Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells

Background. Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc). Autoantibodies (Abs) against endothelial cell antigens have been implicated in SSc and SRC. However, their detailed roles remain poorly defined. Pro-inflammatory cytokine interleukin-6 (IL-6) h...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Michèle Simon, Christian Lücht, Isa Hosp, Hongfan Zhao, Dashan Wu, Harald Heidecke, Janusz Witowski, Klemens Budde, Gabriela Riemekasten, Rusan Catar
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	systemic sclerosis scleroderma renal crisis PAR-1 receptor IL-6 autoantibodies Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/54d0d6d892034a8d8723ae85ac93ce36
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:54d0d6d892034a8d8723ae85ac93ce36
record_format	dspace
spelling	oai:doaj.org-article:54d0d6d892034a8d8723ae85ac93ce362021-11-11T17:14:39ZAutoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells10.3390/ijms2221117931422-00671661-6596https://doaj.org/article/54d0d6d892034a8d8723ae85ac93ce362021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11793https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Background. Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc). Autoantibodies (Abs) against endothelial cell antigens have been implicated in SSc and SRC. However, their detailed roles remain poorly defined. Pro-inflammatory cytokine interleukin-6 (IL-6) has been found to be increased in SSc, but its role in SRC is unclear. Here, we aimed to determine how the autoantibodies from patients with SSc and SRC affect IL-6 secretion by micro-vascular endothelial cells (HMECs). Methods. Serum IgG fractions were isolated from either SSc patients with SRC (n = 4) or healthy individuals (n = 4) and then each experiment with HMECs was performed with SSc-IgG from a separate patient or separate healthy control. IL-6 expression and release by HMECs was assessed by quantitative reverse transcription and quantitative PCR (RT-qPCR) and immunoassays, respectively. The mechanisms underlying the production of IL-6 were analyzed by transient HMEC transfections with IL-6 promoter constructs, electrophoretic mobility shift assays, Western blots and flow cytometry. Results. Exposure of HMECs to IgG from SSc patients, but not from healthy controls, resulted in a time- and dose-dependent increase in IL-6 secretion, which was associated with increased AKT, p70S6K, and ERK1/2 signalling, as well as increased c-FOS/AP-1 transcriptional activity. All these effects could be reduced by the blockade of the endothelial PAR-1 receptor and/or c-FOS/AP-1silencing. Conclusions. Autoantibodies against PAR-1 found in patients with SSc and SRC induce IL-6 production by endothelial cells through signalling pathways controlled by the AP-1 transcription factor. These observations offer a greater understanding of adverse endothelial cell responses to autoantibodies present in patients with SRC.Michèle SimonChristian LüchtIsa HospHongfan ZhaoDashan WuHarald HeideckeJanusz WitowskiKlemens BuddeGabriela RiemekastenRusan CatarMDPI AGarticlesystemic sclerosisscleroderma renal crisisPAR-1 receptorIL-6autoantibodiesBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11793, p 11793 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	systemic sclerosis scleroderma renal crisis PAR-1 receptor IL-6 autoantibodies Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	systemic sclerosis scleroderma renal crisis PAR-1 receptor IL-6 autoantibodies Biology (General) QH301-705.5 Chemistry QD1-999 Michèle Simon Christian Lücht Isa Hosp Hongfan Zhao Dashan Wu Harald Heidecke Janusz Witowski Klemens Budde Gabriela Riemekasten Rusan Catar Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells
description	Background. Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc). Autoantibodies (Abs) against endothelial cell antigens have been implicated in SSc and SRC. However, their detailed roles remain poorly defined. Pro-inflammatory cytokine interleukin-6 (IL-6) has been found to be increased in SSc, but its role in SRC is unclear. Here, we aimed to determine how the autoantibodies from patients with SSc and SRC affect IL-6 secretion by micro-vascular endothelial cells (HMECs). Methods. Serum IgG fractions were isolated from either SSc patients with SRC (n = 4) or healthy individuals (n = 4) and then each experiment with HMECs was performed with SSc-IgG from a separate patient or separate healthy control. IL-6 expression and release by HMECs was assessed by quantitative reverse transcription and quantitative PCR (RT-qPCR) and immunoassays, respectively. The mechanisms underlying the production of IL-6 were analyzed by transient HMEC transfections with IL-6 promoter constructs, electrophoretic mobility shift assays, Western blots and flow cytometry. Results. Exposure of HMECs to IgG from SSc patients, but not from healthy controls, resulted in a time- and dose-dependent increase in IL-6 secretion, which was associated with increased AKT, p70S6K, and ERK1/2 signalling, as well as increased c-FOS/AP-1 transcriptional activity. All these effects could be reduced by the blockade of the endothelial PAR-1 receptor and/or c-FOS/AP-1silencing. Conclusions. Autoantibodies against PAR-1 found in patients with SSc and SRC induce IL-6 production by endothelial cells through signalling pathways controlled by the AP-1 transcription factor. These observations offer a greater understanding of adverse endothelial cell responses to autoantibodies present in patients with SRC.
format	article
author	Michèle Simon Christian Lücht Isa Hosp Hongfan Zhao Dashan Wu Harald Heidecke Janusz Witowski Klemens Budde Gabriela Riemekasten Rusan Catar
author_facet	Michèle Simon Christian Lücht Isa Hosp Hongfan Zhao Dashan Wu Harald Heidecke Janusz Witowski Klemens Budde Gabriela Riemekasten Rusan Catar
author_sort	Michèle Simon
title	Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells
title_short	Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells
title_full	Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells
title_fullStr	Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells
title_full_unstemmed	Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells
title_sort	autoantibodies from patients with scleroderma renal crisis promote par-1 receptor activation and il-6 production in endothelial cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/54d0d6d892034a8d8723ae85ac93ce36
work_keys_str_mv	AT michelesimon autoantibodiesfrompatientswithsclerodermarenalcrisispromotepar1receptoractivationandil6productioninendothelialcells AT christianlucht autoantibodiesfrompatientswithsclerodermarenalcrisispromotepar1receptoractivationandil6productioninendothelialcells AT isahosp autoantibodiesfrompatientswithsclerodermarenalcrisispromotepar1receptoractivationandil6productioninendothelialcells AT hongfanzhao autoantibodiesfrompatientswithsclerodermarenalcrisispromotepar1receptoractivationandil6productioninendothelialcells AT dashanwu autoantibodiesfrompatientswithsclerodermarenalcrisispromotepar1receptoractivationandil6productioninendothelialcells AT haraldheidecke autoantibodiesfrompatientswithsclerodermarenalcrisispromotepar1receptoractivationandil6productioninendothelialcells AT januszwitowski autoantibodiesfrompatientswithsclerodermarenalcrisispromotepar1receptoractivationandil6productioninendothelialcells AT klemensbudde autoantibodiesfrompatientswithsclerodermarenalcrisispromotepar1receptoractivationandil6productioninendothelialcells AT gabrielariemekasten autoantibodiesfrompatientswithsclerodermarenalcrisispromotepar1receptoractivationandil6productioninendothelialcells AT rusancatar autoantibodiesfrompatientswithsclerodermarenalcrisispromotepar1receptoractivationandil6productioninendothelialcells
_version_	1718432116077756416

Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells

Ejemplares similares