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 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.

A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis

“…NF-κB activation in acinar cells is a key intracellular event in AP and modulates a variety of inflammatory genes ( 24 ). STAT3 is activated by IL-6 trans-signaling and involved in pancreatic damage in AP ( 9 , 10 ). SOCS3 functions to negatively regulate NF-κB and STAT3 signaling pathways ( 25 ).…”

“…IL-6 production correlates with the severity of disease in mice, like in the human pancreatitis ( 8 ). The expression of IL-6 promotes phosphorylation of several down-stream targets including the signal transducer and activator of transcription 3 (STAT3) ( 9 ). Meanwhile, in pancreas, the phosphorylation of STAT3 via IL-6 trans-signaling connects the pancreatic damage to systemic complications ( 10 ).…”

ChickenCCDC152shares an NFYB-regulated bidirectional promoter with agrowth hormone receptorantisense transcript and inhibits cells proliferation and migration

“…It has been reported that CCDC genes play important roles in the process of gene transcription [ 14 , 29 , 43 ]. In this study, the chicken CCDC152 can regulate the GHR-AS-I6-CCDC152 bidirectional promoter through JAK/STAT3/5 signaling pathway, which have been reported by other researchers to mediate genes′ transcription [ 44 , 45 ] and participate in cells proliferation, growth, differentiation, migration and invasion [ 46 , 47 ]. Previous studies have shown that CCDC genes are relative to cellular progression, such as the cell cycle, proliferation and migration [ 28 , 29 , 48 ].…”

Signaling in the Physiology and Pathophysiology of Pancreatic Stellate Cells – a Brief Review of Recent Advances

“…Other pathophysiologically relevant factors associated with PSC activation include hyperglycemia (Nomiyama et al, 2007), hypoxia (Masamune et al, 2008), and oxidative stress (Casini et al, 2000). It is widely accepted that signaling pathways, such as the MAPK/ERK (Jaster et al, 2002;Yoshida et al, 2004), PI3K (McCarroll et al, 2004, Smad (Ohnishi et al, 2004), Jak/STAT (Komar et al, 2017), PKC (Nomiyama et al, 2007), and Hedgehog (Li et al, 2014), play a crucial role in PSC physiology and have been subjects of previous reviews . However, recent evidence has indicated that the Hippo and Wnt pathways as well as authophagy and calcium signaling might be equally important players in PSCs.…”