Escherichia coli Shiga toxin 1 and TNF-alpha induce cytokine release by human cerebral microvascular endothelial cells.
Infection with Shiga toxin (Stx)-producing Escherichia coli can lead to development of hemolytic uremic syndrome (HUS). Patients with severe HUS often exhibit central nervous system (CNS) pathology, which is thought to involve damage to brain endothelium, a component of the blood-brain barrier. We hypothesized that this neuropathology occurs when cerebral endothelial cells of the blood-brain barrier, sensitized by exogenous TNF-alpha and stimulated by Stx1, produce and release proinflammatory cytokines. This was tested by measuring changes in cytokine mRNA and protein expression in human brain endothelial cells (hBEC) in vitro when challenged by TNF-alpha and/or Stx. High doses of Stx1 alone were somewhat cytotoxic to hBEC; Stx1-treated cells produced increased amounts of IL-6 mRNA and secreted this cytokine. IL-1beta and TNF-alpha mRNA, but not protein, were increased, and IL-8 secretion increased without an observed increase in mRNA. Cells pretreated with TNF-alpha were more sensitive to Stx1, displaying greater Stx1-induction of mRNA for TNF-alpha, IL-1beta, and IL-6, and secretion of IL-6 and IL-8. These observations suggest that in the pathogenesis of HUS, Stx can induce cytokine release from hBEC, which may contribute toward the characteristic CNS neuropathology.
Eisenhauer
Patricia B
PB
Program in Glycobiology, Shriver Center, University of Massachusetts Medical School, Waltham, MA, USA.
Jacewicz
Mary S
MS
Conn
Kelly J
KJ
Koul
Omanand
O
Wells
John M
JM
Fine
Richard E
RE
Newburg
David S
DS
D001921:Brain / Q000098:blood supply* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000276:immunology* / Q000473:pathology; D004926:Escherichia coli / Q000472:pathogenicity; D005786:Gene Expression Regulation; D006463:Hemolytic-Uremic Syndrome / Q000150:complications; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D022622:Shiga Toxin 1 / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D022622:Shiga Toxin 1; D014409:Tumor Necrosis Factor-alpha