Escherichia coli Shiga toxin 1 and TNF-α induce cytokine release by human cerebral microvascular endothelial cells

• Published in: Microbial pathogenesis 2004-04, Vol.36 (4), p.189-196
• Main Authors: Eisenhauer, Patricia B, Jacewicz, Mary S, Conn, Kelly J, Koul, Omanand, Wells, John M, Fine, Richard E, Newburg, David S
• Format: Article
• Language: English
• Subjects: Bacteriology; Biological and medical sciences; Brain - blood supply; Brain - pathology; Brain endothelial cells; Cells, Cultured; Cytokines; Cytokines - biosynthesis; Cytokines - genetics; Cytokines - secretion; Endothelial Cells - immunology; Endothelial Cells - pathology; Escherichia coli; Escherichia coli - pathogenicity; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Hemolytic uremic syndrome; Hemolytic-Uremic Syndrome - complications; Humans; Interleukin-1 - biosynthesis; Interleukin-1 - genetics; Interleukin-1 - secretion; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Interleukin-6 - secretion; Interleukin-8 - biosynthesis; Interleukin-8 - genetics; Interleukin-8 - secretion; Microbiology; Miscellaneous; RNA, Messenger - analysis; RNA, Messenger - genetics; Shiga toxin; Shiga Toxin 1 - toxicity; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0882-4010; 1096-1208
• DOI: 10.1016/j.micpath.2003.11.004

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-α 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-α 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-1β and TNF-α mRNA, but not protein, were increased, and IL-8 secretion increased without an observed increase in mRNA. Cells pretreated with TNF-α were more sensitive to Stx1, displaying greater Stx1-induction of mRNA for TNF-α, IL-1β, 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.