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Crosstalk between Human Microvascular Endothelial Cells and Tubular Epithelial Cells Modulates Pro-Inflammatory Responses Induced by Shiga Toxin Type 2 and Subtilase Cytotoxin

1
Laboratorio de Fisiopatogenia, Departamento de Fisiología, Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires 1121, Argentina
2
Laboratorio de Inmunidad Innata, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina, Buenos Aires 1425, Argentina
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Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires 1121, Argentina
4
Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, Australia
*
Author to whom correspondence should be addressed.
Toxins 2019, 11(11), 648; https://doi.org/10.3390/toxins11110648
Received: 11 October 2019 / Revised: 1 November 2019 / Accepted: 5 November 2019 / Published: 7 November 2019
Hemolytic uremic syndrome (HUS) is a consequence of Shiga toxin (Stx)-producing Escherichia coli (STEC) infection and is the most frequent cause of acute renal failure (ARF) in children. Subtilase cytotoxin (SubAB) has also been associated with HUS pathogenesis. We previously reported that Stx2 and SubAB cause different effects on co-cultures of human renal microvascular endothelial cells (HGEC) and human proximal tubular epithelial cells (HK-2) relative to HGEC and HK-2 monocultures. In this work we have analyzed the secretion of pro-inflammatory cytokines by co-cultures compared to monocultures exposed or not to Stx2, SubAB, and Stx2+SubAB. Under basal conditions, IL-6, IL-8 and TNF-α secretion was different between monocultures and co-cultures. After toxin treatments, high concentrations of Stx2 and SubAB decreased cytokine secretion by HGEC monocultures, but in contrast, low toxin concentrations increased their release. Toxins did not modulate the cytokine secretion by HK-2 monocultures, but increased their release in the HK-2 co-culture compartment. In addition, HK-2 monocultures were stimulated to release IL-8 after incubation with HGEC conditioned media. Finally, Stx2 and SubAB were detected in HGEC and HK-2 cells from the co-cultures. This work describes, for the first time, the inflammatory responses induced by Stx2 and SubAB, in a crosstalk model of renal endothelial and epithelial cells. View Full-Text
Keywords: Shiga toxin; Subtilase cytotoxin; Hemolytic Uremic Syndrome; endothelial/epithelial human renal cells; co-cultures; cytokines Shiga toxin; Subtilase cytotoxin; Hemolytic Uremic Syndrome; endothelial/epithelial human renal cells; co-cultures; cytokines
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Álvarez, R.S.; Jancic, C.; Garimano, N.; Sacerdoti, F.; Paton, A.W.; Paton, J.C.; Ibarra, C.; Amaral, M.M. Crosstalk between Human Microvascular Endothelial Cells and Tubular Epithelial Cells Modulates Pro-Inflammatory Responses Induced by Shiga Toxin Type 2 and Subtilase Cytotoxin. Toxins 2019, 11, 648.

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