Role of Cyclooxygenase-2 in Cytokine-induced β-Cell Dysfunction and Damage by Isolated Rat and Human Islets

Heitmeier, Monique R.; Kelly, Colleen B.; Ensor, Nancy J.; Gibson, Kenneth A.; Mullis, Karen G.; Corbett, John A.; Maziasz, Timothy J.

doi:10.1074/jbc.m410978200

Cited by 44 publications

(40 citation statements)

References 43 publications

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“…Furthermore, treatment of islets with S100b alone or in the presence of these inhibitors did not significantly affect glucose-induced insulin secretion. These results are consistent with published results showing that cytokine-induced PTGS2 did not affect insulin secretion in islets [22,23] and further support observations that PTGS2 inhibitors failed to prevent cytokine-induced beta cell dysfunction [23]. In addition, a very recent study [24] showed that PTGS2 inhibition enhances anti-tumour immunity.…”

Section: Discussionsupporting

confidence: 92%

Increased expression of cyclooxygenase-2 in human pancreatic islets treated with high glucose or ligands of the advanced glycation endproduct-specific receptor (AGER), and in islets from diabetic mice

et al. 2005

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Aims/hypothesis: The cyclooxygenase-2 (PTGS2, previously known as COX2) enzyme and its products, such as prostaglandin E 2 (PGE 2 ), have been implicated in the pathogenesis of several inflammatory diseases including islet dysfunction under diabetic conditions. In this study we evaluated whether diabetic conditions in vitro, such as highglucose (HG) culture or AGE, or in vivo in animal models of diabetes can induce PTGS2 expression and activity in pancreatic islets. Materials and methods: Isolated human pancreatic islets were treated for 24 h with HG (25 mmol/l) or with S100b (5 mg/l), a specific ligand for the AGEspecific receptor. PTGS2 and cyclooxygenase-1 (PTGS1, previously known as COX1) mRNA, protein expression and product PGE 2 were analysed by RT-PCR, Western blots and specific enzyme immunoassay respectively. Islet PTGS2 production in animal models was assessed by immunofluorescence. Results: Treatment of human pancreatic islets with HG and S100b led to a three-five-fold induction of PTGS2 mRNA (p<0.001). PTGS2 protein and its product PGE 2 (351.4±13.05 fg/ml vs control 39.4±0.11 fg/ml) were also increased (p<0.001). Pretreatment with specific inhibitors demonstrated the involvement of protein kinase C and oxidant stress in S100b-and HG-induced PTGS2 expression. However, insulin secretion was not significantly altered by S100b. Double immunofluorescent staining showed increased PTGS2 production in pancreatic islets from diabetic mice relative to corresponding controls. Conclusion/ interpretation: These results show for the first time that diabetes as well as diabetic conditions such as AGE and HG in vitro can directly upregulate the expression of the inflammatory PTGS2 gene in pancreatic islets. This might contribute to the pathogenesis of islet dysfunction in diabetes.

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Section: Discussionsupporting

confidence: 92%

Increased expression of cyclooxygenase-2 in human pancreatic islets treated with high glucose or ligands of the advanced glycation endproduct-specific receptor (AGER), and in islets from diabetic mice

et al. 2005

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“…Cytokine-induced ␤-cell killing, in contrast, requires the expression of several genes (e.g., iNOS, COX2, etc. ), is dependent on nuclear factor-B activity, and generally occurs over a period of 1 to several days (16,32,36,44).…”

Section: Discussionmentioning

confidence: 99%

Pro- and Antiapoptotic Proteins Regulate Apoptosis but Do Not Protect Against Cytokine-Mediated Cytotoxicity in Rat Islets and β-Cell Lines

Collier

Fueger²,

Hohmeier³

et al. 2006

Diabetes

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Type 1 diabetes results from islet ␤-cell death and dysfunction induced by an autoimmune mechanism. Proinflammatory cytokines such as interleukin-1␤ and ␥-interferon are mediators of this ␤-cell cytotoxicity, but the mechanism by which damage occurs is not well understood. In the current study, we present multiple lines of evidence supporting the conclusion that cytokine-induced killing of rat ␤-cells occurs predominantly by a nonapoptotic mechanism, including the following: 1) A rat ␤-cell line selected for resistance to cytokine-induced cytotoxicity (833/15) is equally sensitive to killing by the apoptosis-inducing agents camptothecin and etoposide as a cytokine-sensitive cell line (832/ 13). 2) Overexpression of a constitutively active form of the antiapoptotic protein kinase Akt1 in 832/13 cells provides significant protection against cell killing induced by camptothecin and etoposide but no protection against cytokine-mediated damage. 3) Small interfering RNA-mediated suppression of the proapoptotic protein Bax enhances viability of 832/13 cells upon exposure to the known apoptosis-inducing drugs but not the inflammatory cytokines. 4) Exposure of primary rat islets or 832/13 cells to the inflammatory cytokines causes cell death as evidenced by the release of adenylate kinase activity into the cell medium, with no attendant increase in caspase 3 activation or annexin V staining. In contrast, camptothecin-and etoposide-induced killing is associated with robust increases in caspase 3 activation and annexin V staining. 5) Camptothecin increases cellular ATP levels, whereas inflammatory cytokines lower ATP levels in both ␤-cell lines and primary islets. We conclude that proinflammatory cytokines cause ␤-cell cytotoxicity primarily through a nonapoptotic mechanism linked to a decline in ATP levels.

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“…In addition to the effects on Ccl2, Dex, MS4, and MS6 all suppressed expression of the cyclooxygenase-2 gene (data not shown), which participates in the synthesis of prostaglandin E 2 in islet ␤-cells (37,38). We also investigated the effects of MS4 and MS6 on Ccl20, a distinct chemokine gene known to be up-regulated in islets of NOD mice and in human islets exposed to cytokines (39).…”

Section: Interleukin-1␤-mediated Ccl2 and Ccl20 Transcript And Proteimentioning

confidence: 93%

Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

Burke

May

Noland³

et al. 2015

Journal of Biological Chemistry

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Background: Glucocorticoids impair islet ␤-cell function via glucocorticoid receptor (GR) activation. Results: Thiobenzothiazole-modified hydrocortisone compounds exhibit anti-inflammatory properties with reduced impact on insulin secretion. Conclusion: Novel glucocorticoids can be engineered to reduce impact on ␤-cell mass and function. Significance: Improved GR agonists will be beneficial in a variety of clinical settings.

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Role of Cyclooxygenase-2 in Cytokine-induced β-Cell Dysfunction and Damage by Isolated Rat and Human Islets

Cited by 44 publications

References 43 publications

Increased expression of cyclooxygenase-2 in human pancreatic islets treated with high glucose or ligands of the advanced glycation endproduct-specific receptor (AGER), and in islets from diabetic mice

Increased expression of cyclooxygenase-2 in human pancreatic islets treated with high glucose or ligands of the advanced glycation endproduct-specific receptor (AGER), and in islets from diabetic mice

Pro- and Antiapoptotic Proteins Regulate Apoptosis but Do Not Protect Against Cytokine-Mediated Cytotoxicity in Rat Islets and β-Cell Lines

Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

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