KINASE INHIBITORS ABROGATE IFN-GAMMA-INDUCED CLASS-II TRANSACTIVATOR AND CLASS-II MHC GENE-EXPRESSION IN ASTROGLIOMA CELL-LINES

Multiple kinase events, involving both tyrosine (tyr) kinase and serin e/threonine (ser/thr) kinase activity, are required for IFN-gamma-indu ced class II MHC mRNA and protein expression in primary rat astrocytes . In this study, we examined the necessity of ser/thr and tyr kinase a ctivity for IFN-gamma-induced stimulation of class II MHC gene express ion in the human astroglioma cell lines CRT and CH235, as well as the involvement of these kinases in IFN-gamma-induced expression of the cl ass II transactivator (CIITA), a protein critical for IFN-gamma-induce d transcription of class II MHC genes. We show that general ser/thr ki nase inhibitors, inhibitors of the ser/thr kinase mitogen-activated pr otein kinase (MAPK), and tyr kinase inhibitors reduce IFN-gamma-induce d class II MHC mRNA and protein expression in a dose-dependent manner. As well, these inhibitors abrogate IFN-gamma-induced CIITA mRNA expre ssion in the astroglioma cell lines. We have further demonstrated that cells constitutively expressing the CIITA protein (2fTGHLCIITA) show no decrease in CIITA or class II MHC mRNA expression in the presence o f ser/thr and tyr kinase inhibitors. Collectively, these data indicate that ser/thr kinase activity, possibly MAPK, and tyr kinase activity are required for IFN-gamma-induced expression of CIITA mRNA, and the s ubsequent expression of class II MHC genes. (C) 1998 Elsevier Science B.V. All rights reserved.