Enhancement of survival by LPA via Erk1/Erk2 and PI 3-kinase/Akt pathways in a murine hepatocyte cell line

2001 ◽  
Vol 281 (6) ◽  
pp. C2010-C2019 ◽  
Author(s):  
Yuri Y. Sautin ◽  
James M. Crawford ◽  
Stanislav I. Svetlov
Keyword(s):  
Cell Line ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Protective Effects ◽  
Hepatocellular Injury ◽  
Cell Protection ◽  
Lpa Receptor ◽  
Hepatocyte Cell Line ◽  
Tnf Α ◽  
Murine Hepatocyte

First published September 5, 2001; 10.1152/ajpcell.00077.2001.—Protective mechanisms for lysophosphatidic acid (LPA) against cell death caused by Clostridium difficile toxin, or tumor necrosis factor-α (TNF-α) plus d-galactosamine, were investigated in a murine hepatocyte cell line AML12 expressing Edg2 LPA receptor. In these models of hepatocellular injury, LPA prevented hepatocyte damage, suppressed apoptosis, and enhanced cell survival in a dose-dependent fashion. The protective effects of LPA were abolished by wortmannin and LY-294002, specific inhibitors of phosphatidylinositol 3-phosphate kinase (PI 3-kinase), and by PD-98059 and U-0126, inhibitors of MEK1/MEK2. In nontreated hepatocytes, LPA elicited a gradual and sustained increase in phosphorylation of Erk1/Erk2 over 180 min of stimulation and downstream phosphorylation of p90RSK and transcription factor Elk-1. In C. difficile toxin-treated cells, LPA-induced phosphorylation of Erk1/Erk2 was rapid but transient, while p90RSK and Elk-1 phosphorylation did not change significantly. LPA stimulated phosphorylation of Akt in a time-dependent manner in both intact and toxin-treated AML12 hepatocytes. Wortmannin and LY-294002 abolished phosphorylation of Akt, further supporting activation of PI 3-kinase/Akt as a signaling pathway, which mediates hepatocyte protection by LPA. Taken together, these results demonstrate that LPA prevents cell apoptosis induced by C. difficile toxin and TNF-α/d-galactosamine in the AML12 murine hepatocyte cell line. Cell protection by LPA involves activation of the mitogen-activated protein kinase Erk1/Erk2 cascade and PI 3-kinase-dependent phosphorylation of Akt.

Effect of Curculigo orchioides on Reflux Esophagitis by Suppressing Proinflammatory Cytokines

2012 ◽  
Vol 40 (06) ◽  
pp. 1241-1255 ◽  
Author(s):  
Sae-Kang Ku ◽  
Jae-Soo Kim ◽  
Young-Bae Seo ◽  
Yong-Ung Kim ◽  
Seung-Lark Hwang ◽  
...  
Keyword(s):  
Reflux Esophagitis ◽  
Group Treatment ◽  
Control Group ◽  
Esophageal Mucosa ◽  
Dependent Manner ◽  
Protective Effects ◽  
Model Group ◽  
Curculigo Orchioides ◽  
Intact Group ◽  
Tnf Α

This study was performed to investigate effects of Curculigo orchioides rhizome (curculiginis rhizome) on acute reflux esophigitis (RE) in rats that are induced by pylorus and forestomach ligation operation. Proinflammatory cytokine, as well as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were all assayed and the expression of TNF-α and COX2 analyzed by RT-PCR. The esophagic tissue damage of reflux esophagitis rat was increased compared to that of normal intact group. However, the esophagic damage percentage from the extract of curculiginis rhizoma (ECR) 600 mg/kg and ECR 300 mg/kg were significantly lower than that of the RE control group. Administration of α-tocopherol (30 mg/kg) and ECR (600 mg/kg, 300 mg/kg, and 150 mg/kg) had a significant effect on the gastric acid pH in rats with induced reflux esophagitis (p < 0.05). The treatment with ECR significantly reduced the production of cytokines TNF-α, IL-1β and IL-6 levels compared to the model group (p < 0.05). The expression of TNF-α and COX2 in the intact esophageal mucosa was low while those of the RE control group were significantly higher due to an inflammatory reaction in the esophagus. Compare to the model group, treatment with α-tocopherol or ECR significantly inhibited the expression levels of COX2 and TNF-α in a dose-dependent manner. These results suggest that anti-inflammatory and protective effects of ECR could attenuate the severity of reflux esophagitis and prevent esophageal mucosal damage.

fMLP induces Hsp27 expression, attenuates NF-κB activation, and confers intestinal epithelial cell protection

2007 ◽  
Vol 292 (4) ◽  
pp. G1070-G1078 ◽  
Author(s):  
Ryan M. Carlson ◽  
Stephan R. Vavricka ◽  
Jyrki J. Eloranta ◽  
Mark W. Musch ◽  
Donna L. Arvans ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
Target Genes ◽  
Bacterial Flora ◽  
Epithelial Cell Line ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Cell Protection ◽  
Hsp27 Expression ◽  
Tnf Α

Sustained expression of cytoprotective intestinal epithelial heat shock proteins (Hsps), particularly Hsp27, depends on stimuli derived from bacterial flora. In this study, we examined the role of the bacterial chemotactic peptide fMLP in stimulating colonic epithelial Hsp expression at concentrations encountered in a physiological milieu. Treatment of the polarized human intestinal epithelial cell line Caco2bbe with physiological concentrations of fMLP (10–100 nM) induced expression of Hsp27, but not Hsp72, in a time- and concentration-dependent manner. Induction of Hsp27 by fMLP was specific since the fMLP analogs MRP and MLP were not effective. Hsp27 induction by fMLP was blocked by the fMLP-receptor antagonist BOC-FLFLF and was blocked when the dipeptide transporter PepT1, an entry pathway for fMLP, was silenced. fMLP activated both the p38 and ERK1/2 MAP kinase pathways in Caco2bbe cells, but not the SAPK/JNK pathway. The p38 inhibitor SB203580, but not the MEK-1 inhibitor PD98059, blocked Hsp27 induction by fMLP. fMLP treatment inhibited actin depolymerization and decreased transepithelial resistance caused by the oxidant monochloramine, and this inhibition was reversed by silencing Hsp27 expression. fMLP pretreatment also inhibited activation of proinflammatory transcription factor NF-κB by TNF-α in Caco2bbe cells, reducing induction of NF-κB target genes by TNF-α both in human intestinal biopsies and Caco2bbe cells. In conclusion, fMLP may contribute to the maintenance of intestinal homeostasis by mediating physiological expression of Hsp27, enhancing cellular protection, and negatively regulating the inflammatory response.

scholarly journals Effect of Kabasura Kudineer Extract on Inflammatory Cytokines [Interleukin-6 and Tumour Necrosis Factor-α] in Lung Cancer Cell Line A549

2021 ◽  
pp. 653-660
Author(s):  
M. Afrin Nisha ◽  
S. Preetha ◽  
J. Selvaraj ◽  
G. Sridevi
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Inflammatory Cytokines ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Human Lung Cancer ◽  
Dependent Manner ◽  
Lung Cancer Cell ◽  
Tnf Α

Background: Kabasura kudineer is widely known for its anticancer efficiency. Kabasura kudineer is a customary formulation used by siddha practitioners for effectively managing common respiratory illness. Herbal medicines are acknowledged as a great approach to lung cancer therapy. Aim of the study is to know about the anticancer property of Kabasura kudineer extract on inflammatory cytokines IL-6 and TNF-α in lung cancer cell line (A549). Materials and Methods: Human lung cancer cell line (A549) was purchased from National Centre for Cell Sciences (NCCS), Pune, India. Cell viability test was done by MTT assay. Gene expression analysis was done by Real Time-PCR. The obtained data were analysed statistically by one-way analysis of variance and Duncan’s multiple range test with Graph Pad Prism version 5 to analyse the significance. The significance was considered at p<0.05 level in Duncan’s test. Results and Discussion: Kabasura kudineer caused a marked increase in cell death in dose dependent manner. AT the end of 48 hours, maximum inhibition was at 400 and 500 μg/ml. Kabasura kudineer extract reduced the expression of IL-6 and TNF-α compared to the control cells. Conclusion: This study concluded that Kabasura kudineer extract has anticancer activity on lung cancer cell lines (A549).

Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice

1999 ◽  
Vol 277 (3) ◽  
pp. G702-G708 ◽  
Author(s):  
Alix de la Coste ◽  
Monique Fabre ◽  
Nathalie McDonell ◽  
Arlette Porteu ◽  
Helène Gilgenkrantz ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transgenic Mice ◽  
Fas Ligand ◽  
Dependent Manner ◽  
Protective Effects ◽  
Tnf Α ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Factor Α

Fas ligand (CD95L) and tumor necrosis factor-α (TNF-α) are pivotal inducers of hepatocyte apoptosis. Uncontrolled activation of these two systems is involved in several forms of liver injury. Although the broad antiapoptotic action of Bcl-2 and Bcl-xL has been clearly established in various apoptotic pathways, their ability to inhibit the Fas/CD95- and TNF-α-mediated apoptotic signal has remained controversial. We have demonstrated that the expression of BCL-2 in hepatocytes protects them against Fas-induced fulminant hepatitis in transgenic mice. The present study shows that transgenic mice overexpressing[Formula: see text]in hepatocytes are also protected from Fas-induced apoptosis in a dose-dependent manner. Bcl-xL and Bcl-2 were protective without any change in the level of endogenous[Formula: see text]or Bax and inhibited hepatic caspase-3-like activity. In vivo injection of TNF-α caused massive apoptosis and death only when transcription was inhibited. Under these conditions,[Formula: see text]mice were partially protected from liver injury and death but PK-BCL-2 mice were not. A similar differential protective effect of Bcl-xL and Bcl-2 transgenes was observed when Fas/CD95 was activated and transcription blocked. These results suggest that apoptosis triggered by activation of both Fas/CD95 and TNF-α receptors is to some extent counteracted by the transcription-dependent protective effects, which are essential for the antiapoptotic activity of Bcl-2 but not of Bcl-xL. Therefore, Bcl-xL and Bcl-2 appear to have different antiapoptotic effects in the liver whose characterization could facilitate their use to prevent the uncontrolled apoptosis of hepatocytes.

scholarly journals In Vivo and In Vitro Evaluation of the Protective Effects of Hesperidin in Lipopolysaccharide-Induced Inflammation and Cytotoxicity of Cell

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 478 ◽  
Author(s):  
Rasha Al-Rikabi ◽  
Hanady Al-Shmgani ◽  
Yaser Hassan Dewir ◽  
Salah El-Hendawy
Keyword(s):  
Breast Cancer ◽  
Chromatin Condensation ◽  
Control Group ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Protective Effects ◽  
Mcf7 Cells ◽  
Tnf Α

(1) Background: Plant flavonoids are efficient in preventing and treating various diseases. This study aimed to evaluate the ability of hesperidin, a flavonoid found in citrus fruits, in inhibiting lipopolysaccharide (LPS) induced inflammation, which induced lethal toxicity in vivo, and to evaluate its importance as an antitumor agent in breast cancer. The in vivo experiments revealed the protective effects of hesperidin against the negative LPS effects on the liver and spleen of male mice. (2) Methods: In the liver, the antioxidant activity was measured by estimating the concentration of glutathione (GSH) and catalase (CAT), whereas in spleen, the concentration of cytokines including IL-33 and TNF-α was measured. The in vitro experiments including MTT assay, clonogenity test, and sulforhodamine 101 stain with DAPI (4′, 6-diamidino-2-phenylindole) were used to assess the morphological apoptosis in breast cancer cells. (3) Results: The results of this study revealed a significant increase in the IL-33 and TNF-α cytokine levels in LPS challenged mice along with a considerable elevation in glutathione (GSH); moreover, the catalase (CAT) level was higher compared to that of the control group. Cytotoxicity of the MCF-7 cell line revealed significant differences among the groups treated with different concentrations when compared to the control groups, in a concentration-dependent manner. Hesperidin significantly inhibited the colony formation of MCF7 cells when compared to that of control. Clear changes were observed in the cell shape, including cell shrinkage and chromatin condensation, which were associated with a later apoptotic stage. (4) Conclusion: The results indicate that hesperidin might be a potential candidate in preventing diseases.

scholarly journals Bikunin Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Induction in Macrophages

2004 ◽  
Vol 11 (6) ◽  
pp. 1140-1147 ◽  
Author(s):  
Hidenori Matsuzaki ◽  
Hiroshi Kobayashi ◽  
Tatsuo Yagyu ◽  
Kiyoshi Wakahara ◽  
Toshiharu Kondo ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Dose Dependent ◽  
Necrosis Factor

ABSTRACT Bikunin, a Kunitz-type protease inhibitor, exhibits anti-inflammatory activity in protection against cancer and inflammation. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on tumor necrosis factor alpha (TNF-α) production in human peripheral mononuclear cells stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show the following results. (i) LPS induced TNF-α expression in time- and dose-dependent manners through phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. (ii) Bikunin inhibits LPS-induced up-regulation of TNF-α protein expression in a dose-dependent manner, reaching 60% inhibition at the highest doses of bikunin tested (5.0 μM). (iii) Inhibition by bikunin of TNF-α induction correlates with the suppressive capacity of ERK1/2, JNK, and p38 signaling pathways, implicating repressions of at least three different signals in the inhibition. (iv) Bikunin blocks the induction of TNF-α target molecules interleukin-1β (IL-1β) and IL-6 proteins. (v) Bikunin is functional in vivo, and this glycoprotein blocks systemic TNF-α release in mice challenged with LPS. (vi) Finally, bikunin can prevent LPS-induced lethality. In conclusion, bikunin significantly inhibits LPS-induced TNF-α production, suggesting a mechanism of anti-inflammation by bikunin through control of cytokine induction during inflammation. Bikunin might be a candidate for the treatment of inflammation, including septic shock.

Role of CCL5 and Interleukin-6 in the Biology of Waldenström Macroglobulinemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 688-688
Author(s):  
Sherine F. Elsawa ◽  
Anne J. Novak ◽  
Steven C. Ziesmer ◽  
Thomas E. Witzig ◽  
Steven P. Treon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Line ◽  
Stromal Cells ◽  
Gene Array ◽  
Serum Levels ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Malignant Cells ◽  
Monoclonal Protein

Abstract Waldenström macroglobulinemia (WM) is a B-cell malignancy that is characterized by the production of a monoclonal IgM protein, a lymphoplasmacytic infiltrate in the bone marrow, and associated symptoms including anemia, lymphadenopathy and hyperviscosity. The aberrant production of a monoclonal IgM in the serum is a major factor causing significant morbidity in patients with this disease, yet little is known about the mechanisms that regulate monoclonal protein synthesis. While recent gene array studies and serum analysis have shown that IL-6 is elevated in WM patients suggesting an important role for this cytokine in this disease, the precise role played by IL-6 in WM is unknown. Using a multiplex ELISA approach to screen sera from WM patients, we confirmed that IL-6 was significantly elevated (p<0.0019) in patients (n=20) compared to controls (n=20). Serum levels of IL-6 in WM patients correlated with elevated levels of β2-microglobulin (p<0.0019). Additionally, we also found that serum levels of CCL5 (Rantes) were significantly elevated in WM patients (p<0.0001). CCL5 has been shown to regulate IL-6 secretion, and we therefore wanted to determine if CCL5 influenced IL-6 expression in WM and what the subsequent consequence of IL-6 stimulation was on WM cells. To define the source of IL-6 in the tumor microenvironment, we used stromal cells from the bone marrow of healthy donors, malignant cells from patients with WM, and the BCWM.1 WM cell line, and tested their ability to secrete IL-6 by ELISA. All cell types secreted IL-6, with stromal cells secreting the most. We then tested the ability of CCL5 to induce IL-6 secretion by WM and stromal cells. CCL5 significantly increased IL-6 secretion by stromal cells (p<0.03) and also increased IL-6 secretion by fresh CD19+ CD138+ cells from WM patients (p<0.02). Using fresh patient WM cells and the BCWM.1 WM cell line as a model, we then determined the effect of IL-6 on growth of WM cells. We found that IL-6 had a modest effect (mean=20% increase, range=5–41%) on cell proliferation (p<0.0039) but had no effect on cell viability. In contrast, when we addressed the role of IL-6 on IgM secretion, we found that IL-6 increased IgM secretion by BCWM.1 cells in a dose-dependent manner. The IL-6 mediated increase in IgM secretion was abolished in the presence of neutralizing antibodies to IL-6. When we analyzed the downstream signaling events activated by IL-6 in WM cells we found that stimulation of BCWM.1 cells, which express the IL-6R, resulted in phosphorylation of Stat1, Stat3 and Erk1/2, but not Akt. Using a mitogen activated protein kinase (MAPK) inhibitor, we could inhibit the IL-6-mediated phosphorylation of Erk1/2. Similarly, using a JAK1 Inhibitor, we could inhibit IL-6 mediated signaling through Stat1 and Stat3. In summary, we have clearly shown that IL-6 significantly upregulates IgM secretion by WM cells and increases their proliferation. We have also demonstrated the ability of both the malignant cells and the stromal cells to secrete IL-6, and that this secretion is regulated in part by CCL5. We have found that WM cells express IL-6R, and that IL-6 induced signaling is through both the MAPK and Jak/Stat pathways. Therapies targeting IL-6 secretion or the IL-6 signaling pathways may therefore provide clinical benefit to patients with WM; not just by inhibiting the malignant cells but by down regulating the production of the monoclonal protein.

scholarly journals Ivermectin induces P-glycoprotein expression and function through mRNA stabilization in murine hepatocyte cell line

2012 ◽  
Vol 83 (2) ◽  
pp. 269-278 ◽  
Author(s):  
Cécile Ménez ◽  
Laïla Mselli-Lakhal ◽  
Magali Foucaud-Vignault ◽  
Patrick Balaguer ◽  
Michel Alvinerie ◽  
...  
Keyword(s):  
Cell Line ◽  
Mrna Stabilization ◽  
Hepatocyte Cell Line ◽  
P Glycoprotein ◽  
And Function ◽  
Murine Hepatocyte
Sign in / Sign up

Export Citation Format

Share Document