Differential selectivity of CIITA promoter activation by IFN-gamma and IRF-1 in astrocytes and macrophages: CIITA promoter activation is not affectedby TNF-alpha

During demyelinating disease of the central nervous system (CNS), locally e levated cytokine levels may induce upregulation of MHC class II molecules o n otherwise low expressing or negative cell types such as microglia and ast rocytes, since IFN-gamma has been shown to induce MHC class II expression o n these cell types in vitro. While many transcription factors are involved with MHC class II expression, only the class II transactivator (CIITA) is t ightly coordinated with IFN-gamma-inducibility. Control of CIITA gene expre ssion is complex, involving four distinct promoters, two of which (promoter s III and IV) are IFN-gamma-inducible in certain cell types. Here we demons trate that IFN-gamma treatment of rat astrocytes induces only CIITA promote r IV activity in contrast to the murine macrophage cell line RAW 264.7 that uses both IFN-gamma-inducible promoters. In contrast to previously publish ed reports, promoter IV activation is completely dependent upon an intact i nterferon regulatory factor-1 (IRF-1) but not STAT1 binding site using prom oter constructs specifically mutated at these positions. Importantly, while TNF-alpha is able to synergize with IFN-gamma to increase astrocyte MHC cl ass II expression in vitro, we show that treatment of rat astrocytes with T NF-alpha has no effect on CIITA promoter activity. These data demonstrate t hat TNF-alpha augments MHC class II expression through a mechanism downstre am or independent of CIITA induction. (C) 1999 Elsevier Science B.V. All ri ghts reserved.