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| Item Type: | Article |
|---|---|
| Title: | IL11 activates pancreatic stellate cells and causes pancreatic inflammation, fibrosis and atrophy in a mouse model of pancreatitis |
| Creators Name: | Ng, B., Viswanathan, S., Widjaja, A.A., Lim, W.W., Shekeran, S.G., Goh, J.W.T., Tan, J., Kuthubudeen, F., Lim, S.Y., Xie, C., Schafer, S., Adami, E. and Cook, S.A. |
| Abstract: | Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, which specifically express IL11RA in the pancreas, results in transient STAT3 phosphorylation, sustained ERK activation and PSC activation. In contrast, IL6 stimulation of PSCs caused sustained STAT3 phosphorylation but did not result in ERK activation or PSC transformation. Pancreatitis factors, including TGFβ, CTGF and PDGF, induced IL11 secretion from PSCs and a neutralising IL11RA antibody prevented PSC activation by these stimuli. This revealed an important ERK-dependent role for autocrine IL11 activity in PSCs. In mice, IL11 was increased in the pancreas after pancreatic duct ligation, and in humans, IL11 and IL11RA levels were elevated in chronic pancreatitis. Following pancreatic duct ligation, administration of anti-IL11RA to mice reduced pathologic (ERK, STAT, NF-κB) signalling, pancreatic atrophy, fibrosis and pro-inflammatory cytokine (TNFα, IL6 and IL1β) levels. This is the first description of IL11-mediated activation of PSCs, and the data suggest IL11 as a stromal therapeutic target in pancreatitis. |
| Keywords: | IL11, IL6, gp130, Immune, ERK, Therapy, Cytokine, Animals, Mice |
| Source: | International Journal of Molecular Sciences |
| ISSN: | 1422-0067 |
| Publisher: | MDPI |
| Volume: | 23 |
| Number: | 7 |
| Page Range: | 3549 |
| Date: | 24 March 2022 |
| Official Publication: | https://doi.org/10.3390/ijms23073549 |
| PubMed: | View item in PubMed |
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