Repression of class II major histocompatibility complex genes by cyclic AMP is mediated by conserved promoter elements.
The induction of cell surface expression of class II major histocompatibility complex (MHC) antigens by interleukin (IL)-4 and interferon (IFN)-gamma is inhibited by elevation of intracellular cyclic (c)AMP, which is caused by immunomodulatory agents such as E series prostaglandins (PGEs). To investigate the mechanism of this downregulation, we have analyzed the consequences of elevating intracellular cAMP on cell surface expression, mRNA levels, and promoter activity of the murine A alpha and E beta class II MHC genes. Elevation of cAMP resulted in a coordinate repression of both basal and inducible A alpha and E beta expression. 151 and 192 base pairs of A alpha and E beta promoter sequence, respectively, were sufficient for conferring repression by cAMP on a reporter gene. A mutational analysis of the A alpha promoter revealed that cAMP downregulation is mediated by the conserved S and X1 DNA elements, which are also necessary for induction by cytokines. Downregulation by cAMP was not dependent on an intact X2 site, which is identical in sequence to the CRE element which mediates the positive regulation of several genes by cAMP. These results identify the DNA elements which mediate repression of class II MHC genes by cAMP and show that the same DNA sequences can mediate both positive and negative regulation of class II MHC expression.
Ivashkiv
L B
LB
Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115.
Glimcher
L H
LH
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D000242:Cyclic AMP / Q000032:analysis / Q000502:physiology*; D005802:Genes, MHC Class II; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007371:Interferon-gamma / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis
D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D015124:8-Bromo Cyclic Adenosine Monophosphate; D007371:Interferon-gamma; D000242:Cyclic AMP; D015500:Chloramphenicol O-Acetyltransferase; D011494:Protein Kinases