Structure and negative transcriptional regulation by glucocorticoids of the acute-phase rat alpha 1-inhibitor III gene.
DNA clones representing the negative acute-phase gene coding for the plasma proteinase inhibitor alpha 1-inhibitor III were isolated from a rat genomic library. Structural analysis established the existence of at least four different members of the alpha 1-inhibitor III gene family. Partial DNA sequence analysis of the 5'-terminal regions was performed for the alpha 1-inhibitor III gene and the related alpha 1-inhibitor IV gene. The transcription start site of the alpha 1-inhibitor III gene was located by S1 mapping and primer extension. No stable alpha 1-inhibitor IV mRNA was detected in rat liver. In an experimentally induced acute-phase reaction, the transcription rate of the alpha 1-inhibitor III gene was reduced 12.7-fold at 6 h after stimulation. Four hours after injection of a high dose of dexamethasone into rats, the transcription rate of this gene was reduced 9-fold. Thus, glucocorticoids alone are capable of causing a strong transient down-regulation of the transcription of this gene in rats, independent of other inflammatory mediators. An inverted consensus glucocorticoid responsive element (5'GGACACAATAT3') shared with the glucocorticoid-regulated alpha 1-fetoprotein, alpha 2u-globulin, and alpha 1-acid glycoprotein genes was detected by computer-assisted sequence analysis in the promoter proximal 5'-flanking region of the alpha 1-inhibitor III gene.
Northemann
W
W
Department of Immunology, Research Institute of Scripps Clinic, La Jolla, California 92037.
Shiels
B R
BR
Braciak
T A
TA
Fey
G H
GH
D000209:Acute-Phase Proteins; D000210:Acute-Phase Reaction / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family; D011480:Protease Inhibitors / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D015183:Restriction Mapping; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic / Q000187:drug effects*
D000209:Acute-Phase Proteins; D011480:Protease Inhibitors; C017894:alpha 1-inhibitor 3; D003907:Dexamethasone; D004247:DNA