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| Item Type: | Article |
|---|---|
| Title: | Control of neutrophil influx during peritonitis by transcriptional cross-regulation of chemokine CXCL1 by IL-17 and IFN-γ |
| Creators Name: | Catar, R.A., Chen, L., Cuff, S.M., Kift-Morgan, A., Eberl, M., Kettritz, R., Kamhieh-Milz, J., Moll, G., Li, Q., Zhao, H., Kawka, E., Zickler, D., Parekh, G., Davis, P., Fraser, D.J., Dragun, D., Eckardt, K.U., Jörres, A. and Witowski, J. |
| Abstract: | Neutrophil infiltration is a hallmark of peritoneal inflammation, but mechanisms regulating neutrophil recruitment in patients with peritoneal dialysis (PD)-related peritonitis are not fully defined. We examined 104 samples of PD effluent collected during acute peritonitis for correspondence between a broad range of soluble parameters and neutrophil counts. We observed an association between peritoneal IL-17 and neutrophil levels. This relationship was evident in effluent samples with low but not high IFN-γ levels, suggesting a differential effect of IFN-γ concentration on neutrophil infiltration. Surprisingly, there was no association of neutrophil numbers with the level of CXCL1, a key IL-17-induced neutrophil chemoattractant. We investigated therefore the production of CXCL1 by human peritoneal mesothelial cells (HPMCs) under in vitro conditions mimicking clinical peritonitis. Stimulation of HPMCs with IL-17 increased CXCL1 production through induction of transcription factor SP1 and activation of the SP1-binding region of the CXCL1 promoter. These effects were amplified by TNFα. In contrast, IFN-γ dose-dependently suppressed IL-17-induced SP1 activation and CXCL1 production through a transcriptional mechanism involving STAT1. The SP1-mediated induction of CXCL1 was also observed in HPMCs exposed to PD effluent collected during peritonitis and containing IL-17 and TNFα, but not IFN-γ. Supplementation of the effluent with IFN-γ led to a dose-dependent activation of STAT1 and a resultant inhibition of SP1-induced CXCL1 expression. Transmesothelial migration of neutrophils in vitro increased upon stimulation of HPMCs with IL-17 and was reduced by IFN-γ. In addition, HPMCs were capable of binding CXCL1 at their apical cell surface. These observations indicate that changes in relative peritoneal concentrations of IL-17 and IFN-γ can differently engage SP1-STAT1, impacting on mesothelial cell transcription of CXCL1, whose release and binding to HPMC surface may determine optimal neutrophil recruitment and retention during peritonitis. |
| Keywords: | Mesothelial Cells, CXCL1, IL-17, IFN-γ, Peritonitis, Peritoneal Dialysis |
| Source: | Journal of Pathology |
| ISSN: | 0022-3417 |
| Publisher: | Wiley |
| Volume: | 251 |
| Number: | 2 |
| Page Range: | 175-186 |
| Date: | June 2020 |
| Official Publication: | https://doi.org/10.1002/path.5438 |
| PubMed: | View item in PubMed |
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