Increased Mitogen-Activated Protein Kinase Activities Stimulated with Interleukin-1-Beta and Mechanism(s) of the Kinase Signaling Pathways in Rat Gastric Epithelial Cells

Tominaga, Kazunari; Kim, Shokei; Itoh, Hiroshi; Kuroki, Tetsuo

doi:10.1159/000007733

Cited by 8 publications

(7 citation statements)

References 42 publications

(40 reference statements)

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“…5 and 6, IL-1β induced phosphorylation of ERK, and this was inhibited specifically by PD98059. These results are consistent with those reported in other cell types (Beales, 2002;Tominaga et al, 2000;Yang et al, 2000;Zhai et al, 2004). In addition, IL-1β-induced phosphorylation of ERK was completely inhibited by IL-1ra and AG1478 (Fig.…”

Section: Discussionsupporting

confidence: 93%

Involvement of endogenous transforming growth factor-α in signal transduction pathway for interleukin-1β-induced hepatocyte proliferation

Kimura

Moteki

Ogihara

2014

European Journal of Pharmacology

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We studied the effects of interleukin (IL)-1β on DNA synthesis and cell proliferation in primary cultures of adult rat hepatocytes in order to elucidate the mechanisms of its action. Hepatocyte parenchymal cells maintained in a serum-free, defined medium synthesized DNA and proliferated in the presence of IL-1β (3-30 ng/ml), but not IL-1α (0.1-30 ng/ml) in a time- and dose-dependent manner. Specific inhibitors of growth-related signal transducers, such as AG1478, LY294002, PD98059, and rapamycin, completely abolished IL-1β-stimulated hepatocyte DNA synthesis and proliferation. Western blot analysis showed that IL-1β significantly stimulated mitogen-activated protein (MAP) kinase activation within 10 min. Addition of a monoclonal antibody against transforming growth factor (TGF)-α, but not a monoclonal antibody against insulin-like growth factor-I, to the culture dose-dependently inhibited IL-1β-induced hepatocyte mitogenesis. Culture medium TGF-α levels increased significantly within 3 min in response to IL-1β from baseline levels. Peak TGF-α levels (33 pg/ml) were reached at 10 min after IL-1β stimulation. These results indicate that the proliferative mechanism of action of IL-1β is mediated through an increase in autocrine secretion of TGF-α from primary cultured hepatocytes. Secreted TGF-α, in turn, acts as a complete mitogen to induce hepatocyte mitogenesis through the receptor tyrosine kinase/phosphatidylinositol 3-kinase/MAP kinase/mammalian target of rapamycin pathway.

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Section: Discussionsupporting

confidence: 93%

Involvement of endogenous transforming growth factor-α in signal transduction pathway for interleukin-1β-induced hepatocyte proliferation

Kimura

Moteki

Ogihara

2014

European Journal of Pharmacology

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“…This suggests that activation of the ERK pathway is important in mediating the growth stimulatory actions of IL-1β. Activation of MAP kinase cascades, including the p42 and p44 ERK pathways and p46JNK and p55JNK c-Jun NH 2 -terminal kinases by IL-1β has been demonstrated in rat gastric epithelial cells [41,42], but the functional importance of these pathways was not examined. Activation of ERKs and JNKs was inhibited by genistein [41], consistent with the inference of the current study that MAPKs lie downstream of tyrosine activity in IL-1β-induced signalling.…”

Section: Discussionmentioning

confidence: 99%

Effect of Interlukin-1β on proliferation of gastric epithelial cells in culture

Beales

2002

BMC Gastroenterol

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BackgroundHelicobacter pylori is the main risk factor for the development of non-cardia gastric cancer. Increased proliferation of the gastric mucosa is a feature of H. pylori infection. Mucosal interkeukin-1β production is increased in H. pylori infection and IL-1β genotypes associated with increased pro-inflammatory activity are risk factors for the development of gastric cancer. The effect of IL-1β on gastric epithelial cell proliferation has been examined in this study.MethodsAGS cells were cultured with IL-1β. DNA synthesis was assed by [3H]thymidine incorporation and total viable cell numbers by MTT assay.ResultsIL-1β dose dependently increased DNA synthesis and cell numbers. The enhanced proliferation was blocked by interleukin-1 receptor antagonist. Addition of neutralising antibody to GM-CSF reduced IL-1β-stimulated proliferation by 31 ± 4 %. GM-CSF alone significantly stimulated proliferation. Addition or neutralisation of IL-8 had no effect on basal or IL-1β-stimulated proliferation. The tyrosine kinase inhibitor genistein completely blocked IL-1β-stimulated proliferation and inhibition of the extracellular signal related kinase pathway with PD 98059 inhibited IL-1β stimulated proliferation by 58 ± 5 %.ConclusionsIL-1β stimulates proliferation in gastric epithelial cells. Autocrine stimulation by GM-CSF contributes to this proliferative response. Signalling via tyrosine kinase activity is essential to the mitogenic response to IL-1β. The extracellular signal related kinase pathway is involved in, but not essential to downstream signalling. IL-1β may contribute to the hyperproliferation seen in H. pylori- infected gastric mucosa, and be involved in the carcinogenic process.

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“…We previously reported that IL-1ß induces MAPK activation, including extracellular signal-regulated kinases (ERK), JNK, and p38 MAPK, in normal rat gastric epithelial cells (RGMI cells) and weakly inhibits cell proliferation (20). In contrast, serum stimulation (2%) induces phosphorylated-ERK, -JNK, and -p38 MAPK as well as the expression of cyclooxygenase-2, a potent proliferative factor for gastrointestinal normal and cancer cells, in MKN 45 cells (gastric cancer cell line) and HT-29 cells (21).…”

Section: Discussionmentioning

confidence: 99%

Growth inhibition of colon cancer cells by transfection of dominant-negative apoptosis signal-regulating kinase-1

Kuwamura

Tominaga²,

Shiota³

et al. 2007

Oncol Rep

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Abstract. Apoptosis signal-regulating kinase-1 (ASK-1) is an important molecule for the pro-apoptotic signaling. ASK-1 also contributes to the cellular survival for many types of cells. Thus, ASK-1 has a broad range of biological activities depending on the cell type. The present study assessed the role(s) of ASK-1 in colorectal cancer cells (HT-29) by using adenovirus vectors expressing wild-type (WT)-ASK-1 or dominant-negative (DN) mutant of ASK-1 and recombinant adenovirus containing the bacterial ß-galactosidase gene (Ad-LacZ), a negative control for Ad-DN-ASK-1. Selective phosphorylation of ASK-1 at Thr 845, a kinase domain site, but not Ser 83 nor 967 sites was induced by serum stimulation in a time-dependent manner. Transfection with Ad-DN-ASK-1 inhibited the serum-induced phosphorylation of p38 mitogen-activated protein kinase, a downstream molecule of ASK-1. Transfection with Ad-DN-ASK-1 diminished the serum-induced cell proliferation in a dose-dependent manner, whereas WT-ASK-1 increased it. Apoptosis assessed by Hoechst staining was induced in the Ad-DN-ASK-1 treated cells. In vivo transfection of Ad-DN-ASK-1 into tumor xenografts of HT-29 cells in nude mice significantly decreased the tumor volume on day 29. Cleaved caspase-3 was found in the tumors of DN-ASK-1 treated mice. We obtained the first evidence that DN-ASK-1 transfection exerted significant antitumor effects on colon cancer mediated by apoptosis.

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Increased Mitogen-Activated Protein Kinase Activities Stimulated with Interleukin-1-Beta and Mechanism(s) of the Kinase Signaling Pathways in Rat Gastric Epithelial Cells

Cited by 8 publications

References 42 publications

Involvement of endogenous transforming growth factor-α in signal transduction pathway for interleukin-1β-induced hepatocyte proliferation

Involvement of endogenous transforming growth factor-α in signal transduction pathway for interleukin-1β-induced hepatocyte proliferation

Effect of Interlukin-1β on proliferation of gastric epithelial cells in culture

Growth inhibition of colon cancer cells by transfection of dominant-negative apoptosis signal-regulating kinase-1

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