Cyclooxygenase-2 is required for activated pancreatic stellate cells to respond to proinflammatory cytokines

2007 ◽  
Vol 292 (1) ◽  
pp. C259-C268 ◽  
Author(s):  
Hiroyoshi Aoki ◽  
Hirohide Ohnishi ◽  
Kouji Hama ◽  
Satoshi Shinozaki ◽  
Hiroto Kita ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Inflammatory Responses ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Cyclooxygenase 2 ◽  
Dominant Negative ◽  
Pancreatic Stellate Cells ◽  
Cox 2 ◽  
Dependent Pathway ◽  
Tgf Β1

Cyclooxygenase-2 (COX-2) mediates various inflammatory responses and is expressed in pancreatic tissue from patients with chronic pancreatitis. To examine the role of COX-2 in chronic pancreatitis, we investigated its participation in regulating functions of pancreatic stellate cells (PSCs), using isolated rat PSCs. COX-2 was expressed in culture-activated PSCs but not in freshly isolated quiescent PSCs. TGF-β1, IL-1β, and IL-6 enhanced COX-2 expression in activated PSCs, concomitantly increasing the expression of α-smooth muscle actin (α-SMA), a parameter of PSC activation. The COX-2 inhibitor NS-398 blocked culture activation of freshly isolated quiescent PSCs. NS-398 also inhibited the enhancement of α-SMA expression by TGF-β1, IL-1β, and IL-6 in activated PSCs. These data indicate that COX-2 is required for the initiation and promotion of PSC activation. We further investigated the mechanism by which cytokines enhance COX-2 expression in PSCs. Adenovirus-mediated expression of dominant negative Smad2/3 inhibited the increase in expression of COX-2, α-SMA, and collagen-1 mediated by TGF-β1 in activated PSCs. Moreover, dominant negative Smad2/3 expression attenuated the expression of COX-2 and α-SMA enhanced by IL-1β and IL-6. Anti-TGF-β neutralizing antibody also attenuated the increase in COX-2 and α-SMA expression caused by IL-1β and IL-6. IL-6 as well as IL-1β enhanced TGF-β1 secretion from PSCs. These data indicate that Smad2/3-dependent pathway plays a central role in COX-2 induction by TGF-β1, IL-1β, and IL-6. Furthermore, IL-1β and IL-6 promote PSC activation by enhancing COX-2 expression indirectly through Smad2/3-dependent pathway by increasing TGF-β1 secretion from PSCs.

scholarly journals Hic-5 is required for activation of pancreatic stellate cells and development of pancreatic fibrosis in chronic pancreatitis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lin Gao ◽  
Xiao-Feng Lei ◽  
Aya Miyauchi ◽  
Masahito Noguchi ◽  
Tomokatsu Omoto ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Matrix Proteins ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Pathological Conditions ◽  
Potential Marker ◽  
Actin Expression ◽  
Tgf Β1

Abstract Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP). However, little is known about the mechanisms of PSC activation. PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-β1-induced protein. In this study, we investigated whether Hic-5 activates PSCs, which promote pancreatic fibrosis development in CP. Hic-5-knockout and wild type mice were subjected to caerulein injection to induce CP. Hic-5 expression was strongly upregulated in activated PSCs from human CP tissue and from mouse pancreatic fibrosis in caerulein-induced CP. Hic-5 deficiency significantly attenuated mouse pancreatic fibrosis and PSC activation in the experimental murine CP model. Mechanistically, Hic-5 knock down significantly inhibited the TGF-β/Smad2 signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. Taken together, we propose Hic-5 as a potential marker of activated PSCs and a novel therapeutic target in CP treatment.

scholarly journals Transgenic expression of cyclooxygenase-2 in pancreatic acinar cells induces chronic pancreatitis

2019 ◽  
Vol 316 (1) ◽  
pp. G179-G186
Author(s):  
Haojie Huang ◽  
Jiaxiang Chen ◽  
Lisi Peng ◽  
Yao Yao ◽  
Defeng Deng ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Transgenic Mice ◽  
Fibrous Tissue ◽  
Acinar Cells ◽  
Cyclooxygenase 2 ◽  
Therapeutic Interventions ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Transgenic Expression ◽  
Cox 2

Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX-2 can cause chronic pancreatitis. To investigate the roles of pancreatic acinar COX-2 in fibrogenesis and the development of chronic pancreatitis, COX-2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several profibrogenic factors related to chronic pancreatitis were evaluated. COX-2 was expressed in the pancreas of the transgenic mice, as detected by Western blot analysis. Immunohistochemical staining showed COX-2 was specifically expressed in pancreatic acinar cells. COX-2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition, and acinar-to-ductal metaplasia. Quantitative RT-PCR and immunostaining showed that profibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX-2 transgenic mice. Expression of COX-2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. NEW & NOTEWORTHY COX-2 expression is observed in pancreatic tissues of human chronic pancreatitis. In this study, we showed that COX-2 expression caused the development of chronic pancreatitis in transgenic mice, supporting the idea that COX-2 inhibition may be an effective preventive and therapeutic strategy.

scholarly journals Pancreatic Stellate Cells (PSCs) express Cyclooxygenase-2 (COX-2) and pancreatic cancer stimulates COX-2 in PSCs

2005 ◽  
Vol 4 (1) ◽  
Author(s):  
Seiya Yoshida ◽  
Michael Ujiki ◽  
Xian-Zhong Ding ◽  
Carolyn Pelham ◽  
Mark S Talamonti ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stellate Cells ◽  
Cyclooxygenase 2 ◽  
Pancreatic Stellate Cells ◽  
Cox 2

Autocrine loop between TGF-β1 and IL-1β through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells

2006 ◽  
Vol 290 (4) ◽  
pp. C1100-C1108 ◽  
Author(s):  
Hiroyoshi Aoki ◽  
Hirohide Ohnishi ◽  
Kouji Hama ◽  
Takako Ishijima ◽  
Yukihiro Satoh ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Stellate Cells ◽  
Dominant Negative ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Autocrine Loop ◽  
Dose Dependent ◽  
Tgf Β1

Pancreatic stellate cells (PSCs) are activated during pancreatitis and promote pancreatic fibrosis by producing and secreting ECMs such as collagen and fibronectin. IL-1β has been assumed to participate in pancreatic fibrosis by activating PSCs. Activated PSCs secrete various cytokines that regulate PSC function. In this study, we have examined IL-1β secretion from culture-activated PSCs as well as its regulatory mechanism. RT-PCR and ELISA have demonstrated that PSCs express IL-1β mRNA and secrete IL-1β peptide. Inhibition of TGF-β1 activity secreted from PSCs by TGF-β1-neutralizing antibody attenuated IL-1β secretion from PSCs. Exogenous TGF-β1 increased IL-1β expression and secretion by PSCs in a dose-dependent manner. Adenovirus-mediated expression of dominant-negative (dn)Smad2/3 expression reduced both basal and TGF-β1-stimulated IL-1β expression and secretion by PSCs. Coexpression of Smad3 with dnSmad2/3 restored IL-1β expression and secretion by PSCs, which were attenuated by dnSmad2/3 expression. In contrast, coexpression of Smad2 with dnSmad2/3 did not alter them. Furthermore, inhibition of IL-1β activity secreted from PSCs by IL-1β-neutralizing antibody attenuated TGF-β1 secretion from PSCs. Exogenous IL-1β enhanced TGF-β1 expression and secretion by PSCs. IL-1β activated ERK, and PD-98059, a MEK1 inhibitor, blocked IL-1β enhancement of TGF-β1 expression and secretion by PSCs. We propose that an autocrine loop exists between TGF-β1 and IL-1β in activated PSCs through Smad3- and ERK-dependent pathways.

scholarly journals Baicalin Ameliorates Pancreatic Fibrosis by Inhibiting the Activation of Pancreatic Stellate Cells in Mice with Chronic Pancreatitis

2021 ◽  
Vol 11 ◽  
Author(s):  
Jianwei Fan ◽  
Lifang Duan ◽  
Nan Wu ◽  
Xiaofan Xu ◽  
Jiaqi Xin ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Type I ◽  
Alpha Smooth Muscle Actin

Pancreatic inflammation and fibrosis are typical pathological features in chronic pancreatitis (CP). Activated pancreatic stellate cells (PSCs) have been regarded as the core event in the development of pancreatic fibrosis and are considered to be the key target for treatment of CP. Baicalin (C21H18O11), the main chemical composition of Baikal skullcap in the traditional Chinese medicines Dachaihu decoction (DCHD) and Xiaochaihu decoction (XCHD), has shown significant effects in the treatment of pancreatic fibrosis in CP mice; however, whether baicalin can inhibit the activation of PSCs and its underlying mechanism remain unclear. In this study, the influence of baicalin on activated PSCs in vitro and in vivo was investigated, and the results showed that Baicalin could significantly ameliorate the degree of pancreatic inflammation and fibrosis, while decreasing the levels of alpha-smooth muscle actin (α-SMA), F4/80 (surface markers of mouse macrophages), nuclear factor kappa-B (NF-κB), monocyte chemotactic protein 1 (MCP-1), and collagen type I alpha 1 (COL1A1)in the pancreas. Moreover, NF-κB and α-SMA were co-expressed in the pancreas of CP mice. Baicalin treatment markedly reduced the expression of co-location of α-SMA and NF-κB. In vitro, the protein expression levels of transforming growth factor-β receptor 1 (TGF-βR1), phosphorylated TGF-β activated kinase 1 p-TAK 1, and NF-κBp65 in PSCs were all remarkably reduced after treatment with baicalin. In addition, baicalin could inhibit MCP-1 mRNA expression in supernatant of activated PSCs, as well as the excessive migration of macrophages. Taken together, our findings indicated that baicalin could inhibit the TGF-β1/TGF-βR1/TAK1/NF-κB signaling pathway of activated PSCs, reduce the secretion of MCP-1, and further decrease the infiltration of macrophages and inflammation cells of the local microenvironment of the pancreas. Thus, this study provides a reliable experimental basis for baicalin in the prevention and treatment of CP.

Externally applied pressure activates pancreatic stellate cells through the generation of intracellular reactive oxygen species

2007 ◽  
Vol 293 (5) ◽  
pp. G972-G978 ◽  
Author(s):  
Hiroshi Asaumi ◽  
Shiro Watanabe ◽  
Masashi Taguchi ◽  
Mitsuo Tashiro ◽  
Makoto Otsuki
Keyword(s):  
Reactive Oxygen Species ◽  
Chronic Pancreatitis ◽  
Smooth Muscle Actin ◽  
Applied Pressure ◽  
Reactive Oxygen ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ros Generation ◽  
Oxygen Species ◽  
Tissue Pressure

Local tissue pressure is higher in chronic pancreatitis than in the normal pancreas. We reported recently that pressure application induces synthesis of extracellular matrix (ECM) and cytokines in pancreatic stellate cells (PSCs) and that epigallocatechin gallate (EGCG), a potent antioxidant, inhibits the transformation of PSCs from quiescent to activated phenotype and ethanol-induced synthesis of ECM and cytokines in PSCs. These results suggest that oxidative stress and reactive oxygen species (ROS) are important in PSC activation. The aim of this study was to clarify the effects of ROS on activation and functions of pressure-stimulated PSCs. We used freshly isolated rat PSCs and culture-activated PSCs. Pressure was applied on rat cultured PSCs by adding compressed helium gas into a pressure-loading apparatus. PSCs were cultured with or without antioxidants (EGCG and N-acetyl cysteine) under normal or elevated pressure. Externally applied high pressure (80 mmHg) resulted in a gradual decrease of superoxide dismutase activity in PSCs and increased intracellular ROS generation as early as 30 s, reaching a peak level at 1 h. Antioxidants significantly inhibited ROS generation. Pressure increased the expression levels of α-smooth muscle actin, α1(I)-procollagen, and TGF-β1 in PSCs. EGCG suppressed these alterations, abolished pressure-induced phosphorylation of p38 MAPK, and suppressed pressure-induced PSC transformation to activated phenotype. Our results indicated that ROS is a key player in pressure-induced PSC activation and ECM synthesis. Antioxidants could be potentially effective against the development of pancreatic fibrosis in patients with chronic pancreatitis.

Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis

2011 ◽  
Vol 301 (5) ◽  
pp. G846-G855 ◽  
Author(s):  
Ana María González ◽  
Tània Garcia ◽  
Esther Samper ◽  
Mariana Rickmann ◽  
Eva Cristina Vaquero ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Area Fraction ◽  
Pancreatic Stellate Cells ◽  
Protective Effects ◽  
Collagen Network ◽  
Tgf Β1

Tocotrienols exhibit anti-inflammatory properties over macrophages and promote cytotoxicity in activated pancreatic stellate cells, suggesting that they may limit chronic pancreatitis progression. We aimed to quantitate the effect of oral tocotrienols on a rat model of chronic pancreatic injury. Chronic-like pancreatitis was induced by repeated arginine pancreatitis. Palm oil tocotrienol-rich fraction (TRF) was given by gavage before and after pancreatitis inductions. Amylase and hydroxyproline were determined in pancreatic homogenates; collagen, fibronectin, α-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and phosphorylated Smad3 were assessed by Western blotting. Transforming growth factor (TGF)-β1 was measured in plasma. Morphological assessment included light microscopy, fibrosis area fraction, and collagen network fractal analysis. Arginine pancreatitis induced pancreatic atrophy and increased hydroxyproline that ameliorated after TRF. Arginine increased TGF-β1 (185 ± 40 vs. 15 ± 2 ng/ml; P <0.01) that was blunted by TRF (53 ± 19; P < 0.01). TRF reduced protease and Smad3 activation, collagen, and fibronectin. α-SMA increased and GFAP diminished in arginine pancreatitis, consistent with long-term stellate cell activation, and TRF reverted these changes to basal. Arginine pancreatitis increased fibrosis area fraction (4.5 ± 0.3% vs. 0.2 ± 0.2%), collagen network complexity (fractal dimension 1.52 ± 0.03 vs. 1.42 ± 0.01; P < 0.001), and inhomogeneity (lacunarity 0.63 ± 0.03 vs. 0.40 ± 0.02; P < 0.001), which were all reduced by TRF (1.3 ± 0.4%, 1.43 ± 0.02%, and 0.51 ± 0.03%, respectively; P < 0.01). Best correlation coefficients were obtained when comparing fibrosis area fraction with lacunarity ( r = 0.88) and both parameters with pancreatic weight ( r = −0.91 and −0.79, respectively). TRF administered only before pancreatitis best, but not fully, recapitulated the beneficial effects of TRF. Tocotrienols improve quantitative measures of chronic pancreatic damage. They may be of benefit in human chronic pancreatitis.

scholarly journals IL-15 regulates fibrosis and inflammation in a mouse model of chronic pancreatitis

2018 ◽  
Vol 315 (6) ◽  
pp. G954-G965 ◽  
Author(s):  
Murli Manohar ◽  
Hemanth Kumar Kandikattu ◽  
Alok Kumar Verma ◽  
Anil Mishra
Keyword(s):  
Chronic Pancreatitis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Interferon Γ ◽  
Cancer Tissue ◽  
Inkt Cells ◽  
Interleukin 15 ◽  
Potential Strategy ◽  
Tgf Β1

Pancreatitis is an inflammatory disease characterized by the induction of several proinflammatory cytokines like interleukin (IL)-6, IL-8, IL-1β, and IL-1. Recently, the multifunctional innate cytokine IL-15 has been implicated in the protection of several diseases, including cancer. Tissue fibrosis is one of the major problems in successfully treating chronic pancreatitis pathogenesis. Therefore, we tested the hypothesis that recombinant IL-15 (rIL-15) treatment may induce innate tissue responses and its overexpression will improve the pathogenesis of cerulein-induced chronic pancreatitis, associated remodeling, and fibrosis. We observed atrophy of acinar cells, increased inflammation, and increased deposition of perivascular collagen, the upregulated protein level of transforming growth factor (TGF)-β1, α-smooth muscle actin (α-SMA), and collagen-1 in cerulein-induced chronic pancreatitis in mice. Furthermore, we reported that rIL-15 treatment protects mice from the cerulein-induced chronic pancreatitis pathogenesis, including acinar cell atrophy, and perivascular accumulation of tissue collagen followed by downregulation of profibrotic genes such as TGF-β1, α-SMA, collagen-1, collagen-3, and fibronectin in cerulein-induced chronic pancreatitis in mice. Mechanistically, we show that IL-15-mediated increase of interferon-γ-responsive invariant natural killer T (iNKT) cells in the blood and tissue protects cerulein-induced pancreatic pathogenesis in mice. Of note, a reduction in iNKT cells was also observed in human chronic pancreatitis compared with normal individuals. Taken together, these data suggest that IL-15 treatment may be a novel therapeutic strategy for treating chronic pancreatitis pathogenesis. NEW & NOTEWORTHY Pancreatic fibrosis is a major concern for the successful treatment of chronic pancreatitis and pancreatic cancer. Therefore, restriction in the progression of fibrosis is the promising approach to manage the pancreatitis pathogenesis. Herein, we present in vivo evidences that pharmacological treatment of recombinant interleukin-15 improves remodeling and fibrosis in cerulein-induced chronic pancreatitis in mice. Our observations indicate that interleukin-15 immunotherapy may be a possible and potential strategy for restricting the progression of fibrosis in chronic pancreatitis.

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