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J. Biol. Chem., Vol. 276, Issue 2, 1653-1659, January 12, 2001
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1*
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**
From the The inducible isoform of nitric-oxide synthase
(NOS2) catalyzes the production of nitric oxide (NO), which
participates in the pathophysiology of systemic inflammatory diseases
such as sepsis. NOS2 is transcriptionally up-regulated by endotoxin and inflammatory cytokines, and down-regulated by transforming growth factor (TGF)- Cardiovascular and Pulmonary and
Critical Care Divisions, Brigham and Women's Hospital, Boston,
Massachusetts 02115, the § Department of Medicine, Harvard
Medical School, Boston, Massachusetts 02115, and the ¶ Department
of Biochemistry and Biophysics, Washington State University, Pullman,
Washington 99164
1. Recently we have shown that high mobility group (HMG)-I(Y) protein, an architectural transcription factor, contributes to NOS2 gene transactivation by inflammatory
mediators. The aim of the present study was to determine whether
regulation of HMG-I(Y) by TGF-1 contributes to the TGF-1-mediated
suppression of NOS2. By Northern blot analysis, we show that TGF-1
decreased cytokine-induced HMG-I(Y) mRNA levels in vascular smooth
muscle cells and macrophages in vitro and in
vivo. Western analysis confirmed the down-regulation of HMG-I(Y)
protein by TGF-1. To determine whether the down-regulation of
HMG-I(Y) contributed to a decrease in NOS2 gene
transactivation by TGF-1, we performed cotransfection experiments.
Overexpression of HMG-I(Y) was able to restore cytokine inducibility of
the NOS2 promoter that was suppressed by TGF-1. The effect of
TGF-1 on NOS2 gene transactivation was not related to a
decrease in binding of HMG-I(Y) to the promoter of the NOS2
gene, but due to a decrease in endogenous HMG-I(Y) protein. These data
provide the first evidence that cytokine-induced HMG-I(Y) can be
down-regulated by TGF-1. This down-regulation of HMG-I(Y)
contributes to the TGF-1-mediated decrease in NOS2 gene
transactivation by proinflammatory stimuli.
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