0 1 A a DT 2 12 nongenomic nongenomic JJ 13 22 mechanism mechanism NN 23 26 for for IN 27 48 progesterone-mediated progesterone-mediated JJ 49 66 immunosuppression immunosuppression NN 66 67 : : : 68 78 inhibition inhibition NN 79 81 of of IN 82 84 K+ k+ NN 85 93 channels channel NNS 93 94 , , , 95 99 Ca2+ ca2+ NN 100 109 signaling signaling NN 109 110 , , , 111 114 and and CC 115 119 gene gene NN 120 130 expression expression NN 131 133 in in IN 134 135 T t NN 136 147 lymphocytes lymphocyte NNS 147 148 . . . 150 153 The the DT 154 163 mechanism mechanism NN 164 166 by by IN 167 172 which which WDT 173 185 progesterone progesterone NN 186 192 causes cause VBZ 193 202 localized localized JJ 203 214 suppression suppression NN 215 217 of of IN 218 221 the the DT 222 228 immune immune JJ 229 237 response response NN 238 244 during during IN 245 254 pregnancy pregnancy NN 255 258 has have VBZ 259 267 remained remain VBN 268 275 elusive elusive JJ 275 276 . . . 277 282 Using use VBG 283 288 human human JJ 289 290 T t NN 291 302 lymphocytes lymphocyte NNS 303 306 and and CC 307 308 T t NN 309 313 cell cell NN 314 319 lines line NNS 319 320 , , , 321 323 we we PRP 324 328 show show VBP 329 333 that that IN 334 346 progesterone progesterone NN 346 347 , , , 348 350 at at IN 351 365 concentrations concentration NNS 366 371 found find VBN 372 374 in in IN 375 378 the the DT 379 387 placenta placenta NN 387 388 , , , 389 396 rapidly rapidly RB 397 400 and and CC 401 411 reversibly reversibly RB 412 418 blocks block VBZ 419 432 voltage-gated voltage-gated JJ 433 436 and and CC 437 454 calcium-activated calcium-activated JJ 455 457 K+ k+ NN 458 466 channels channel NNS 467 468 ( ( ( 468 470 KV KV NNP 471 474 and and CC 475 478 KCa KCa NNP 478 479 , , , 480 492 respectively respectively RB 492 493 ) ) ) 493 494 , , , 495 504 resulting result VBG 505 507 in in IN 508 522 depolarization depolarization NN 523 525 of of IN 526 529 the the DT 530 538 membrane membrane NN 539 548 potential potential NN 548 549 . . . 550 552 As as IN 553 554 a a DT 555 561 result result NN 561 562 , , , 563 567 Ca2+ ca2+ NN 568 577 signaling signaling NN 578 581 and and CC 582 589 nuclear nuclear JJ 590 596 factor factor NN 597 599 of of IN 600 609 activated activate VBN 610 611 T t NN 612 617 cells cell NNS 618 619 ( ( ( 619 632 NF-AT)-driven nf-at)-driven JJ 633 637 gene gene NN 638 648 expression expression NN 649 652 are be VBP 653 662 inhibited inhibit VBN 662 663 . . . 664 676 Progesterone Progesterone NNP 677 681 acts act VBZ 682 690 distally distally RB 691 693 to to TO 694 697 the the DT 698 705 initial initial JJ 706 711 steps step NNS 712 714 of of IN 715 716 T t NN 717 721 cell cell NN 722 730 receptor receptor NN 731 732 ( ( ( 732 745 TCR)-mediated tcr)-mediated JJ 746 752 signal signal NN 753 765 transduction transduction NN 765 766 , , , 767 772 since since IN 773 775 it it PRP 776 782 blocks block VBZ 783 792 sustained sustained JJ 793 797 Ca2+ ca2+ NN 798 805 signals signal NNS 806 811 after after IN 812 824 thapsigargin thapsigargin NN 825 836 stimulation stimulation NN 836 837 , , , 838 840 as as RB 841 845 well well RB 846 848 as as IN 849 860 oscillatory oscillatory JJ 861 865 Ca2+ ca2+ NN 866 873 signals signal NNS 873 874 , , , 875 878 but but CC 879 882 not not RB 883 886 the the DT 887 891 Ca2+ ca2+ NN 892 901 transient transient JJ 902 907 after after IN 908 911 TCR TCR NNP 912 923 stimulation stimulation NN 923 924 . . . 925 927 K+ k+ NN 928 935 channel channel NN 936 944 blockade blockade NN 945 947 by by IN 948 960 progesterone progesterone NN 961 963 is be VBZ 964 972 specific specific JJ 972 973 ; ; : 974 979 other other JJ 980 987 steroid steroid NN 988 996 hormones hormone NNS 997 1000 had have VBD 1001 1007 little little JJ 1008 1010 or or CC 1011 1013 no no DT 1014 1020 effect effect NN 1020 1021 , , , 1022 1030 although although IN 1031 1034 the the DT 1035 1047 progesterone progesterone NN 1048 1058 antagonist antagonist NN 1059 1061 RU RU NNP 1062 1065 486 486 CD 1066 1070 also also RB 1071 1078 blocked block VBD 1079 1081 KV KV NNP 1082 1085 and and CC 1086 1089 KCa KCa NNP 1090 1098 channels channel NNS 1098 1099 . . . 1100 1112 Progesterone Progesterone NNP 1113 1124 effectively effectively RB 1125 1132 blocked block VBD 1133 1134 a a DT 1135 1140 broad broad JJ 1141 1149 spectrum spectrum NN 1150 1152 of of IN 1153 1155 K+ k+ NN 1156 1164 channels channel NNS 1164 1165 , , , 1166 1174 reducing reduce VBG 1175 1179 both both CC 1180 1185 Kv1.3 kv1.3 NN 1186 1189 and and CC 1190 1213 charybdotoxin-resistant charybdotoxin-resistant JJ 1214 1224 components component NNS 1225 1227 of of IN 1228 1230 KV KV NNP 1231 1238 current current NN 1239 1242 and and CC 1243 1246 KCa KCa NNP 1247 1254 current current NN 1255 1257 in in IN 1258 1259 T t NN 1260 1265 cells cell NNS 1265 1266 , , , 1267 1269 as as RB 1270 1274 well well RB 1275 1277 as as IN 1278 1286 blocking block VBG 1287 1294 several several JJ 1295 1301 cloned clone VBN 1302 1304 KV KV NNP 1305 1313 channels channel NNS 1314 1323 expressed express VBN 1324 1326 in in IN 1327 1331 cell cell NN 1332 1337 lines line NNS 1337 1338 . . . 1339 1351 Progesterone Progesterone NNP 1352 1355 had have VBD 1356 1362 little little JJ 1363 1365 or or CC 1366 1368 no no DT 1369 1375 effect effect NN 1376 1378 on on IN 1379 1380 a a DT 1381 1387 cloned clone VBN 1388 1401 voltage-gated voltage-gated JJ 1402 1405 Na+ na+ NN 1406 1413 channel channel NN 1413 1414 , , , 1415 1417 an an DT 1418 1424 inward inward JJ 1425 1434 rectifier rectifier NN 1435 1437 K+ k+ NN 1438 1445 channel channel NN 1445 1446 , , , 1447 1449 or or CC 1450 1452 on on IN 1453 1463 lymphocyte lymphocyte NN 1464 1468 Ca2+ ca2+ NN 1469 1472 and and CC 1473 1476 Cl- cl- NN 1477 1485 channels channel NNS 1485 1486 . . . 1487 1489 We we PRP 1490 1497 propose propose VBP 1498 1502 that that IN 1503 1509 direct direct JJ 1510 1520 inhibition inhibition NN 1521 1523 of of IN 1524 1526 K+ k+ NN 1527 1535 channels channel NNS 1536 1538 in in IN 1539 1540 T t NN 1541 1546 cells cell NNS 1547 1549 by by IN 1550 1562 progesterone progesterone NN 1563 1574 contributes contribute VBZ 1575 1577 to to TO 1578 1598 progesterone-induced progesterone-induced JJ 1599 1616 immunosuppression immunosuppression NN 1616 1617 . . .