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.
Highlights
Chronic pancreatitis (CP) is characterized by persistent inflammation and fibrosis of the pancreas
Our results demonstrate that both the STAT3 and MAPK pathways are activated in cultured mouse and human pancreatic stellate cells (PSC) from the setting of CP and pancreatic ductal adenocarcinoma (PDAC)
Supernatants from these cells further demonstrated elevated levels of several immunomodulatory factors, including IL-6, monocyte chemoattractant protein-1 (MCP-1), and CXCL10, as compared to a human pancreas-derived fibroblast line (HPF), which served as a control (Fig. 2c,d)
Summary
10 RLT-PSC mouse non-immortalized human human human human human non-immortalized non-immortalized immortalized non-immortalized immortalized. Untreated and MEK162-treated cells remained Oil-Red O negative (Fig. 4b,c) Taken together, these phenotypic profiles indicate that ruxolitinib treatment reduced PSC activation in vitro. To examine the impact of ruxolitinib on biomarkers relevant to CP in vivo, we utilized the well-characterized murine model of caerulein-induced chronic pancreatitis (Fig. 5a) In this proof of concept study, oral administration of ruxolitinib for one week in mice with established pancreatitis led to reduced pSTAT3 in the pancreata as determined by IHC (Fig. 5b). This short-term treatment resulted in a trend toward restored serum lipase levels (Fig. 5c). Assessment of CD3+ cells by IHC as a biomarker of inflammation indicated a trend toward a decrease in ruxolitinib-treated mice (Fig. 5d), no difference in α-SMA staining was observed between groups (data not shown)
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