dc.contributor.author
Simon, Michèle
dc.contributor.author
Lücht, Christian
dc.contributor.author
Hosp, Isa
dc.contributor.author
Zhao, Hongfan
dc.contributor.author
Wu, Dashan
dc.contributor.author
Heidecke, Harald
dc.contributor.author
Witowski, Janusz
dc.contributor.author
Budde, Klemens
dc.contributor.author
Riemekasten, Gabriela
dc.contributor.author
Catar, Rusan
dc.date.accessioned
2022-01-28T15:12:24Z
dc.date.available
2022-01-28T15:12:24Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/33803
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-33523
dc.description.abstract
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.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
systemic sclerosis
en
dc.subject
scleroderma renal crisis
en
dc.subject
PAR-1 receptor
en
dc.subject
autoantibodies
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
11793
dcterms.bibliographicCitation.doi
10.3390/ijms222111793
dcterms.bibliographicCitation.journaltitle
International Journal of Molecular Sciences
dcterms.bibliographicCitation.number
21
dcterms.bibliographicCitation.originalpublishername
MDPI AG
dcterms.bibliographicCitation.volume
22
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
34769227
dcterms.isPartOf.eissn
1422-0067