Increased Serum IL-10 and Endothelin Levels in Hemolytic Uremic Syndrome Caused by <i>Escherichia coli</i> O157

Abstract

Background: Shiga toxin, produced by Escherichia coli O157:H7, is important for the pathogenicity of the epidemic form of hemolytic uremic syndrome (HUS). This toxin has recently been found to stimulate endothelin-1 synthesis in cultured endothelial cells in vitro. Methods: We investigated endothelin and cytokine levels in sera during a large outbreak of E. coli O157:H7 infection in Osaka, Japan, in 1996. Eleven patients with HUS and 9 patients with hemorrhagic colitis at the onset of E. coli O157:H7 infection were studied. Results: Serum IL-6 (p < 0.01), IL-8 (p < 0.05), IL-10 (p < 0.001) and endothelin (p < 0.001) levels were significantly increased in patients with HUS compared to those with colitis only. The serum thrombomodulin level, a molecular marker of endothelial damage, also showed a significant positive correlation with serum IL-6 (p < 0.01), IL-8 (p < 0.01), IL-10 (p < 0.01) and endothelin (p < 0.001) levels. In a HUS patient, the increase in serum IL-10 and endothelin levels reached a plateau prior to the peak of serum creatinine levels. Conclusion: Increased serum endothelin synthesis by Shiga toxin in vivo was proven in HUS secondary to E. coli O157:H7 infection. Increased serum endothelin and IL-10 levels were speculated to be associated with the development of HUS through vascular endothelial damage caused by E. coli O157:H7 infection.

Shigatoxin-Induced Endothelin-1 Expression in Cultured Podocytes Autocrinally Mediates Actin Remodeling

“…We focused on the vasoconstrictor peptide ET-1 found to be elevated in plasma and urine of children during the acute phase of HUS. 40,41 In the kidney, ET-1 is produced by all glomerular cell types and by tubules, 42 and when bound to the ET A receptor, it elicits different biological activities, including contraction, proliferation, and inflammatory cell recruitment. 43 The present results indicate that Stx-2, at subtoxic concentrations, enhanced gene expression of ET-1 in cultured murine podocytes, followed by increased synthesis of the mature peptide.…”

Phenotype markers and function of neutrophils in children with hemolytic uremic syndrome

“…PGE 2 inhibits chemotaxis [39] and aggregation [40] of PMN and nitric oxide metabolites inhibit CD18-dependent PMN adhesion [41]. Different researchers have reported high plasma concentrations of nitrite and nitrate [42,43], as well as IL-10 and IL-1Ra [27,28,43], during HUS. All these findings suggest that most patients show a pattern of mediators concordant with an anti-inflammatory status, which probably has been preceded by an inflammatory state.…”

Pathogenesis of Shiga Toxin-Associated Hemolytic Uremic Syndrome

“…Various circulating inflammatory mediators, including ILs, chemokines, soluble adhesion molecules, growth factors, cytokine receptors, and acute phase response proteins, are abnormally increased in children with D ϩ HUS (7,92,124,126,(135)(136)(137)(138)(139)(140)(141)(142)(143)(144)(145)(146)(147)(148). Although these studies do not prove that the elevated inflammatory mediators have a role in the pathogenesis of disease, they indicate a marked host inflammatory response.…”

“…Abnormally high levels of endothelin have been reported in the serum and urine of patients with HUS (144,147,160), reflecting the degree of renal injury, but possibly contributing to it by vasoactive potency.…”