This study explores the in vitro relationship between
Shiga toxin-producing Shigella spp. and Escherichia coli and the development of vascular complications in humans following
bacillary dysentery. We propose that
lipopolysaccharide (LPS;
endotoxin) may combine with
Shiga toxin to facilitate vascular damage characteristic of
hemolytic uremic syndrome. We have examined the direct cytotoxic effects of
Shiga toxin and LPS on human umbilical vein endothelial cells (HUVEC) in culture.
Shiga toxin alone was cytotoxic to HUVEC, whereas LPS was noncytotoxic at concentrations at or below 10 micrograms/ml. Combinations of LPS with
Shiga toxin resulted in a synergistic cytotoxic effect. The synergistic cytotoxic response of HUVEC to
Shiga toxin plus LPS was dose dependent for both agents and was maximal at 24 h of exposure. This synergistic response was enhanced by preincubation of HUVEC with LPS. LPS (1 micrograms/ml) alone depressed HUVEC
protein synthesis in a transient manner and enhanced the
protein synthesis-inhibiting activity of
Shiga toxin. The synergistic cytotoxic activity of LPS analogs was as follows, in decreasing order: complete LPS =
diphosphoryl lipid A greater than
monophosphoryl lipid A greater than deacylated LPS. These results are consistent with a role for
Shiga toxin and LPS in the development of
hemolytic uremic syndrome at the level of the vascular endothelium in humans.