Curcumin blocks activation of pancreatic stellate cells

Abstract

Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis and inflammation. Inhibition of activation and cell functions of PSCs is a potential target for the treatment of pancreatic fibrosis and inflammation. The polyphenol compound curcumin is the yellow pigment in curry, and has anti-inflammatory and anti-fibrotic properties. We here evaluated the effects of curcumin on the activation and cell functions of PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype unless otherwise stated. The effects of curcumin on proliferation, alpha-smooth muscle actin gene expression, monocyte chemoattractant protein (MCP)-1 production, and collagen expression were examined. The effect of curcumin on the activation of freshly isolated cells in culture was also assessed. Curcumin inhibited platelet-derived growth factor (PDGF)-induced proliferation, alpha-smooth muscle actin gene expression, interleukin-1beta- and tumor necrosis factor (TNF)-alpha-induced MCP-1 production, type I collagen production, and expression of type I and type III collagen genes. Curcumin inhibited PDGF-BB-induced cyclin D1 expression and activation of extracellular signal-regulated kinase (ERK). Curcumin inhibited interleukin-1beta- and TNF-alpha-induced activation of activator protein-1 (AP-1) and mitogen-activated protein (MAP) kinases (ERK, c-Jun N-terminal kinase (JNK), and p38 MAP kinase), but not of nuclear factor-kappaB (NF-kappaB). In addition, curcumin inhibited transformation of freshly isolated cells to myofibroblast-like phenotype. In conclusion, curcumin inhibited key cell functions and activation of PSCs.

NADPH oxidase plays a crucial role in the activation of pancreatic stellate cells

“…These findings agree with the previous study showing that DPI inhibited angiotensin II-induced activation of ERK, JNK, p38 MAPK, and AP-1 in hepatic stellate cells (6). Although it is possible that NF-B is regulated by ROS-generating system that is not inhibited by DPI in PSCs, the failure of NF-B inhibition agrees with our previous findings in PSCs that antioxidant polyphenols failed to inhibit NF-B activation (29,30). It has been recognized that redoxdependent activation of NF-B is cell and stimulus specific, as opposed to the concept that oxidative stress is a common mediator of diverse NF-B activators (18,24).…”

“…DPI did not affect IL-1-induced degradation of IB-␣ (data not shown), further supporting the notion that DPI did not inhibit NF-B activation. It has been shown that activation of MAPKs plays a key role in the PDGF-induced proliferation and IL-1-induced chemokine production in PSCs (25,29,30). DPI inhibited IL-1␤-and PDGF-induced activation of ERK, JNK, and p38 MAPK (Fig.…”

“…Along this line, previous studies have suggested a role of intracellular oxidant in the activation and cell functions, especially collagen synthesis, of PSCs (3,27). Antioxidants such as plant polyphenols inhibited the activation and cell functions of PSCs (29,30). NADPH oxidase might be a source of oxidants in injured pancreas.…”

Signal transduction in pancreatic stellate cells

“…It has been shown that antioxidants including plant polyphenols inhibited the activation and cell functions in PSCs both in vitro and in vivo [15,51,[84][85][86][87][88][89][90][91]. For example, ethanol-or acetaldehyde-induced collagen production was inhibited by antioxidants such as vitamin E and N-acetly-cysteine [15,51].…”

“…Similarly, epigallocatechin-3-gallate inhibited pressure-induced a-SMA expression, type I collagen production, TGF-b1 production, and transformation to a myofibroblast-like phenotype [85]. Other plant polyphenols, such as ellagic acid and curcumin, inhibited the proliferation, MCP-1 production, collagen expression, a-SMA expression, and transformation to myofibroblastlike cells [86,87]. Ellagic acid was shown to inhibit the development of pancreatic fibrosis in vivo in male WBN/ Kob rats [88].…”