Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo

Abstract Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators...

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Autores principales:	Hannah M. Komar, Gregory Serpa, Claire Kerscher, Erin Schwoegl, Thomas A. Mace, Ming Jin, Ming-Chen Yang, Ching-Shih Chen, Mark Bloomston, Michael C. Ostrowski, Phil A. Hart, Darwin L. Conwell, Gregory B. Lesinski
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bcb9cbba4cc94215a5ab8cb2fdcff9f5
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spelling	oai:doaj.org-article:bcb9cbba4cc94215a5ab8cb2fdcff9f52021-12-02T12:32:28ZInhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo10.1038/s41598-017-01973-02045-2322https://doaj.org/article/bcb9cbba4cc94215a5ab8cb2fdcff9f52017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01973-0https://doaj.org/toc/2045-2322Abstract Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro. The well-characterized caerulein model of CP was used to assess the therapeutic efficacy of Jak1/2 inhibition in vivo. Treatment of cultured PSC with the Jak1/2 inhibitor ruxolitinib reduced STAT3 phosphorylation, cell proliferation, and expression of alpha-smooth muscle actin (α-SMA), a marker of PSC activation. Treatment with the MAPK inhibitor, MEK162, had less consistent effects on PSC proliferation and no impact on activation. In the caerulein-induced murine model of CP, administration of ruxolitinib for one week significantly reduced biomarkers of inflammation and fibrosis. These data suggest that the Jak/STAT pathway plays a prominent role in PSC proliferation and activation. In vivo treatment with the Jak1/2 inhibitor ruxolitinib reduced the severity of experimental CP, suggesting that targeting Jak/STAT signaling may represent a promising therapeutic strategy for CP.Hannah M. KomarGregory SerpaClaire KerscherErin SchwoeglThomas A. MaceMing JinMing-Chen YangChing-Shih ChenMark BloomstonMichael C. OstrowskiPhil A. HartDarwin L. ConwellGregory B. LesinskiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hannah M. Komar Gregory Serpa Claire Kerscher Erin Schwoegl Thomas A. Mace Ming Jin Ming-Chen Yang Ching-Shih Chen Mark Bloomston Michael C. Ostrowski Phil A. Hart Darwin L. Conwell Gregory B. Lesinski Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo
description	Abstract Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro. The well-characterized caerulein model of CP was used to assess the therapeutic efficacy of Jak1/2 inhibition in vivo. Treatment of cultured PSC with the Jak1/2 inhibitor ruxolitinib reduced STAT3 phosphorylation, cell proliferation, and expression of alpha-smooth muscle actin (α-SMA), a marker of PSC activation. Treatment with the MAPK inhibitor, MEK162, had less consistent effects on PSC proliferation and no impact on activation. In the caerulein-induced murine model of CP, administration of ruxolitinib for one week significantly reduced biomarkers of inflammation and fibrosis. These data suggest that the Jak/STAT pathway plays a prominent role in PSC proliferation and activation. In vivo treatment with the Jak1/2 inhibitor ruxolitinib reduced the severity of experimental CP, suggesting that targeting Jak/STAT signaling may represent a promising therapeutic strategy for CP.
format	article
author	Hannah M. Komar Gregory Serpa Claire Kerscher Erin Schwoegl Thomas A. Mace Ming Jin Ming-Chen Yang Ching-Shih Chen Mark Bloomston Michael C. Ostrowski Phil A. Hart Darwin L. Conwell Gregory B. Lesinski
author_facet	Hannah M. Komar Gregory Serpa Claire Kerscher Erin Schwoegl Thomas A. Mace Ming Jin Ming-Chen Yang Ching-Shih Chen Mark Bloomston Michael C. Ostrowski Phil A. Hart Darwin L. Conwell Gregory B. Lesinski
author_sort	Hannah M. Komar
title	Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo
title_short	Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo
title_full	Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo
title_fullStr	Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo
title_full_unstemmed	Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo
title_sort	inhibition of jak/stat signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/bcb9cbba4cc94215a5ab8cb2fdcff9f5
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Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo

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