Down-regulation of high mobility group-I(Y) protein contributes to the inhibition of nitric-oxide synthase 2 by transforming growth factor-beta 1

Citation
A. Pellacani et al., Down-regulation of high mobility group-I(Y) protein contributes to the inhibition of nitric-oxide synthase 2 by transforming growth factor-beta 1, J BIOL CHEM, 276(2), 2001, pp. 1653-1659
Citations number
51
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
276
Issue
2
Year of publication
2001
Pages
1653 - 1659
Database
ISI
SICI code
0021-9258(20010112)276:2<1653:DOHMGP>2.0.ZU;2-#
Abstract
The inducible isoform of nitric oxide synthase (NOS2) catalyzes the product ion of nitric oxide (NO), which participates in the pathophysiology of syst emic inflammatory diseases such as sepsis. NOS2 is transcriptionally up-reg ulated by endotoxin and inflammatory cytokines, and down-regulated by trans forming growth factor (TGF)-beta1, Recently we have shown that high mobilit y group (HMG)-I(Y) protein, an architectural transcription factor, contribu tes to NOS2 gene transactivation by inflammatory mediators. The aim of the present study was to determine whether regulation of HMG-ICY) by TGF-beta1 contributes to the TGF-beta1-mediated suppression of NOS2, By Northern blot analysis, we show that TGF-beta1 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 -beta1, To determine whether the down-regulation of HMG-I(Y) contributed to a decrease in NOS2 gene transactivation by TGF-beta1, we performed cotrans fection experiments. Overexpression of HMG-I(Y) was able to restore cytokin e inducibility of the NOS2 promoter that was suppressed by TGF-beta1, The e ffect of TGF-beta1 on NOS2 gene transactivation was not related to a decrea se in binding of HMG-I(Y) to the promoter of the NOS2 gene, but due to a de crease in endogenous HMG-ICY) protein. These data provide the first evidenc e that cytokine-induced HMG-I(Y) can be down-regulated by TGF-beta1, This d ownregulation of HMG-I(Y) contributes to the TGF-beta1-mediated decrease in NOS2 gene transactivation by proinflammatory stimuli.