052 1056 with with IN 1057 1066 decreased decrease VBN 1067 1075 tyrosine tyrosine NN 1076 1091 phosphorylation phosphorylation NN 1092 1095 and and CC 1096 1103 nuclear nuclear JJ 1104 1117 translocation translocation NN 1118 1120 of of IN 1121 1126 STAT6 STAT6 NNP 1127 1130 and and CC 1131 1134 was be VBD 1135 1138 not not RB 1139 1146 evident evident JJ 1147 1153 unless unless IN 1154 1157 the the DT 1158 1163 cells cell NNS 1164 1168 were be VBD 1169 1181 preincubated preincubate VBN 1182 1186 with with IN 1187 1190 IFN IFN NNP 1191 1194 for for IN 1195 1197 at at IN 1198 1203 least least JJS 1204 1205 1 1 CD 1206 1208 hr hr NN 1209 1215 before before IN 1216 1220 IL-4 il-4 NN 1221 1232 stimulation stimulation NN 1232 1233 . . . 1234 1245 Furthermore furthermore RB 1245 1246 , , , 1247 1257 inhibition inhibition NN 1258 1260 by by IN 1261 1264 IFN IFN NNP 1265 1270 could could MD 1271 1273 be be VB 1274 1281 blocked block VBN 1282 1284 by by IN 1285 1296 cotreatment cotreatment NN 1297 1301 with with IN 1302 1313 actinomycin actinomycin NN 1314 1315 D D NNP 1316 1319 and and CC 1320 1330 correlated correlate VBD 1331 1341 temporally temporally RB 1342 1346 with with IN 1347 1356 induction induction NN 1357 1359 of of IN 1360 1363 the the DT 1364 1372 JAK/STAT JAK/STAT NNP 1373 1383 inhibitory inhibitory JJ 1384 1388 gene gene NN 1388 1389 , , , 1390 1396 SOCS-1 SOCS-1 NNP 1396 1397 . . . 1398 1404 Forced force VBN 1405 1415 expression expression NN 1416 1418 of of IN 1419 1425 SOCS-1 socs-1 NN 1426 1428 in in IN 1429 1430 a a DT 1431 1441 macrophage macrophage NN 1442 1446 cell cell NN 1447 1451 line line NN 1451 1452 , , , 1453 1459 RAW264 RAW264 NNP 1459 1460 , , , 1461 1469 markedly markedly RB 1470 1480 suppressed suppress VBD 1481 1497 trans-activation trans-activation NN 1498 1500 of of IN 1501 1503 an an DT 1504 1518 IL-4-inducible il-4-inducible JJ 1519 1527 reporter reporter NN 1528 1530 as as RB 1531 1535 well well RB 1536 1538 as as IN 1539 1544 IL-6- IL-6- NNP 1545 1548 and and CC 1549 1566 IFN-gamma-induced ifn-gamma-induced JJ 1567 1575 reporter reporter NN 1576 1580 gene gene NN 1581 1589 activity activity NN 1589 1590 . . . 1591 1596 These these DT 1597 1605 findings finding NNS 1606 1617 demonstrate demonstrate VBP 1618 1622 that that IN 1623 1627 IFNs ifn NNS 1628 1635 inhibit inhibit VBP 1636 1648 IL-4-induced il-4-induced JJ 1649 1659 activation activation NN 1660 1662 of of IN 1663 1668 STAT6 STAT6 NNP 1669 1672 and and CC 1673 1688 STAT6-dependent stat6-dependent JJ 1689 1693 gene gene NN 1694 1704 expression expression NN 1704 1705 , , , 1706 1708 at at IN 1709 1714 least least JJS 1715 1717 in in IN 1718 1722 part part NN 1722 1723 , , , 1724 1726 by by IN 1727 1735 inducing induce VBG 1736 1746 expression expression NN 1747 1749 of of IN 1750 1756 SOCS-1 socs-1 NN 1756 1757 . . .