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| Status |
Public on Feb 22, 2021 |
| Title |
IL11 is elevated in systemic sclerosis and IL11-dependent ERK signaling is needed for the profibrotic activity of TGFβ in dermal fibroblasts |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Objectives: Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with human dermal fibroblast (HDF) activation.
Methods: We measured serum IL11 levels in healthy volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches.
Results: In patients with SSc, serum IL11 levels are elevated as compared to healthy controls. Transforming growth factor beta (TGFβ) isoforms 1, 2 or 3 induced IL11 secretion from HDFs, which highly express IL11RA and the gp130 co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 consistently and robustly stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation. IL11 induced STAT phosphorylation to a lesser extent than ERK and only at high IL11 concentrations. IL11-stimulated ERK activation and fibrosis phenotypes were absent in skin fibroblasts from patients with homozygous loss-of-function mutation in IL11RA. Inhibition of IL11 signaling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacologic inhibition of ERK activity.
Conclusions: These data reveal an important contribution of IL11-related ERK activity for TGFβ-stimulated fibrosis phenotypes in HDFs and suggest IL11 as a potential therapeutic target in SSc.
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| Overall design |
We sequenced the transcriptome of human dermal fibroblasts (n=4) from a healthy donor.
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| Contributor(s) |
Adami E, Viswanathan S, Widjaja A, Ng B, Chothani S, Zhihao N, Tan J, Lio PM, Altunoglu U, Ghosh K, Paleja B, Schafer S, Reversade B, Albani S, Low AH, O'Reilly S, Cook S |
| Citation(s) |
33590875 |
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| Submission date |
Dec 09, 2020 |
| Last update date |
May 24, 2021 |
| Contact name |
Eleonora Adami |
| E-mail(s) |
eleonora.adami@duke-nus.edu.sg
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| Organization name |
Duke-NUS Medical School
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| Department |
CVMD
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| Street address |
8 College Road
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| City |
Singapore |
| ZIP/Postal code |
169857 |
| Country |
Singapore |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA683969 |
| SRA |
SRP297450 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE162966_human_small.counts.txt.gz |
4.6 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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