Cellular distribution and contribution of cyclooxygenase (COX)-2 to diabetogenesis in NOD mouse

Luo, Cheng; Kallajoki, Markku; Gross, René; Mulari, Mika; Teros, T.; Ylinen, Laura M. J.; Makinen, Marty; Laine, Jukka; Simell, Olli

doi:10.1007/s00441-002-0628-6

Cited by 26 publications

(22 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data suggest that the PGE 2 generated under these circumstances would protect the β-cells from cytokine-mediated apoptosis. Consistent with this, the surviving β-cells in islets from NOD mice showing advanced insulitis expressed both COX2 and insulin [51]. In addition, the up-regulation of both AA and PGE 2 that occurs under hyperglycaemic conditions [12][13][14] may act as a defence mechanism to protect β-cells under conditions of enhanced apoptosis such as those experienced in response to elevated saturated fatty acids, which are known to predispose towards Type 2 diabetes.…”

Section: Discussionsupporting

confidence: 57%

“…Thus, although COX2 has been proposed to play a role in islet dysfunction [16] the inability of COX2 inhibitors to prevent cytokine-mediated islet destruction and the absence of β-cell damage in response to exogenous PGE 2 [50] suggest a dissociation between cytokine-induced COX2 upregulation [35;36] and β-cell destruction. Furthermore, the upregulation of COX2 in β-cells in the NOD mouse model of Type 1 diabetes [51] could be a protective response to the diabetic environment rather than a causal link in β-cell destruction. Our data suggest that the PGE 2 generated under these circumstances would protect the β-cells from cytokine-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-Apoptotic Effects of Arachidonic Acid and Prostaglandin E<sub>2</sub> in Pancreatic β-Cells

Papadimitriou

King

Jones

et al. 2007

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The polyunsaturated fatty acid arachidonic acid (AA) has been implicated in β-cell defence mechanisms and prostaglandin (PG) products of cyclooxygenase (COX) 2 action confer resistance to alloxan-induced apoptosis in insulin-secreting RIN cells. We have now investigated the anti-apoptotic effects of AA and its metabolite, PGE₂, in the MIN6 mouse insulin-secreting β-cell line and mouse islets. Methods: Apoptosis was determined in MIN6 β-cell and mouse islet extracts by measurement of capase-3 activity, and COX2 mRNA levels were quantified by real-time RT-PCR. Results: Exposure of MIN6 cells to AA (3.1-12.5µM) caused concentration-dependent reductions in apoptosis, and similar results were obtained when endogenous AA levels were elevated in cytosolic phospholipase A₂-overexpressing MIN6 cells. 25mM glucose caused both a significant up-regulation of MIN6 cell COX2 mRNA levels and a decrease in apoptosis. Inhibition of MIN6 cell COX2 activity with a selective inhibitor, NS-398 (10-100µM), increased apoptosis and exogenous PGE₂ (0.2-5µM) reduced NS-398-induced apoptosis in a concentration-dependent manner. The protective effects of AA and PGE₂ were also observed in primary mouse islets. Conclusion: These data show that AA and its COX2-generated metabolite, PGE₂, can protect β-cells from apoptosis.

show abstract

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Anti-Apoptotic Effects of Arachidonic Acid and Prostaglandin E<sub>2</sub> in Pancreatic β-Cells

Papadimitriou

King

Jones

et al. 2007

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…tion in HIT cells and islets treated with IL-1␤ for 24 h (25) and to prevent low dose streptozotocin-induced diabetes in mice (29). Immunostaining studies showed that COX-2 is expressed in islet-infiltrating macrophages, and that insulin and COX-2 expression disappeared concomitantly from ␤-cells when NOD mice progressed toward overt diabetes (30). These results suggested that COX-2 activation might play a pathogenic role in type 1 diabetes.…”

Section: Nuclear Factors From Rinm5f Cells Specifically Bind the Cox-mentioning

confidence: 67%

Transcriptional Regulation of Cyclooxygenase-2 Gene in Pancreatic β-Cells

Yang

Bleich

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Prostaglandin E 2 (PGE 2 ) has been shown to negatively affect pancreatic ␤-cell function, and its inducible synthesis is mediated in part by cycloxygenase-2 (COX-2). Regulation of basal and inducible COX-2 gene expression in pancreatic ␤-cells is not fully understood. In this report, we used pancreatic ␤-cells (RINm5F) to explore the molecular mechanisms regulating COX-2 promoter activity. Through deletion analysis of a ؊907/؉70-bp 5 upstream region of the mouse COX-2 gene, we identified an inhibition domain (؊804/؊371) and an activation domain (؊371/؉70). The highest promoter activity was seen when the promoter was reduced to ؊371 bp. Several cis-acting elements were selected for site-directed mutations in the activation domain. We identified three sites that were essential for basal COX-2 promoter activity: 1) CCAAT/enhancer-binding protein (C/EBP), 2) aryl hydrocarbon receptor (AhR), and 3) cAMP response element-binding protein (CREB). Single mutation of each individual site inhibited 70 -80% of basal COX-2 promoter activity. Double mutation of the AhR and CREBbinding sites showed synergy in repressing COX-2 promoter activity as did mutation of all three sites. We demonstrated that the transcription factors from RINm5F nuclear extracts specifically bound to oligonucleotides containing C/EBP, AhR, or CREB consensus sites. Forskolin, an activator of adenyl cyclase, increased COX-2 promoter activity via the CREB site. COX-2 promoter activity was also increased by 2,3,7,8-tetrachlorodibenzo-p-dioxin, an AhR activator, through the AhR site. Both forskolin and 2,3,7,8-tetrachlorodibenzo-p-dioxin increased COX-2 mRNA in a dose-dependent manner. We consider these three transcriptional regulators of COX-2 expression to be potential targets for the prevention of ␤-cell damage mediated by PGE 2 .

show abstract

“…The products of PTGS2, such as PGE2, have been shown to inhibit glucose-induced insulin secretion (Robertson et al 1974;Robertson 1998). Furthermore, the expression of PTGS2 in pancreatic β-cells is tightly linked with that of insulin, and PTGS2 inhibition enhances insulin secretion in a dose-dependent manner (Robertson 1998;Luo et al 2002). The PTGS2-dependent production of PGE2 has been postulated to regulate insulin production and secretion in β-cells (Robertson and Chen 1977;Robertson 1998).…”

Section: Introductionmentioning

confidence: 99%

Association of a promoter variant in the inducible cyclooxygenase-2 gene (PTGS2) with type�2 diabetes mellitus in Pima Indians

Konheim

Wolford

2003

Human Genetics

View full text Add to dashboard Cite

Recent studies have suggested that prostaglandin-endoperoxide synthase-2 (PTGS2), also known as cyclo-oxygenase 2, plays an etiological role in the development of type 2 diabetes mellitus (T2DM). PTGS2 generates prostaglandins, which negatively modulate glucose-stimulated insulin secretion, and functions as a mediator of the inflammatory response, which is associated with decreased insulin sensitivity. Moreover, the gene encoding this enzyme, PTGS2, is located on 1q25.2, a region that has been linked with early onset T2DM in Pima Indians. To determine the possible role played by PTGS2 in modulating susceptibility to T2DM, we screened approximately 7.0 kb of the gene, corresponding to the promoter, coding sequence, and flanking exon-intron boundaries, and identified five variants, including three single nucleotide polymorphisms (SNPs) in the promoter, one intronic SNP, and one in the 3' untranslated region. With the exception of one rare promoter SNP (minor allele frequency <0.03), all SNPs were typed in approximately 1000 Pima Indians. The range of frequencies for the more common alleles was 0.65-0.88, and we found substantial linkage disequilibrium between all PTGS2 SNP pairs (D'>/=0.95). Variant alleles at two markers, rs20417 and rs2066826, which are located in the promoter and intron 6, respectively, were in strong linkage disequilibrium with each other (D'=0.97) and were associated with a higher prevalence of T2DM. For marker rs20417, individuals with the variant CC genotype had a 30% higher T2DM prevalence compared with subjects with the GG genotype (odds ratio=1.6 per copy of C allele; P=0.01). The variant C allele of rs20417 has been associated with decreased PTGS2 promoter activity, thereby suggesting a possible biological consequence attributable to this polymorphism. These findings indicate that genetic variants in PTGS2 may play a role in mediating susceptibility to T2DM in Pima Indians and are consistent with the hypothesis that chronic inflammation may contribute to the development of T2DM in some individuals.

show abstract

Cellular distribution and contribution of cyclooxygenase (COX)-2 to diabetogenesis in NOD mouse

Cited by 26 publications

References 17 publications

Anti-Apoptotic Effects of Arachidonic Acid and Prostaglandin E<sub>2</sub> in Pancreatic β-Cells

Anti-Apoptotic Effects of Arachidonic Acid and Prostaglandin E<sub>2</sub> in Pancreatic β-Cells

Transcriptional Regulation of Cyclooxygenase-2 Gene in Pancreatic β-Cells

Association of a promoter variant in the inducible cyclooxygenase-2 gene (PTGS2) with type�2 diabetes mellitus in Pima Indians

Contact Info

Product

Resources

About