Inhibition of p38 mitogen-activated protein kinase ameliorates cytokine up-regulated shigatoxin-1 toxicity in human brain microvascular endothelial cells.
Brain injury in hemolytic-uremic syndrome (HUS) may be enhanced by inflammatory cytokine up-regulation of endothelial cell sensitivity to shigatoxin (Stx). The present study investigated whether inflammatory cytokine up-regulation of Stx toxicity could be ameliorated by inhibiting candidate signal transduction pathways. Exposure of human brain endothelial cells (HBECs) to tumor necrosis factor (TNF) greatly increased Stx-1 and Stx-2 cytotoxicity; this was reduced by inhibition of p38 mitogen-activated protein kinase (MAPK), but not c-Jun kinase. SB203580, a specific inhibitor of p38 MAPK, reduced TNF-stimulated Stx cytotoxicity in HBECs, TNF-stimulated (125)Stx-1 binding to intact HBECs, the cellular content of Gb3 (galactose alpha 1,4, galactose ss 1,4, glucose-ceramide) (the Stx receptor), and TNF-stimulated Gb3 synthase and glucosylceramide synthase activities but did not affect lactosylceramide synthase activities or mRNA content. Thus, inhibition of p38 MAPK substantially reduces inflammatory cytokine up-regulation of Stx-receptor synthesis and cell-surface expression, thereby decreasing Stx cytotoxicity. Inhibition of p38 MAPK may be of therapeutic benefit in HUS.
Stricklett
Peter K
PK
Division of Nephrology, University of Utah School of Medicine, and Salt Lake Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
Hughes
Alisa K
AK
Kohan
Donald E
DE
D001921:Brain / Q000098:blood supply*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005700:Galactosyltransferases / Q000378:metabolism; D005964:Glucosyltransferases / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008833:Microcirculation; D011725:Pyridines / Q000494:pharmacology*; D022622:Shiga Toxin 1 / Q000378:metabolism / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D014281:Trihexosylceramides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D022622:Shiga Toxin 1; D014281:Trihexosylceramides; D014409:Tumor Necrosis Factor-alpha; C018549:globotriaosylceramide; D005700:Galactosyltransferases; D005964:Glucosyltransferases; C045097:UDP-galactose-lactosylceramide alpha 1-4-galactosyltransferase; C023246:ceramide glucosyltransferase; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580