0 12 Requirements requirement NNS 13 16 for for IN 17 26 induction induction NN 27 29 of of IN 30 37 vitamin vitamin NN 38 48 D-mediated d-mediated JJ 49 53 gene gene NN 54 64 regulation regulation NN 65 67 in in IN 68 74 normal normal JJ 75 80 human human JJ 81 82 B b NN 83 94 lymphocytes lymphocyte NNS 94 95 . . . 97 103 Mature mature JJ 104 109 human human JJ 110 121 lymphocytes lymphocyte NNS 122 125 are be VBP 126 132 unique unique JJ 133 140 targets target NNS 141 143 of of IN 144 145 1 1 CD 146 171 alpha,25-dihydroxyvitamin alpha,25-dihydroxyvitamin NN 172 174 D3 d3 NN 175 176 ( ( ( 176 177 1 1 CD 178 194 alpha,25(OH)2D3) alpha,25(oh)2d3) NN 195 197 in in IN 198 202 that that DT 203 210 vitamin vitamin NN 211 212 D D NNP 213 222 receptors receptor NNS 223 224 ( ( ( 224 227 VDR VDR NNP 227 228 ) ) ) 229 232 are be VBP 233 236 not not RB 237 251 constitutively constitutively RB 252 261 expressed express VBN 261 262 , , , 263 266 and and CC 267 275 specific specific JJ 276 284 cellular cellular JJ 285 295 activation activation NN 296 303 signals signal NNS 304 307 are be VBP 308 316 required require VBN 317 320 for for IN 321 325 both both CC 326 329 the the DT 330 343 up-regulation up-regulation NN 344 346 of of IN 347 350 VDR VDR NNP 351 354 and and CC 355 368 establishment establishment NN 369 371 of of IN 372 382 reactivity reactivity NN 383 385 to to TO 386 389 the the DT 390 400 lipophilic lipophilic JJ 401 407 ligand ligand NN 407 408 . . . 409 418 Treatment Treatment NNP 419 421 of of IN 422 423 B B NNP 424 435 lymphocytes lymphocyte NNS 436 440 with with IN 441 444 the the DT 445 453 cytokine cytokine NN 454 458 IL-4 il-4 NN 459 460 ( ( ( 460 464 IL-4 il-4 NN 464 465 ) ) ) 465 466 , , , 467 469 in in IN 470 473 the the DT 474 481 absence absence NN 482 484 of of IN 485 490 prior prior JJ 491 501 activation activation NN 501 502 , , , 503 510 induces induce VBZ 511 512 a a DT 513 517 weak weak JJ 518 531 up-regulation up-regulation NN 532 534 of of IN 535 538 VDR VDR NNP 539 549 expression expression NN 550 553 but but CC 554 559 fails fail VBZ 560 562 to to TO 563 571 generate generate VB 572 579 vitamin vitamin NN 580 592 D-responsive d-responsive JJ 593 600 element element NN 601 602 ( ( ( 602 616 VDRE)-reactive vdre)-reactive JJ 617 624 nuclear nuclear JJ 625 632 protein protein NN 633 642 complexes complex NNS 643 645 or or CC 646 648 to to TO 649 657 initiate initiate VB 658 661 the the DT 662 669 genomic genomic JJ 670 683 transcription transcription NN 684 686 of of IN 687 704 25-hydroxyvitamin 25-hydroxyvitamin NN 705 707 D3 d3 NN 708 722 24-hydroxylase 24-hydroxylase NN 722 723 . . . 724 735 Stimulation stimulation NN 736 738 of of IN 739 740 B B NNP 741 752 lymphocytes lymphocyte NNS 753 755 by by IN 756 762 either either CC 763 771 ligation ligation NN 772 774 of of IN 775 779 CD40 CD40 NNP 780 782 Ag Ag NNP 783 785 or or CC 786 799 cross-linking cross-linke VBG 800 803 the the DT 804 806 Ig Ig NNP 807 815 receptor receptor NN 816 818 is be VBZ 819 823 also also RB 824 836 insufficient insufficient JJ 837 839 to to TO 840 846 render render VB 847 848 B B NNP 849 860 lymphocytes lymphocyte NNS 861 871 responsive responsive JJ 872 874 to to TO 875 876 1 1 CD 877 892 alpha,25(OH)2D3 alpha,25(oh)2d3 NN 892 893 . . . 894 901 However however RB 901 902 , , , 903 907 this this DT 908 916 apparent apparent JJ 917 921 lack lack NN 922 924 of of IN 925 933 response response NN 934 936 to to TO 937 940 the the DT 941 951 secosterol secosterol NN 952 955 can can MD 956 958 be be VB 959 967 overcome overcome VBN 968 970 by by IN 971 982 stimulation stimulation NN 983 985 of of IN 986 987 B B NNP 988 999 lymphocytes lymphocyte NNS 1000 1004 with with IN 1005 1006 a a DT 1007 1018 combination combination NN 1019 1021 of of IN 1022 1027 these these DT 1028 1036 cellular cellular JJ 1037 1047 activation activation NN 1048 1055 signals signal NNS 1055 1056 , , , 1057 1062 which which WDT 1063 1066 are be VBP 1067 1077 sufficient sufficient JJ 1078 1080 to to TO 1081 1085 lead lead VB 1086 1088 to to TO 1089 1091 G1 g1 NN 1092 1096 cell cell NN 1097 1102 cycle cycle NN 1103 1114 progression progression NN 1114 1115 . . . 1116 1118 In in IN 1119 1122 the the DT 1123 1131 presence presence NN 1132 1134 of of IN 1135 1136 1 1 CD 1137 1152 alpha,25(OH)2D3 alpha,25(oh)2d3 NN 1152 1153 , , , 1154 1162 cellular cellular JJ 1163 1173 activation activation NN 1174 1184 associated associate VBN 1185 1189 with with IN 1190 1201 stimulation stimulation NN 1202 1204 of of IN 1205 1209 such such JJ 1210 1211 a a DT 1212 1223 progression progression NN 1224 1231 appears appear VBZ 1232 1234 to to TO 1235 1237 be be VB 1238 1248 sufficient sufficient JJ 1249 1252 for for IN 1253 1256 the the DT 1257 1270 up-regulation up-regulation NN 1271 1273 of of IN 1274 1277 VDR VDR NNP 1278 1285 message message NN 1286 1289 and and CC 1290 1297 protein protein NN 1298 1301 and and CC 1302 1311 necessary necessary JJ 1312 1315 for for IN 1316 1319 the the DT 1320 1333 establishment establishment NN 1334 1336 of of IN 1337 1341 VDRE VDRE NNP 1342 1349 binding binding NN 1350 1359 complexes complex NNS 1360 1363 and and CC 1364 1367 the the DT 1368 1377 induction induction NN 1378 1380 of of IN 1381 1395 24-hydroxylase 24-hydroxylase NN 1396 1403 message message NN 1403 1404 . . . 1405 1416 Furthermore furthermore RB 1416 1417 , , , 1418 1426 biologic biologic JJ 1427 1436 functions function NNS 1437 1440 are be VBP 1441 1450 modulated modulate VBN 1450 1451 , , , 1452 1454 in in IN 1455 1459 that that IN 1460 1463 the the DT 1464 1471 hormone hormone NN 1472 1480 inhibits inhibit VBZ 1481 1494 proliferation proliferation NN 1495 1497 in in IN 1498 1499 a a DT 1500 1506 subset subset NN 1507 1509 of of IN 1510 1513 the the DT 1514 1523 activated activate VBN 1524 1525 B b NN 1526 1531 cells cell NNS 1531 1532 . . . 1533 1538 These these DT 1539 1551 observations observation NNS 1552 1559 suggest suggest VBP 1560 1564 that that IN 1565 1575 reactivity reactivity NN 1576 1578 to to TO 1579 1580 1 1 CD 1581 1596 alpha,25(OH)2D3 alpha,25(oh)2d3 NN 1597 1599 is be VBZ 1600 1607 tightly tightly RB 1608 1617 regulated regulate VBN 1618 1620 in in IN 1621 1622 B B NNP 1623 1634 lymphocytes lymphocyte NNS 1634 1635 , , , 1636 1645 requiring require VBG 1646 1654 specific specific JJ 1655 1662 signals signal NNS 1663 1666 for for IN 1667 1670 its its PRP$ 1671 1681 initiation initiation NN 1681 1682 . . .