Guanine-nucleotide exchange factor H1 mediates lipopolysaccharide-induced interleukin 6 and tumor necrosis factor α expression in endothelial cells via activation of nuclear factor κB.
Shock
; 37(5): 531-8, 2012 May.
Article
em En
| MEDLINE
| ID: mdl-22301607
ABSTRACT
The development of sepsis is multifactorial. Tissue damage and organ dysfunction may be caused not only by the microorganisms but also by the inflammatory mediators released in response to the infection. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) levels in serum are well known to be upregulated in humans with sepsis and can be used to predict outcome. Using human umbilical vein endothelial cells, we analyzed the role of guanine-nucleotide exchange factor H1 (GEF-H1) on lipopolysaccharide (LPS)-dependent IL-6/TNF-α expression in endothelial cells. Lipopolysaccharide upregulated IL-6 secretion in a dose- and time-dependent manner. Specific inactivation of RhoA/Cdc42/Rac1 by Clostridium difficile toxin B-10463 (TcdB-10463) reduced LPS-induced nuclear factor κB (NF-κB) p65 phosphorylation, IL-6/TNF-α messenger RNA (mRNA), and IL-6/TNF-α protein productions. Guanine-nucleotide exchange factor H1 protein expression remained on a high level among 1 to 9 h in response to LPS challenge of endothelial cells. Inhibition of GEF-H1 by specific small interfering RNA or inactivation of Rho-associated kinase with Y-27632 not only significantly reduced LPS-induced p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) activities but also blocked LPS-induced NF-κB translocation and activation, thereby inhibiting IL-6/TNF-α mRNA and protein productions. Furthermore, SB203580 (p38 inhibitor) but not PD98059 (ERK1/2 inhibitor) blocked LPS-induced NF-κB activation; however, both inhibitors significantly suppressed IL-6/TNF-α mRNA and protein expression. In summary, our data suggest that LPS rapidly upregulates GEF-H1 expression. Activated Rho-associated kinase by GEF-H1 subsequently activates p38 and ERK1/2, thereby increasing IL-6/TNF-α expression in endothelial cells. P38 and ERK1/2 regulate LPS-induced IL-6/TNF-α expression through an NF-κB-dependent manner and an NF-κB-independent manner, respectively.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
/
Lipopolissacarídeos
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NF-kappa B
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Interleucina-6
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Fator de Necrose Tumoral alfa
/
Fatores de Troca do Nucleotídeo Guanina
/
Células Endoteliais
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Shock
Assunto da revista:
ANGIOLOGIA
/
CARDIOLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
China