Localization of cyclooxygenase-2 and regulation  of its mRNA expression in gastric ulcers in rats

Takahashi, Satoru; Shigeta, Jun-ichi; Inoue, H.; Tanabe, Tadashi; Okabe, Susumu

doi:10.1152/ajpgi.1998.275.5.g1137

Cited by 66 publications

(79 citation statements)

References 27 publications

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“…In recent years, several reports on the expression of COX-2 in experimentally induced gastric ulcers in laboratory animals have appeared, but COX-2 expression had not yet been documented in naturally occurring gastric ulcers in animals. In contrast to COX-2, COX-1 expression was similar in healthy vs ulcerated stomachs, in agreement with most previous reports (Mizuno et al 1997;Kishimoto et al 1998;Takahashi et al 1998).…”

Section: Discussionsupporting

confidence: 92%

Induction of Cyclo-oxygenase-2 Expression in Naturally Occurring Gastric Ulcers

Lajoie

Sirois

Doré

2002

J Histochem Cytochem.

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S U M M A R Y Cyclo-oxygenase-2 (COX-2) is believed to participate in the repair of gastric ulcer. Like humans, pigs frequently develop gastric ulcers and thus represent an attractive animal model in which to study the repair process of naturally occurring gastric ulcers. However, expression of COX in the pig stomach has not been reported. The objectives of this study were to determine whether COX isoenzymes are expressed in porcine gastric ulcers and to characterize the porcine COX-2 cDNA. Normal stomachs ( n ϭ 5) and those with gastric ulcers ( n ϭ 35) were studied by immunohistochemistry and immunoblotting analysis. Reverse transcription-polymerase chain reaction (RT-PCR) was used to isolate the complete porcine COX-2 cDNA. COX-1 staining was present in normal stomach and in ulcerated areas. No COX-2 was detected in normal stomach, but COX-2 was strongly expressed in the ulcerated area in 28/35 (80%) gastric ulcers ( p Ͻ 0.01). Immunoblotting analysis confirmed the restricted expression of COX-2 in the ulcerated areas. The porcine COX-2 cDNA was shown to code for a 604 amino acid protein that is 89% identical to human COX-2. These results provide the complete primary structure of porcine COX-2 and demonstrate for the first time that the enzyme is induced in naturally occurring porcine gastric ulcers.

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Section: Discussionsupporting

confidence: 92%

Induction of Cyclo-oxygenase-2 Expression in Naturally Occurring Gastric Ulcers

Lajoie

Sirois

Doré

2002

J Histochem Cytochem.

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“…Such an approach is appealing, given recent reports that document significant myofibroblast COX-2 expression during acute and chronic inflammation (9,24,45,49,54) and during the early phases of colonic polyp formation and cancer progression (38,49,59). It should be noted, however, that while inhibition of COX-2 expression and activity is desirable in the context of colorectal carcinogenesis, its absence can have a negative impact on the course and resolution of colitis in experimental models (3,35,41).…”

Section: Discussionmentioning

confidence: 99%

Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction

Mifflin¹,

Saada²,

Mari³

et al. 2002

American Journal of Physiology-Cell Physiology

130

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Elevated mucosal interleukin-1 (IL-1) levels are frequently seen during acute and chronic intestinal inflammation, and IL-1 neutralization lessens the severity of inflammation. One major effect of IL-1 is the increased release of eicosanoid mediators via induction of cyclooxygenase-2 (COX-2). One site of COX-2-derived prostaglandin synthesis during acute and chronic intestinal inflammation is the intestinal myofibroblast. COX-2 expression has also been documented in these cells in colonic neoplasms. Thus an understanding of the regulation of COX-2 expression in human intestinal myofibroblasts is important. As an initial step toward this goal we have characterized IL-1α signaling pathways that induce COX-2 expression in cultured human intestinal myofibroblasts. IL-1 treatment resulted in a dramatic transcriptional induction of COX-2 gene expression. Activation of nuclear factor-κB (NF-κB), extracellular signal-regulated protein kinase (ERK), p38, and protein kinase C (PKC) signaling pathways was each necessary for optimal COX-2 induction. In contrast to what occurs in other cell types, including other myofibroblasts such as renal mesangial cells, PKC inhibition did not prevent IL-1-induced NF-κB or mitogen activated protein kinase/ stress-activated protein kinase activation, suggesting a novel role for PKC isoforms during this process. The stimulatory effects of PKC, NF-κB, ERK-1/2, and presumably c-Jun NH2-terminal kinase activation were exerted at the transcriptional level, whereas p38 activation resulted in increased stability of the COX-2 message. We conclude that, in intestinal myofibroblasts, IL-1-mediated induction of COX-2 expression is a complex process that requires input from multiple signaling pathways. Each parallel pathway acts in relative autonomy, the sum of their actions culminating in a dramatic increase in COX-2 transcription and message stability.

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“…However, other studies (1,29) have demonstrated that TNF-␣ coactivates the NF-B transcription factor pathway, which limits apoptosis through antiapoptotic gene transcription. The expression of TNF-␣ is also increased at the ulcer sites in rat stomachs presumably secreted by macrophages and mononuclear cells (8,21,26,32).…”

mentioning

confidence: 98%

“…The early phase is characterized by rapid epithelial cell migration in the absence of proliferation, whereas the late phase involves cell division and cell proliferation to fill in the defect and restore mucosal architecture (23,27,32). Cytokines and growth factors can stimulate cyclooxygenase-2 (COX-2) expression in different tissues, and increased COX-2 expression has been demonstrated to be important in gastric mucosal defense and ulcer healing (2,4,13,17,26). TNF-␣ has been reported to indirectly stimulate cell migration through the increased production of hepatocyte growth factor and interleukin-8 (24,32).…”

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confidence: 99%

Tumor necrosis factor-α stimulates gastric epithelial cell proliferation

Luo

Shin

Yang

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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is a cytokine produced during gastric mucosal injury. We examined whether TNF-␣ could promote mucosal repair by stimulation of epithelial cell proliferation and explored further the underlying mechanisms in a rat gastric mucosal epithelial cell line (RGM-1). TNF-␣ treatment (1-10 ng/ml) for 12 or 24 h significantly increased cell proliferation but did not induce apoptosis in RGM-1 cells. TNF-␣ treatment significantly increased cytosolic phospholipase A2 and cyclooxygenase-2 (COX-2) protein expression and PGE2 level but did not affect the protein levels of EGF, basic fibroblast growth factor, and COX-1 in RGM-1 cells. The mRNA of TNF receptor (TNF-R) 2 but not of TNF-R1 was also increased. Dexamethasone dose dependently inhibited the stimulatory effect of TNF-␣ on cell proliferation, which was associated with a significant decrease in cellular COX-2 expression and PGE2 level. A selective COX-2 inhibitor 3-(3-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5 H-furan-2-one (DFU) by itself had no effect on basal cell proliferation but significantly reduced the stimulatory effect of TNF-␣ on RMG-1 cells. Combination of dexamethasone and DFU did not produce an additive effect. PGE2 significantly reversed the depressive action of dexamethasone on cell proliferation. These results suggest that TNF-␣ plays a regulatory role in epithelial cell repair in the gastric mucosa via the TNF-␣ receptor and activation of the arachidonic acid/PG pathway. cyclooxygenase; dexamethasone; phospholipase A2; prostaglandin E2

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Localization of cyclooxygenase-2 and regulation of its mRNA expression in gastric ulcers in rats

Cited by 66 publications

References 27 publications

Induction of Cyclo-oxygenase-2 Expression in Naturally Occurring Gastric Ulcers

Induction of Cyclo-oxygenase-2 Expression in Naturally Occurring Gastric Ulcers

Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction

Tumor necrosis factor-α stimulates gastric epithelial cell proliferation

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