0 3 p38 p38 NN 4 21 mitogen-activated mitogen-activated JJ 22 29 protein protein NN 30 36 kinase kinase NNP 37 45 mediates mediate VBZ 46 52 signal signal NN 53 64 integration integration NN 65 67 of of IN 68 76 TCR/CD28 tcr/cd28 NN 77 90 costimulation costimulation NN 91 93 in in IN 94 101 primary primary JJ 102 108 murine murine JJ 109 110 T t NN 111 116 cells cell NNS 116 117 . . . 119 126 Optimal optimal JJ 127 128 T t NN 129 133 cell cell NN 134 144 activation activation NN 145 153 requires require VBZ 154 157 two two CD 158 165 signals signal NNS 165 166 , , , 167 170 one one CD 171 180 generated generate VBN 181 183 by by IN 184 187 TCR TCR NNP 188 191 and and CC 192 199 another another DT 200 202 by by IN 203 206 the the DT 207 211 CD28 cd28 NN 212 225 costimulatory costimulatory JJ 226 234 receptor receptor NN 234 235 . . . 236 238 In in IN 239 243 this this DT 244 249 study study NN 249 250 , , , 251 253 we we PRP 254 266 investigated investigate VBD 267 270 the the DT 271 281 regulation regulation NN 282 284 of of IN 285 306 costimulation-induced costimulation-induced JJ 307 324 mitogen-activated mitogen-activated JJ 325 332 protein protein NN 333 339 kinase kinase NNP 340 341 ( ( ( 341 345 MAPK MAPK NNP 345 346 ) ) ) 347 357 activation activation NN 358 360 in in IN 361 368 primary primary JJ 369 374 mouse mouse NN 375 376 T t NN 377 382 cells cell NNS 382 383 . . . 384 386 In in IN 387 395 contrast contrast NN 396 398 to to TO 399 403 that that DT 404 412 reported report VBN 413 416 for for IN 417 422 human human JJ 423 429 Jurkat Jurkat NNP 430 431 T t NN 432 437 cells cell NNS 437 438 , , , 439 441 we we PRP 442 447 found find VBD 448 452 that that IN 453 456 p38 p38 NN 457 461 MAPK mapk NN 461 462 , , , 463 466 but but CC 467 470 not not RB 471 474 Jun Jun NNP 475 487 NH2-terminal nh2-terminal JJ 488 494 kinase kinase NNP 495 496 ( ( ( 496 499 JNK JNK NNP 499 500 ) ) ) 500 501 , , , 502 504 is be VBZ 505 511 weakly weakly RB 512 521 activated activate VBN 522 526 upon upon IN 527 538 stimulation stimulation NN 539 543 with with IN 544 550 either either CC 551 559 anti-CD3 anti-cd3 NN 560 562 or or CC 563 572 anti-CD28 anti-cd28 NN 573 575 in in IN 576 582 murine murine JJ 583 593 thymocytes thymocyte NNS 594 597 and and CC 598 605 splenic splenic JJ 606 607 T t NN 608 613 cells cell NNS 613 614 . . . 615 622 However however RB 622 623 , , , 624 627 p38 p38 NN 628 632 MAPK mapk NN 633 635 is be VBZ 636 645 activated activate VBN 646 654 strongly strongly RB 655 658 and and CC 659 674 synergistically synergistically RB 675 677 by by IN 678 684 either either CC 685 693 CD3/CD28 cd3/cd28 NN 694 704 coligation coligation NN 705 707 or or CC 708 716 PMA/Ca2+ pma/ca2+ NN 717 726 ionophore ionophore NN 727 738 stimulation stimulation NN 738 739 , , , 740 745 which which WDT 746 752 mimics mimic VBZ 753 774 TCR-CD3/CD28-mediated tcr-cd3/cd28-mediated JJ 775 784 signaling signaling NN 784 785 . . . 786 796 Activation Activation NNP 797 799 of of IN 800 803 p38 p38 NN 804 808 MAPK mapk NN 809 819 correlates correlate VBZ 820 827 closely closely RB 828 832 with with IN 833 836 the the DT 837 848 stimulation stimulation NN 849 851 of of IN 852 853 T t NN 854 858 cell cell NN 859 872 proliferation proliferation NN 872 873 . . . 874 876 In in IN 877 885 contrast contrast NN 885 886 , , , 887 898 PMA-induced pma-induced JJ 899 902 JNK JNK NNP 903 913 activation activation NN 914 916 is be VBZ 917 926 inhibited inhibit VBN 927 929 by by IN 930 934 Ca2+ ca2+ NN 935 944 ionophore ionophore NN 944 945 . . . 946 947 T t NN 948 952 cell cell NN 953 966 proliferation proliferation NN 967 970 and and CC 971 981 production production NN 982 984 of of IN 985 989 IL-2 il-2 NN 989 990 , , , 991 995 IL-4 il-4 NN 995 996 , , , 997 1000 and and CC 1001 1010 IFN-gamma IFN-gamma NNP 1011 1018 induced induce VBN 1019 1021 by by IN 1022 1026 both both CC 1027 1030 CD3 cd3 NN 1031 1034 and and CC 1035 1043 CD3/CD28 cd3/cd28 NN 1044 1052 ligation ligation NN 1053 1056 and and CC 1057 1060 the the DT 1061 1068 nuclear nuclear JJ 1069 1079 expression expression NN 1080 1082 of of IN 1083 1086 the the DT 1087 1092 c-Jun c-jun NN 1093 1096 and and CC 1097 1102 ATF-2 atf-2 NN 1103 1111 proteins protein NNS 1112 1115 are be VBP 1116 1120 each each DT 1121 1128 blocked block VBN 1129 1131 by by IN 1132 1135 the the DT 1136 1139 p38 p38 NN 1140 1144 MAPK mapk NN 1145 1154 inhibitor inhibitor NN 1155 1163 SB203580 sb203580 NN 1163 1164 . . . 1165 1168 Our our PRP$ 1169 1177 findings finding NNS 1178 1189 demonstrate demonstrate VBP 1190 1194 that that IN 1195 1198 p38 p38 NN 1199 1203 MAPK mapk NN 1204 1205 1 1 CD 1205 1206 ) ) ) 1207 1212 plays play VBZ 1213 1215 an an DT 1216 1225 important important JJ 1226 1230 role role NN 1231 1233 in in IN 1234 1240 signal signal NN 1241 1252 integration integration NN 1253 1259 during during IN 1260 1273 costimulation costimulation NN 1274 1276 of of IN 1277 1284 primary primary JJ 1285 1290 mouse mouse NN 1291 1292 T t NN 1293 1298 cells cell NNS 1298 1299 , , , 1300 1301 2 2 LS 1301 1302 ) ) ) 1303 1306 may may MD 1307 1309 be be VB 1310 1318 involved involve VBN 1319 1321 in in IN 1322 1325 the the DT 1326 1335 induction induction NN 1336 1338 of of IN 1339 1344 c-Jun c-jun NN 1345 1355 activation activation NN 1356 1359 and and CC 1360 1372 augmentation augmentation NN 1373 1375 of of IN 1376 1380 AP-1 ap-1 NN 1381 1396 transcriptional transcriptional JJ 1397 1405 activity activity NN 1405 1406 , , , 1407 1410 and and CC 1411 1412 3 3 LS 1412 1413 ) ) ) 1414 1423 regulates regulate VBZ 1424 1431 whether whether IN 1432 1433 T t NN 1434 1439 cells cell NNS 1440 1445 enter enter VBP 1446 1447 a a DT 1448 1453 state state NN 1454 1456 of of IN 1457 1467 functional functional JJ 1468 1484 unresponsiveness unresponsiveness NN 1484 1485 . . .