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Differentiation-associated toxin receptor modulation, cytokine production, and sensitivity to Shiga-like toxins in human monocytes and monocytic cell lines

Infections with Shiga toxin-producing Shigella dysenteriae type 1 or Shiga-like toxin (SLT)-producing Escherichia coli cause bloody diarrhea and are associated with an increased risk of acute renal failure and severe neurological complications. Histopathological examination of human and animal tissues suggests that the target cells for toxin action are vascular endothelial cells. Proinflammatory cytokines regulate endothelial cell membrane expression of the glycolipid globotriaosylceramide (Gb(3)) which serves as the toxin receptor, suggesting that the host response to the toxins or other bacterial products may contribute to pathogenesis by regulating target cell sensitivity to the toxins. We examined the effects of purified SLTs on human peripheral blood monocytes (PBMn) and two monocytic cell lines. Undifferentiated THP-1 cells were sensitive to SLTs. Treatment of the cells with a number of differentiation factors resulted in increased toxin resistance which was associated with decreased toxin receptor expression. U-937 cells, irrespective of maturation state, and PBMn were resistant to the toxins. U-937 cells expressed low levels of GB(3), and toxin receptor expression was not altered during differentiation. Treatment of monocytic cells with tumor necrosis factor alpha (TNF-alpha) did not markedly increase sensitivity or alter toxin receptor expression. Undifferentiated monocytic cells failed to synthesize TNF and interleukin 1beta when treated with sublethal concentrations of SLT type I (SLT-I), whereas cells treated with 12-0-tetradecanoylphorbol-13-acetate acquired the ability to produce cytokines when stimulated with SLT-I. When stimulated with SLT-I, U-937 cells produced lower levels of TNF than PBMn and THP-1 cells did.