Inhibition of IFN-gamma induction of class II MHC genes by cAMP and prostaglandins.
Triggering of the cyclic AMP (cAMP) signal transduction pathway inhibits the the interferon gamma (IFN-gamma)-mediated induction of class II major histocompatibility (MHC) genes. We have investigated the mechanism of the inhibition of IFN-gamma induction of the murine A alpha class II MHC gene by cAMP and E series prostaglandins (PGEs). 151 base pairs of the A alpha promoter were sufficient to confer positive regulation by IFN-gamma and negative regulation by cAMP which accurately mirrored the regulation of the endogenous A alpha gene. cAMP also inhibited the IFN-gamma activation of the Fc gamma receptor I (Fc gamma RI) gene promoter, an "early" promoter which is activated immediately after treatment of cells with IFN-gamma. PGEs, which cause an elevation in intracellular cAMP, inhibited the induction of the A alpha promoter, and inhibition was greater in the presence of tumor necrosis factor alpha (TNF alpha). A mutational analysis of the A alpha promoter showed that all four conserved class II promoter elements, the S, X1, X2, and Y boxes, play a role in mediating A alpha promoter activation by IFN-gamma. Mutations in these elements did not diminish the cAMP inhibition of promoter activation by IFN-gamma. Thus, conserved class II promoter sequences which mediate most known examples of positive and negative regulation, including cAMP inhibition of constitutive class II expression, do not mediate cAMP inhibition of IFN-gamma activation of the A alpha promoter. We suggest that this inhibition may be mediated by a novel class II promoter element or by disruption of an early step in the IFN-gamma signal transduction pathway.
Ivashkiv
L B
LB
Department of Cancer Biology, Harvard School of Public Health, Boston 02115.
Ayres
A
A
Glimcher
L H
LH
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005802:Genes, MHC Class II / Q000187:drug effects*; D017930:Genes, Reporter / Q000187:drug effects; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011458:Prostaglandins E / Q000494:pharmacology*; D014162:Transfection
D011458:Prostaglandins E; D007371:Interferon-gamma; D000242:Cyclic AMP