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

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 alpha (TNF-alpha) 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-alpha 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 kappa B (NF