Purified Shiga-like toxins induce expression of proinflammatory cytokines from murine peritoneal macrophages. Academic Article uri icon


  • Infections with Shiga toxin-producing Shigella dysenteriae type 1 and Shiga-like toxin (SLT)-producing Escherichia coli cause outbreaks of bloody diarrhea in which patients are at risk for developing life-threatening complications involving the renal and central nervous systems. Histopathology studies and in vitro experiments suggested that the toxins damage toxin receptor-expressing endothelial cells (EC) lining glomerular and central nervous system capillaries. In the presence of inducible host factors (cytokines), EC sensitivity to SLT toxicity was increased approximately 1 million-fold. We hypothesized that to manifest the vascular lesions characteristic of infection with toxin-producing bacteria, two signals were needed: systemic toxins and elevated proinflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin 1 [IL-1], and IL-6). Human EC do not secrete these cytokines when stimulated with SLTs in vitro, suggesting that additional cells may be involved in pathogenesis. Therefore, we carried out comparative analyses of the capacity of purified (endotoxin-free) SLTs and lipopolysaccharides (LPS) to induce cytokine mRNA and proteins from murine macrophages. The cells were essentially refractory to SLT cytotoxicity, expressing low to undetectable levels of toxin receptor. SLTs and LPS induced TNF activity and IL-6 expression from macrophages, although dose response and kinetics of cytokine induction differed. LPS was a more effective inducing agent than SLTs. SLT-I-induced TNF activity and IL-6 expression were delayed compared with induction mediated by LPS. IL-1 alpha production required approximately 24 h of exposure to SLTs or LPS. Macrophages from LPS-hyporesponsive C3H/HeJ mice produced low levels of TNF activity when treated with SLT-I, suggesting that LPS and SLTs may utilize separate signaling pathways for cytokine induction.

published proceedings

  • Infect Immun

altmetric score

  • 3

author list (cited authors)

  • Tesh, V. L., Ramegowda, B., & Samuel, J. E.

citation count

  • 138

complete list of authors

  • Tesh, VL||Ramegowda, B||Samuel, JE

publication date

  • November 1994