Regulation Of Mhc Class-I And Beta-2-Microglobulin Gene-Expression In Human Neuronal Cells - Factor Binding To Conserved Cis-Acting Regulatory Sequences Correlates With Expression Of The Genes

MHC class I molecules are coexpressed with beta2-microglobulin (beta2-M) on many somatic cells. However, these proteins are normally not present on cells of the central nervous system (CNS). Cells derived from human neuroblastomas were used as a model for investigating the molecular basis for the paucity of MHC class I and beta2-M gene expression in neural cells and for the induction of these genes by two cytokines, IFN-gamma, and TNF-alpha. These cytokines independently increased MHC class I and beta2-M cell surface expression on the neuroblastoma cell lines. IFN-gamma or TNF-alpha also increased MHC class I and beta2-M steady-state RNA levels and the expression of MHC class I and beta2-M CAT reporter constructs transiently transfected into the neuroblastoma cell lines, indicating that the cytokines acted by increasing the transcription of these genes. MHC class I and beta2-M genes share two conserved regulatory elements, an NFkappaB-like site and the IFN consensus sequence, that act as a constitutive enhancer and an IFN-responsive element, respectively. Low MHC class I and beta2-M gene expression in these cells was accounted for by undetectable to low factor binding activity specific for the above regulatory elements of these genes. TNF-alpha increased factor binding activity specific for the NFkappaB-like elements and IFN-gamma increased factor binding activity specific for the IFN consensus sequence elements of the MHC class I and beta2-M genes, but not vice versa. Taken together, our results indicated that IFN-gamma and TNF-alpha increased MHC class I and beta2-M gene expression in the neuroblastoma cell lines by inducing factor binding to the regulatory elements present in both genes.