Interferon-gamma activates multiple pathways to regulate the expression of the genes for major histocompatibility...

The purpose of this study was to obtain additional information on the mechanism by which interferon-gamma (IFN-gamma) is able to regulate gene expression in macrophages. The expression of the genes for class II histocompatibility I-A beta, tumor necrosis factor (TNF) and complement component C3 was assayed after treating bone marrow macrophages with IFN-gamma. Each gene displayed a characteristic pattern of regulation. First, the increase in the level of RNA for each gene followed different kinetics. The level of TNF RNA increased within 15 min after IFN-gamma treatment and reached a plateau after 4 h. In contrast, there was a lag of about 4 h before the level of I-A beta RNA began to rise and a plateau was not reached until 48 h after the IFN-gamma treatment began. C3 gene expression followed an intermediate time course between that for TNF and I-A beta. Second, the expression of I-A beta was inhibited when cells were treated with both IFN-gamma and cycloheximide, while the expression of TNF and C3 was not. Interestingly, the sensitivity to cycloheximide only lasted 30 min following the addition of IFN-gamma, after which cycloheximide had no effect on the expression of I-A beta. Third, lipopolysaccharide abolished the IFN-gamma-induced expression of I-A beta, but enhanced the expression of TNF. Based on these observations, we conclude that IFN-gamma must activate multiple pathways to regulate gene expression in macrophages.