(Hypertension. 1996;27:1009-1017.)
© 1996 American Heart Association, Inc.
Articles |
Tumor Necrosis Factor Activates Angiotensinogen Gene Expression by the Rel A Transactivator
Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994.
From the Departments of Medicine (A.R.B., J.L., K.A.W.) and Human Biological Chemistry and Genetics and the Sealy Center for Molecular Science (A.R.B.), University of Texas Medical Branch, Galveston.
Correspondence to Allan R. Brasier, Division of Endocrinology, MRB 3.142, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1060.
Abstract Angiotensinogen encodes the only known
precursor of angiotensin II, a critical regulator of the
cardiovascular system. Transcriptional control of
angiotensinogen in hepatocytes is an important
regulator of circulating angiotensinogen concentrations.
Angiotensinogen transcription is increased by the
inflammatory cytokine tumor necrosis factor (TNF)-
by a
nuclear factor–
B–like protein binding to an inducible enhancer
called the acute-phase response element. By gel mobility shift
assays, we observe two specific acute-phase response
element–binding complexes, C1 and C2. The abundance of C2 is not
changed by TNF treatment. In contrast, C1 is faintly detected in
untreated cells, and its abundance increases by fivefold after
stimulation. We identify the nuclear factor–B subunits in these
complexes using subunit-specific antibodies in the gel mobility
"supershift" assay. The transcriptionally inert nuclear
factor–B DNA-binding subunit NF-B1 is present in both
control and stimulated hepatocyte nuclei. Its abundance
changes weakly upon TNF stimulation. In contrast, the potent
transactivating protein Rel A is not found in unstimulated
hepatocyte nuclei and is recruited by TNF- into the C1
DNA-binding complex. Overexpression of Rel A results in acute-phase
response element transcription. Cotransfection of a chimeric GAL4–Rel
A protein with GAL4 DNA-binding sites is a strategy that allows for
selective study of Rel A. The GAL4:Rel A chimera is a
TNF-–inducible transactivator. Deletion of the
amino-terminal 254 amino acids of Rel A produces a constitutive
activator (that is no longer TNF- inducible). The
cytokine induction of Rel A, then, is mediated through its
amino-terminal 254 amino acids. We conclude that Rel A:NF-B1 is
a crucial cytokine-inducible transcription factor complex
regulating angiotensinogen gene synthesis in
hepatocytes and may be involved in controlling the
activity of the renin-angiotensin system.
Key Words: nuclear factor kappa B • renin-angiotensin system • angiotensinogen • acute-phase reaction
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