IL-1.beta. induces the coexpression of both nitric oxide synthase and cyclooxygenase by Islets of Langerhans: activation of cyclooxygenase by nitric oxide

Corbett, John A.; Kwon, Guim; Turk, John; McDaniel, Michael L.

doi:10.1021/bi00213a002

Cited by 252 publications

(155 citation statements)

References 31 publications

(26 reference statements)

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“…Previous studies have shown that the expressions of iNOS and COX-2 are coordinately regulated in response to a number of inflammatory mediators (35)(36)(37)(38). One activator of iNOS expression by macrophages is dsRNA (10), and consistent with the previously described coordinate regulation of COX-2 and iNOS expression, dsRNA stimulates COX-2 expression by RAW 264.7 cells (Fig.…”

Section: Effects Of Dsrna and Ifn-␥ On Cox-2 Expression By Macrophagessupporting

confidence: 85%

“…Virus infection has been shown to stimulate COX-2 expression (29 -32), and inhibitors of COX-2 enzymatic activity attenuate virus replication (33,34), suggesting that the expression of COX-2 and the increased production of PGs may play an important role in viral replication. In addition, we and others have shown that under proinflammatory conditions the expression of COX-2 and iNOS appear to be coordinately regulated (35)(36)(37)(38). Using macrophages isolated from PKR Ϫ/Ϫ mice and overexpression of dnPKR, we show that the presence of functional PKR is not required for dsRNA-and EMCV-induced COX-2 expression by macrophages.…”

mentioning

confidence: 64%

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Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection

Steer¹,

Moran

Maggi³

et al. 2003

The Journal of Immunology

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In this study the regulation of macrophage expression of cyclooxygenase-2 (COX-2) in response to dsRNA and virus infection was examined. Treatment of RAW 264.7 macrophages with dsRNA results in COX-2 mRNA accumulation and protein expression and the production of PGE2. Similar to dsRNA, encephalomyocarditis virus (EMCV) infection of RAW 264.7 cells stimulates COX-2 expression and PGE2 accumulation. The dsRNA-dependent protein kinase (PKR), which has been shown to participate in the regulation of gene expression in response to dsRNA and virus infection, does not appear to participate in the regulation of COX-2 expression by macrophages. Expression of dominant negative mutants of PKR in RAW 264.7 cells fails to attenuate dsRNA- and EMCV-induced COX-2 expression or PGE2 production. Furthermore, dsRNA and EMCV stimulate COX-2 expression and PGE2 accumulation to similar levels in macrophages isolated from wild-type and PKR-deficient mice. Recently, a novel PKR-independent role for the calcium-independent phospholipase A2 (iPLA2) in the regulation of inducible NO synthase expression by macrophages in response to virus infection has been identified. The selective iPLA2 suicide substrate inhibitor bromoenol lactone prevents dsRNA- and EMCV-stimulated inducible NO synthase expression; however, bromoenol lactone does not attenuate dsRNA- or EMCV-induced COX-2 expression by macrophages. In contrast, inhibition of NF-κB activation prevents dsRNA-stimulated COX-2 expression and PGE2 accumulation by macrophages. These findings indicate that virus infection and treatment with dsRNA stimulate COX-2 expression by a mechanism that requires the activation of NF-κB and that is independent of PKR or iPLA2 activation.

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Section: Effects Of Dsrna and Ifn-␥ On Cox-2 Expression By Macrophagessupporting

confidence: 85%

mentioning

confidence: 64%

Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection

Steer¹,

Moran

Maggi³

et al. 2003

The Journal of Immunology

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“…Recently, it has been shown that COX-2 expression is also induced in the pancreatic islets under high glucose conditions (9,10). Moreover, IL-1␤ signaling stimulates COX-2 induction and PGE 2 production in pancreatic islets (12,13,18). These results, taken together, suggest that COX-2 plays a role in the IL-1␤-induced ␤-cell damage.…”

Section: Discussionmentioning

confidence: 88%

Destruction of Pancreatic β-Cells by Transgenic Induction of Prostaglandin E2 in the Islets

Oshima

Taketo

Oshima

2006

Journal of Biological Chemistry

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Type 2 diabetes mellitus is characterized by insulin resistance of peripheral tissues and dysfunction of pancreatic ␤-cells. Furthermore, the number of pancreatic ␤-cells decreases as a secondary effect of advanced type 2 diabetes, although the molecular mechanism has not been elucidated. Recently, it has been shown that hyperglycemic conditions induce the expression of cyclooxygenase-2 in pancreatic islets and increase the downstream product prostaglandin E 2 (PGE 2 ). To investigate whether high glucose-induced PGE 2 has an adverse effect on pancreatic ␤-cells, we generated transgenic mice (RIP-C2mE) that express cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in their ␤-cells using the rat insulin-2 gene promoter (RIP). The homozygous RIP-C2mE (Tg/Tg) mice showed severe hyperglycemia from six weeks of age. Although the heterozygous RIP-C2mE (Tg/؊) mice showed normal blood glucose levels throughout their lifetime, this level increased significantly compared with that of wild-type mice when glucose was loaded. The relative number of ␤-cells to the total islet cell number was reduced to 54 and 14% in the RIP-C2mE (Tg/؊) and (Tg/Tg) mice, respectively, whereas that in the wild-type mice was 84%. Importantly, the proliferation rate in the islets of the RIP-C2mE (Tg/Tg) mice at four weeks of age decreased significantly in comparison to that in the wild-type mice. Because ␤-cells replicate not only during the postnatal period but also in the adult pancreas at a basal level, it is possible that increased PGE 2 signaling thus contributes to the reduction of the pancreatic ␤-cell mass through inhibition of proliferation, thereby aggravating diabetes further.Type 2 diabetes mellitus is characterized by the insensitivity of the peripheral tissues to insulin and the reduced function of the pancreatic ␤-cells. It has been suggested that chronic hyperglycemia impairs ␤-cell function as a secondary adverse effect of diabetes (1). Furthermore, the ␤-cell mass in pancreatic islets is reduced significantly in type 2 diabetes patients (2-4). In type 1 diabetes, a complexed autoimmune disease, an inflammatory cytokine interleukin-1␤ (IL-1␤) 2 is an important mediator in the impaired function and destruction of pancreatic ␤-cells (5). For example, the treatment of isolated islets with IL-1 inhibits insulin secretion, and this is followed by islet destruction (6). Moreover, adenoviral transduction of the IL-1 receptor antagonist protein into the islets protects against the IL-1␤-induced dysfunction (7). On the other hand, the long term exposure of islets to high glucose conditions has been shown to result in the induction of IL-1␤, followed by ␤-cell apoptosis (8). This high glucose-induced ␤-cell destruction is prevented by treating the islets with an IL-1 receptor antagonist. Accordingly, it is possible that IL-1␤ plays a pivotal role in type 2 diabetes as well.Recently, it has been reported that high glucose conditions induce the expression of cyclooxygenase-2 (COX-2) in pancreatic islets with an increase of the downs...

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“…Several studies in the literature indicate that NO (in the presence or absence of cytokines) enhances cyclooxygenase activity and PGE 2 production in various cell types including normal human chondrocytes (28)(29)(30)(31)(32)(33). Salvemini et al (34) have shown that injection of iNOS inhibitors into a rodent air pouch model (carrageenan-induced) blocked both iNOS and COX-2 activity in areas of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide.

Amin¹,

Attur²,

Patel³

et al. 1997

J. Clin. Invest.

355

285

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Cartilage specimens from osteoarthritis (OA)-affected patients spontaneously released PGE 2 at 48 h in ex vivo culture at levels at least 50-fold higher than in normal cartilage and 18-fold higher than in normal cartilage ϩ cytokines ϩ endotoxin. The superinduction of PGE 2 production coincides with the upregulation of cyclooxygenase-2 (COX-2) in OA-affected cartilage. Production of both nitric oxide (NO) and PGE 2 by OA cartilage explants is regulated at the level of transcription and translation. Dexamethasone inhibited only the spontaneously released PGE 2 production, and not NO, in OA-affected cartilage. The NO synthase inhibitor H N G -monomethyl-L -arginine monoacetate inhibited OA cartilage NO production by Ͼ 90%, but augmented significantly (twofold) the spontaneous production of PGE 2 in the same explants. Similarly, addition of exogenous NO donors to OA cartilage significantly inhibited PGE 2 production. Cytokine ϩ endotoxin stimulation of OA explants increased PGE 2 production above the spontaneous release. Addition of L -NMMA further augmented cytokine-induced PGE 2 production by at least fourfold. Inhibition of PGE 2 by COX-2 inhibitors (dexamethasone or indomethacin) or addition of exogenous PGE 2 did not significantly affect the spontaneous NO production. These data indicate that human OA-affected cartilage in ex vivo conditions shows ( a ) superinduction of PGE 2 due to upregulation of COX-2, and ( b ) spontaneous release of NO that acts as an autacoid to attenuate the production of the COX-2 products such as PGE 2 . These studies, together with others, also suggest that PGE 2 may be differentially regulated in normal and OA-affected chondrocytes. ( J. Clin. Invest. 1997. 99:1231-1237.)

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IL-1.beta. induces the coexpression of both nitric oxide synthase and cyclooxygenase by Islets of Langerhans: activation of cyclooxygenase by nitric oxide

Cited by 252 publications

References 31 publications

Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection

Regulation of Cyclooxygenase-2 Expression by Macrophages in Response to Double-Stranded RNA and Viral Infection

Destruction of Pancreatic β-Cells by Transgenic Induction of Prostaglandin E2 in the Islets

Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide.

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