0 8 Cellular cellular JJ 9 12 and and CC 13 22 molecular molecular JJ 23 33 mechanisms mechanism NNS 34 36 of of IN 37 46 IFN-gamma IFN-gamma NNP 47 57 production production NN 58 65 induced induce VBN 66 68 by by IN 69 73 IL-2 il-2 NN 74 77 and and CC 78 83 IL-12 il-12 NN 84 86 in in IN 87 88 a a DT 89 94 human human JJ 95 97 NK nk NN 98 102 cell cell NN 103 107 line line NN 107 108 . . . 110 126 Interferon-gamma Interferon-gamma NNP 127 128 ( ( ( 128 137 IFN-gamma IFN-gamma NNP 137 138 ) ) ) 139 141 is be VBZ 142 144 an an DT 145 154 important important JJ 155 171 immunoregulatory immunoregulatory JJ 172 179 protein protein NN 180 188 produced produce VBN 189 202 predominantly predominantly RB 203 205 by by IN 206 207 T t NN 208 213 cells cell NNS 214 217 and and CC 218 223 large large JJ 224 232 granular granular JJ 233 244 lymphocytes lymphocyte NNS 245 246 ( ( ( 246 249 LGL LGL NNP 249 250 ) ) ) 251 253 in in IN 254 262 response response NN 263 265 to to TO 266 275 different different JJ 276 289 extracellular extracellular JJ 290 297 signals signal NNS 297 298 . . . 299 301 In in IN 302 312 particular particular JJ 312 313 , , , 314 317 two two CD 318 330 interleukins interleukin NNS 331 332 ( ( ( 332 335 ILs IL NNP 335 336 ) ) ) 336 337 , , , 338 342 IL-2 il-2 NN 343 346 and and CC 347 352 IL-12 il-12 NN 352 353 , , , 354 358 have have VBP 359 363 been be VBN 364 369 shown show VBN 370 372 to to TO 373 375 be be VB 376 382 potent potent JJ 383 391 inducers inducer NNS 392 394 of of IN 395 404 IFN-gamma IFN-gamma NNP 405 409 gene gene NN 410 420 expression expression NN 421 423 in in IN 424 428 both both CC 429 430 T t NN 431 436 cells cell NNS 437 440 and and CC 441 444 LGL LGL NNP 444 445 . . . 446 454 Although although IN 455 457 it it PRP 458 461 has have VBZ 462 466 been be VBN 467 475 reported report VBN 476 480 that that IN 481 486 there there EX 487 490 are be VBP 491 495 some some DT 496 497 T t NN 498 502 cell cell NN 503 508 lines line NNS 509 513 that that WDT 514 521 produce produce VBP 522 531 IFN-gamma IFN-gamma NNP 532 534 in in IN 535 543 response response NN 544 546 to to TO 547 551 IL-2 il-2 NN 552 555 and and CC 556 561 IL-12 il-12 NN 562 573 stimulation stimulation NN 573 574 , , , 575 580 there there EX 581 584 has have VBZ 585 587 as as RB 588 591 yet yet RB 592 596 been be VBN 597 599 no no DT 600 606 report report NN 607 609 of of IN 610 611 a a DT 612 619 natural natural JJ 620 626 killer killer NN 627 628 ( ( ( 628 630 NK NK NNP 630 631 ) ) ) 632 636 cell cell NN 637 641 line line NN 642 646 that that WDT 647 655 responds respond VBZ 656 658 in in IN 659 660 a a DT 661 668 similar similar JJ 669 675 manner manner NN 675 676 . . . 677 679 In in IN 680 684 this this DT 685 691 report report NN 692 694 we we PRP 695 702 present present VBP 703 711 evidence evidence NN 712 716 that that IN 717 720 the the DT 721 725 cell cell NN 726 730 line line NN 731 736 NK3.3 nk3.3 NN 737 744 derived derive VBN 745 749 from from IN 750 755 human human JJ 756 758 NK nk NN 759 764 cells cell NNS 764 765 , , , 766 774 responds respond VBZ 775 777 to to TO 778 782 both both CC 783 787 IL-2 il-2 NN 788 791 and and CC 792 797 IL-12 il-12 NN 797 798 , , , 799 801 as as IN 802 810 measured measure VBN 811 813 by by IN 814 823 increases increase NNS 824 826 in in IN 827 836 IFN-gamma IFN-gamma NNP 837 840 and and CC 841 863 granulocyte-macrophage granulocyte-macrophage JJ 864 882 colony-stimulating colony-stimulating JJ 883 889 factor factor NN 890 891 ( ( ( 891 897 GM-CSF GM-CSF NNP 897 898 ) ) ) 899 910 cytoplasmic cytoplasmic JJ 911 915 mRNA mrna NN 916 919 and and CC 920 927 protein protein NN 928 938 expression expression NN 938 939 . . . 940 942 In in IN 943 951 addition addition NN 951 952 , , , 953 957 when when WRB 958 962 used use VBN 963 971 together together RB 972 976 IL-2 il-2 NN 977 980 and and CC 981 986 IL-12 il-12 NN 987 997 synergized synergize VBD 998 1000 in in IN 1001 1004 the the DT 1005 1014 induction induction NN 1015 1017 of of IN 1018 1027 IFN-gamma IFN-gamma NNP 1028 1031 and and CC 1032 1038 GM-CSF GM-CSF NNP 1039 1042 and and CC 1043 1047 this this DT 1048 1055 synergy synergy NN 1056 1059 was be VBD 1060 1070 attributed attribute VBN 1071 1073 to to TO 1074 1076 an an DT 1077 1086 increased increase VBN 1087 1099 accumulation accumulation NN 1100 1103 and and CC 1104 1113 stability stability NN 1114 1116 of of IN 1117 1120 the the DT 1121 1130 IFN-gamma IFN-gamma NNP 1131 1134 and and CC 1135 1141 GM-CSF GM-CSF NNP 1142 1147 mRNAs mrna NNS 1147 1148 . . . 1149 1151 To to TO 1152 1163 investigate investigate VB 1164 1167 the the DT 1168 1177 signaling signaling NN 1178 1186 pathways pathway NNS 1187 1195 involved involve VBN 1196 1198 in in IN 1199 1202 the the DT 1203 1207 gene gene NN 1208 1217 induction induction NN 1217 1218 , , , 1219 1223 five five CD 1224 1234 inhibitors inhibitor NNS 1234 1235 , , , 1236 1247 cyclosporin cyclosporin NN 1248 1249 A A NNP 1250 1251 ( ( ( 1251 1254 CsA CsA NNP 1254 1255 ) ) ) 1255 1256 , , , 1257 1269 transforming transform VBG 1270 1276 growth growth NN 1277 1288 factor-beta factor-beta NN 1288 1289 , , , 1290 1303 cycloheximide cycloheximide NN 1303 1304 , , , 1305 1314 genistein genistein NN 1314 1315 , , , 1316 1319 and and CC 1320 1333 staurosporine staurosporine NN 1334 1335 A a NN 1335 1336 , , , 1337 1341 were be VBD 1342 1346 used use VBN 1347 1349 in in IN 1350 1359 analyzing analyze VBG 1360 1363 the the DT 1364 1371 effects effect NNS 1372 1374 of of IN 1375 1379 IL-2 il-2 NN 1380 1383 and and CC 1384 1389 IL-12 il-12 NN 1390 1392 on on IN 1393 1398 NK3.3 nk3.3 NN 1399 1404 cells cell NNS 1404 1405 . . . 1406 1409 The the DT 1410 1417 results result NNS 1418 1425 suggest suggest VBP 1426 1430 that that IN 1431 1441 activation activation NN 1442 1444 of of IN 1445 1452 protein protein NN 1453 1459 kinase kinase NNP 1460 1461 C C NNP 1461 1462 , , , 1463 1466 but but CC 1467 1470 not not RB 1471 1474 new new JJ 1475 1482 protein protein NN 1483 1492 synthesis synthesis NN 1492 1493 , , , 1494 1496 is be VBZ 1497 1505 required require VBN 1506 1509 for for IN 1510 1514 IL-2 il-2 NN 1515 1524 induction induction NN 1525 1527 of of IN 1528 1537 IFN-gamma IFN-gamma NNP 1538 1541 and and CC 1542 1548 GM-CSF GM-CSF NNP 1549 1560 cytoplasmic cytoplasmic JJ 1561 1565 mRNA mrna NN 1565 1566 . . . 1567 1569 In in IN 1570 1578 contrast contrast NN 1578 1579 , , , 1580 1585 IL-12 il-12 NN 1586 1595 induction induction NN 1596 1598 of of IN 1599 1608 IFN-gamma IFN-gamma NNP 1609 1620 cytoplasmic cytoplasmic JJ 1621 1625 mRNA mrna NN 1626 1633 appears appear VBZ 1634 1636 to to TO 1637 1641 only only RB 1642 1651 partially partially RB 1652 1658 depend depend VB 1659 1661 on on IN 1662 1672 activation activation NN 1673 1675 of of IN 1676 1683 protein protein NN 1684 1690 kinase kinase NNP 1691 1693 C. C. NNP 1694 1705 Furthermore Furthermore NNP 1705 1706 , , , 1707 1711 both both DT 1712 1724 transforming transform VBG 1725 1731 growth growth NN 1732 1743 factor-beta factor-beta NN 1744 1747 and and CC 1748 1757 genistein genistein NN 1757 1758 , , , 1759 1760 a a DT 1761 1769 tyrosine tyrosine NN 1770 1776 kinase kinase NNP 1777 1786 inhibitor inhibitor NN 1786 1787 , , , 1788 1793 could could MD 1794 1802 suppress suppress VB 1803 1807 IL-2 il-2 NN 1808 1811 and and CC 1812 1817 IL-12 il-12 NN 1818 1827 signaling signaling NN 1828 1831 but but CC 1832 1835 CsA CsA NNP 1836 1839 was be VBD 1840 1849 generally generally RB 1850 1858 inactive inactive JJ 1858 1859 . . . 1860 1862 It it PRP 1863 1867 also also RB 1868 1871 was be VBD 1872 1880 observed observe VBN 1881 1885 that that IN 1886 1897 suppression suppression NN 1898 1900 of of IN 1901 1909 cytokine cytokine NN 1910 1914 gene gene NN 1915 1925 expression expression NN 1926 1928 by by IN 1929 1934 these these DT 1935 1941 agents agent NNS 1942 1945 was be VBD 1946 1957 independent independent JJ 1958 1960 of of IN 1961 1964 the the DT 1965 1975 inhibition inhibition NN 1976 1978 of of IN 1979 1992 proliferation proliferation NN 1992 1993 . . . 1994 1996 In in IN 1997 2005 addition addition NN 2005 2006 , , , 2007 2011 IL-2 il-2 NN 2012 2015 but but CC 2016 2019 not not RB 2020 2025 IL-12 il-12 NN 2026 2033 induced induce VBD 2034 2041 nuclear nuclear JJ 2042 2049 factors factor NNS 2050 2058 NF-kappa NF-kappa NNP 2059 2060 B B NNP 2061 2064 and and CC 2065 2068 AP1 AP1 NNP 2068 2069 , , , 2070 2073 and and CC 2074 2084 regulation regulation NN 2085 2087 of of IN 2088 2091 the the DT 2092 2099 nuclear nuclear JJ 2100 2106 levels level NNS 2107 2109 of of IN 2110 2115 these these DT 2116 2119 two two CD 2120 2123 DNA dna NN 2124 2131 binding binding NN 2132 2139 protein protein NN 2140 2149 complexes complex NNS 2150 2152 is be VBZ 2153 2163 correlated correlate VBN 2164 2168 with with IN 2169 2178 IFN-gamma IFN-gamma NNP 2179 2182 and and CC 2183 2189 GM-CSF GM-CSF NNP 2190 2194 gene gene NN 2195 2205 expression expression NN 2205 2206 . . . 2207 2212 These these DT 2213 2217 data datum NNS 2218 2226 indicate indicate VBP 2227 2231 that that IN 2232 2236 IL-2 il-2 NN 2237 2240 and and CC 2241 2246 IL-12 il-12 NN 2247 2250 may may MD 2251 2255 have have VB 2256 2264 distinct distinct JJ 2265 2274 signaling signaling NN 2275 2283 pathways pathway NNS 2284 2291 leading lead VBG 2292 2294 to to TO 2295 2298 the the DT 2299 2308 induction induction NN 2309 2311 of of IN 2312 2321 IFN-gamma IFN-gamma NNP 2322 2325 and and CC 2326 2332 GM-CSF GM-CSF NNP 2333 2337 gene gene NN 2338 2348 expression expression NN 2348 2349 , , , 2350 2353 and and CC 2354 2358 that that IN 2359 2362 the the DT 2363 2368 NK3.3 nk3.3 NN 2369 2373 cell cell NN 2374 2378 line line NN 2379 2382 may may MD 2383 2388 serve serve VB 2389 2391 as as IN 2392 2393 a a DT 2394 2399 novel novel JJ 2400 2405 model model NN 2406 2409 for for IN 2410 2420 dissecting dissect VBG 2421 2424 the the DT 2425 2436 biochemical biochemical JJ 2437 2440 and and CC 2441 2450 molecular molecular JJ 2451 2457 events event NNS 2458 2466 involved involve VBN 2467 2469 in in IN 2470 2475 these these DT 2476 2484 pathways pathway NNS 2484 2485 . . .