Shiga toxin-1 regulation of cytokine production by human glomerular epithelial cells

Background/Aims: Inflammatory cytokines may enhance renal injury in post-di arrheal hemolytic uremic syndrome (Stx HUS) by enhancing the cytotoxic effe ct of Shiga toxins (Stx). The sources of inflammatory cytokines in Stx HUS are unclear. Since Stx-1 potently inhibits protein synthesis by glomerular epithelial cells (GEC) and increases cytokine release by renal epithelial c ells, we examined Stx-1 regulation of cytokine production by human GEC. Met hods: Stx-1 (and cycloheximide (CHX), another protein synthesis inhibitor) cytotoxicity, protein synthesis inhibition, and effect on interleukin-1 (IL -1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) release and mRNA levels were determined. Results: Stx-1 alone had a modest stimulatory effe ct on inflammatory cytokine production by GEC that occurred at toxin concen trations ranging from minimal to 50% inhibition of protein synthesis. CHX, at concentrations that produced similar inhibition of protein synthesis, in creased IL-1, IL-6, and TNF protein release and mRNA accumulation, but in a different time- and dose-dependent pattern than Stx. Lipopolysaccharide (L PS) did not change IL-1, but stimulated IL-6 and TNF production. LPS and St x-1 combined stimulated production of all three cytokines to a greater exte nt than either toxin alone. Conclusion: These data indicate that: (1) Stx-1 alone modestly stimulates GEC inflammatory cytokine production; (2) LPS an d Stx-1 combined can potently enhance GEC cytokine release, and (3) this ac tion of Stx-1 may relate in part to inhibition of protein synthesis but can not be fully attributed to this effect. Copyright (C) 2001 S. Karger AG, Ba sel.