Stress-activated protein kinases in the activation of rat hepatic stellate cells in culture

Reeves, Helen L.; Dack, Clare L; Peak, Matthew; Burt, Alastair D.; Day, Christopher P.

doi:10.1016/s0168-8278(00)80398-0

Cited by 73 publications

(49 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…TGF-b1-induced activation of MAP kinases has been required for HSC activation. 33 As shown in Figure 6b, TGF-b1 activated ERK and p38 MAP kinases in HSCs. Moreover, TGF-b1-stimulated MAP kinase activation was hastened in the presence of 10 mg/ml of H. pylori lysates or 50 mM of H 2 O 2 .…”

Section: H Pylori Lysates Elevate Tgf-b1-induced Ijba Degradationmentioning

confidence: 82%

“…28 TGF-b1-induced activation of p38 MAP kinase also has been required for HSC activation. 33 It was extrapolated that MAP kinase-mediated NFkB/AP-1 activation might be increased in the H. pylori plus CCl 4 -treated group based on increased mRNA expression of TNF-a, IL-1b, RANTES, TGF-b1, and PDGF-b, coupled with a corresponding increase of TLR4 and MyD88 expression. According to Seki et al, 23 HSCs other than Kupffer cells are the primary targets that drive fibrogenesis in response to TLR4 ligands.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Helicobacter pylori accelerates hepatic fibrosis by sensitizing transforming growth factor-β1-induced inflammatory signaling

Goo

Park

et al. 2010

Laboratory Investigation

View full text Add to dashboard Cite

Our earlier report has shown that Helicobacter pylori promoted hepatic fibrosis in a murine model. Herein, in order to elucidate the mechanism by which H. pylori accelerate liver fibrosis, the authors investigated the changes in expression levels of mitogen-activated protein kinases (MAPKs), p53-related proteins, antioxidants, and proinflammatory cytokines in liver samples. H. pylori infection enhanced CCl 4 -induced MAP kinase activation and p53 signaling pathway as well as Bax-and proliferating-cell nuclear antigen expressions, whereas H. pylori alone induced neither of these expressions nor hepatic fibrosis. Moreover, mRNA expressions of inflammatory cytokines, glutathione peroxidase expression, and the proliferative index were strongly augmented in livers of the H. pylori with CCl 4 treatment group compared with those of the CCl 4 -alone treatment group, whereas there was no difference in apoptotic index between the two groups. Interestingly, H. pylori treatment increased the number of a-fetoprotein-expressing hepatocytes independently of CCl 4 intoxication. In vitro analyses, using an immortalized rat hepatic stellate cell (HSC) line, revealed that H. pylori lysates increased the proliferation of HSCs, which was boosted by the addition of transforming growth factor-beta1 (TGF-b1). Furthermore, the treatment of H. pylori lysates promoted the translocation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) into the nucleus based on an increase in the degradation of NF-kB inhibitor alpha, in the presence of TGF-b1, as did H 2 O 2 treatment. In conclusion, H. pylori infection along with an elevated TGF-b1 may accelerate hepatic fibrosis through increased TGF-b1-induced pro-inflammatory signaling pathways in HSCs. Moreover, H. pylori infection might increase the risk of TGF-b1-mediated tumorigenesis by disturbing the balance between apoptosis and proliferation of hepatocytes.

show abstract

Section: H Pylori Lysates Elevate Tgf-b1-induced Ijba Degradationmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori accelerates hepatic fibrosis by sensitizing transforming growth factor-β1-induced inflammatory signaling

Goo

Park

et al. 2010

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…These effects seem not to be due to nonspecific cytotoxicity, because the concentrations of the reagents used in this study did not cause cell death. In hepatic stellate cells, Reeves et al (2000) suggested that JNK might be involved for the activation of hepatic stellate cells. They reported that constitutive activity of JNK was higher in transformed cells compared with quiescent cells.…”

Section: Discussionmentioning

confidence: 99%

A c-Jun NH₂-Terminal Kinase Inhibitor SP600125 (Anthra[1,9-cd]pyrazole-6 (2H)-one) Blocks Activation of Pancreatic Stellate Cells

Masamune

Kikuta²,

Suzuki³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

In response to pancreatic injury and in cell culture, pancreatic stellate cells (PSCs) are transformed ("activated") into highly proliferative myofibroblast-like cells that express ␣-smooth muscle actin and produce extracellular matrix components. Activated PSCs are implicated in the pathogenesis of pancreatic fibrosis and inflammation. We here evaluated the effects of SP600125 (anthra[1,9-cd]pyrazole-6 (2H)-one), an inhibitor of c-Jun NH 2 -terminal kinase (JNK), on the activation of PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype unless otherwise stated. Activation of JNK was determined by Western blotting using anti-phosphospecific JNK and c-Jun antibodies. Activation of transcription factors was determined by electrophoretic mobility shift assay. The effects of SP600125 on the key parameters of activation (chemokine production, collagen production, and proliferation) were examined. The effect of SP600125 on the activation of freshly isolated PSCs in culture also was examined. Interleukin-1␤ activated both 46-and 54-kDa JNK, whereas platelet-derived growth factor-BB activated only 46-kDa JNK. SP600125 inhibited interleukin-1␤-induced JNK activity and activator protein-1 activation, but it did not affect the activation of extracellular-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-B. SP600125 inhibited platelet-derived growth factor-induced proliferation, inducible monocyte chemoattractant protein-1 production, and serum-induced type I collagen production. Although SP600125 did not inhibit the transformation, it attenuated the proliferation of freshly isolated PSCs in culture. Collectively, our results suggest a role of JNK in the activation of PSCs, and a potential application of JNK inhibitors for the treatment of pancreatic fibrosis and inflammation.

show abstract

“…A recent study showed that inhibition of p38 by SB-203580 decreased procollagen-␣ 1 (I) mRNA level in HSCs, with a maximal effect in early primary culture (59). Another study reported that the constitutive p38 activity was higher in activated HSCs than in quiescent cells, suggesting a role for p38 in the activation process of HSCs (56). Since the abundance of ␣-SMA in passage 1 HSCs was not altered by treatment with TGF-␤1, DLPC, or both, the activation of HSCs was not a factor involved in the mediation of the antifibrogenic and antioxidant effects of DLPC.…”

Section: Discussionmentioning

confidence: 99%

DLPC decreases TGF-β1-induced collagen mRNA by inhibiting p38 MAPK in hepatic stellate cells

Cao

Mak

Lieber

2002

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Dilinoleoylphosphatidylcholine (DLPC), the active component of polyenylphosphatidylcholine extracted from soybeans, decreases collagen accumulation induced by TGF-β1 in cultured hepatic stellate cells (HSCs). Because DLPC exerts antioxidant effects and TGF-β1 generates oxidative stress, we evaluated whether the antifibrogenic effect of DLPC is linked to its antioxidant action. In passage 1 culture of rat HSCs, TGF-β1 induced a concentration-dependent increase in procollagen-α1(I) mRNA levels and enhanced intracellular H2O2 and superoxide anion formation and lipid peroxidation but decreased GSH levels. These changes were prevented by DLPC. Upregulation of collagen mRNA by TGF-β1 was likewise inhibited by catalase and p38 MAPK inhibitor SB-203580, suggesting involvement of H2O2 and p38 MAPK signaling in this process. TGF-β1 or addition of H2O2 to HSCs activated p38 MAPK with a rise in procollagen mRNA level; these changes were blocked by catalase and SB-203580 and likewise by DLPC. α-Smooth muscle actin abundance in HSCs was not altered by TGF-β1 treatment (with or without DLPC), indicating that downregulation of procollagen mRNA by DLPC was not due to alteration in HSC activation. These results demonstrate that DLPC prevents TGF-β1-induced increase in collagen mRNA by inhibiting generation of oxidative stress and associated H2O2-dependent p38 MAPK activation, which explains its antifibrogenic effect. DLPC, an innocuous phospholipid, may be considered for prevention and treatment of liver fibrosis.

show abstract

Stress-activated protein kinases in the activation of rat hepatic stellate cells in culture

Cited by 73 publications

References 35 publications

Helicobacter pylori accelerates hepatic fibrosis by sensitizing transforming growth factor-β1-induced inflammatory signaling

Helicobacter pylori accelerates hepatic fibrosis by sensitizing transforming growth factor-β1-induced inflammatory signaling

A c-Jun NH₂-Terminal Kinase Inhibitor SP600125 (Anthra[1,9-cd]pyrazole-6 (2H)-one) Blocks Activation of Pancreatic Stellate Cells

DLPC decreases TGF-β1-induced collagen mRNA by inhibiting p38 MAPK in hepatic stellate cells

Contact Info

Product

Resources

About

Stress-activated protein kinases in the activation of rat hepatic stellate cells in culture

Cited by 73 publications

References 35 publications

Helicobacter pylori accelerates hepatic fibrosis by sensitizing transforming growth factor-β1-induced inflammatory signaling

Helicobacter pylori accelerates hepatic fibrosis by sensitizing transforming growth factor-β1-induced inflammatory signaling

A c-Jun NH2-Terminal Kinase Inhibitor SP600125 (Anthra[1,9-cd]pyrazole-6 (2H)-one) Blocks Activation of Pancreatic Stellate Cells

DLPC decreases TGF-β1-induced collagen mRNA by inhibiting p38 MAPK in hepatic stellate cells

Contact Info

Product

Resources

About

A c-Jun NH₂-Terminal Kinase Inhibitor SP600125 (Anthra[1,9-cd]pyrazole-6 (2H)-one) Blocks Activation of Pancreatic Stellate Cells