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

Nephron. 2001 May;88(1):14-23. doi: 10.1159/000045953.

Abstract

Background/aims: Inflammatory cytokines may enhance renal injury in post-diarrheal hemolytic uremic syndrome (Stx HUS) by enhancing the cytotoxic effect 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 cells, we examined Stx-1 regulation of cytokine production by human GEC.

Methods: 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 effect on inflammatory cytokine production by GEC that occurred at toxin concentrations ranging from minimal to 50% inhibition of protein synthesis. CHX, at concentrations that produced similar inhibition of protein synthesis, increased IL-1, IL-6, and TNF protein release and mRNA accumulation, but in a different time- and dose-dependent pattern than Stx. Lipopolysaccharide (LPS) did not change IL-1, but stimulated IL-6 and TNF production. LPS and Stx-1 combined stimulated production of all three cytokines to a greater extent than either toxin alone.

Conclusion: These data indicate that: (1) Stx-1 alone modestly stimulates GEC inflammatory cytokine production; (2) LPS and Stx-1 combined can potently enhance GEC cytokine release, and (3) this action of Stx-1 may relate in part to inhibition of protein synthesis but cannot be fully attributed to this effect.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Cell Survival / drug effects
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Cycloheximide / pharmacology
  • Cytokines / genetics*
  • Cytokines / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Humans
  • Infant
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Kidney Glomerulus / cytology*
  • Kidney Glomerulus / immunology
  • Middle Aged
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / analysis
  • Shiga Toxin 1 / toxicity*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Cytokines
  • Interleukin-1
  • Interleukin-6
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Shiga Toxin 1
  • Tumor Necrosis Factor-alpha
  • Cycloheximide