NCX-1015, a nitric-oxide derivative of prednisolone, enhances regulatory T cells in the lamina propria and protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice

Fiorucci, Stefano; Antonelli, Elisabetta; Distrutti, Eleonora; Soldato, Piero Del; Flower, Roderick J.; Clark, Mark J. Paul; Morelli, Antonio; Perretti, Mauro; Ignarro, Louis J.

doi:10.1073/pnas.232583599

Cited by 68 publications

(63 citation statements)

References 43 publications

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“…Supporting our finding, the in vivo administration of a pred derivate prevented the development of colitis in mice due to potent IL-10 production and probably Treg induction (54). Adaptive Tregs can be of different nature (11,50,55).…”

Section: Cd25supporting

confidence: 76%

Prednisolone Treatment Induces Tolerogenic Dendritic Cells and a Regulatory Milieu in Myasthenia Gravis Patients

Luther

Adamopoulou

Stoeckle

et al. 2009

The Journal of Immunology

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FOXP3-expressing naturally occurring CD4+CD25high T regulatory cells (Treg) are relevant in the control of autoimmunity, and a defect in this cell population has been observed in several human autoimmune diseases. We hypothesized that altered functions of peripheral Treg cells might play a role in the immunopathogenesis of myasthenia gravis, a T cell-dependent autoimmune disease characterized by the presence of pathogenic autoantibodies specific for the nicotinic acetylcholine receptor. We report in this study a significant decrease in the in vitro suppressive function of peripheral Treg cells isolated from myasthenia patients in comparison to those from healthy donors. Interestingly, Treg cells from prednisolone-treated myasthenia gravis patients showed an improved suppressive function compared with untreated patients, suggesting that prednisolone may play a role in the control of the peripheral regulatory network. Indeed, prednisolone treatment prevents LPS-induced maturation of monocyte-derived dendritic cells by hampering the up-regulation of costimulatory molecules and by limiting secretion of IL-12 and IL-23, and enhancing IL-10. In addition, CD4+ T cells cultured in the presence of such tolerogenic dendritic cells are hyporesponsive and can suppress autologous CD4+ T cell proliferation. The results shown in this study indicate that prednisolone treatment promotes an environment that favors immune regulation rather than inflammation.

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Section: Cd25supporting

confidence: 76%

Prednisolone Treatment Induces Tolerogenic Dendritic Cells and a Regulatory Milieu in Myasthenia Gravis Patients

Luther

Adamopoulou

Stoeckle

et al. 2009

The Journal of Immunology

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“…In the present study, we demonstrated that the anti-inflammatory potency of flunisolide could be markedly increased (ϳ40-fold) by addition, through an ester linkage, of a NO-releasing moiety. This increase in potency is consistent with previous studies in which NOreleasing derivatives of prednisolone have been examined in experimental inflammation models (Paul-Clark et al, 2000Fiorucci et al, 2002a;Turesin et al, 2003). NCX-1024 was found to be more active in suppressing endotoxin-induced up-regulation of COX-2 mRNA expression and NF-B activation, which may contribute to the observed increase in anti-inflammatory potency.…”

Section: Discussionsupporting

confidence: 91%

Enhanced Anti-Inflammatory Potency of a Nitric Oxide-Releasing Derivative of Flunisolide: Role of Nuclear Factor-κB

Wallace¹,

Rizzo²,

Cirino³

et al. 2004

J Pharmacol Exp Ther

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Glucocorticoids remain among the most commonly used antiinflammatory drugs, despite significant adverse effects. Other anti-inflammatory drugs, including aspirin, have been coupled through an ester linkage to a nitric oxide-releasing moiety, resulting in an increase in potency and a decrease in adverse effects. Prednisolone has similarly been modified, with marked improvement of its therapeutic index. In the present study, we have evaluated whether a nitric oxide-releasing derivative of another glucocorticoid, flunisolide, would increase its potency as an anti-inflammatory agent and would decrease its systemic toxicity. To evaluate anti-inflammatory potency and efficacy, the carrageenan-airpouch model in the rat was used. Flunisolide and NCX-1024 (flunisolide-21-[4Ј-(nitrooxymethyl) benzoate]) were compared across a range of doses, with both direct injection into the airpouch and oral administration. The ability of these agents to protect the stomach against indomethacininduced damage also was assessed. Effects of oral administration of the two drugs on body weight gain and adrenal suppression were also evaluated. With direct application into the airpouch, NCX-1024 was found to be 41 times more potent than flunisolide in reducing leukocyte accumulation and prostaglandin E 2 generation. The increased potency may be related to an enhanced ability of NCX-1024 to prevent nuclear factor-B activation. When given orally, the two compounds exhibited similar potency. However, orally administered NCX-1024 was more potent at protecting against indomethacininduced gastric damage, caused less reduction of body weight, and, unlike flunisolide, did not cause adrenal atrophy. These studies suggest that NCX-1024 may be an attractive alternative to conventional glucocorticoids, particularly for applications involving topical administration.

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“…Indeed, this approach is effective based on recent reports showing that ·NO donors inhibited atherosclerosis in hypercholesterolemic mice 32 and decreased inflammation of the gastrointestinal tract in a murine model of inflammatory bowel disease. 33 However, if the underlying defect in endothelial cell function could be corrected, then the atherogenic effects of LDL should be eliminated or at least minimized. If LDL induces endothelial cell dysfunction by increasing O 2 ·Ϫ generation, which inactivates ·NO [3][4][5] and HDL improves endothelial-and eNOS-dependent forearm blood flow, 15 then L-4F, an apoA-1 mimetic, should prevent LDL-induced increases in endothelial cell O 2 ·Ϫ generation.…”

Section: Discussionmentioning

confidence: 99%

L-4F, an Apolipoprotein A-1 Mimetic, Restores Nitric Oxide and Superoxide Anion Balance in Low-Density Lipoprotein-Treated Endothelial Cells

Ackerman

et al. 2003

Circulation

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Background-Low-density lipoprotein (LDL) impairs endothelial cell function by uncoupling endothelial nitric oxide synthase (eNOS) activity, which allows superoxide anion (O 2 ·Ϫ ) to be generated rather than nitric oxide (·NO). Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit the development of atherosclerotic lesions in LDL receptor-null mice. Here we hypothesize that L-4F, an apoA-1 mimetic that inhibits atherosclerosis induced by hypercholesterolemia, protects endothelial cell function by preventing LDL from uncoupling eNOS activity. Methods and Results-Bovine aortic endothelial cells were incubated with LDLϮL-4F, and changes in A23187-stimulated ·NO and O 2 ·Ϫ generation were determined by ozone chemiluminescence and superoxide dismutaseinhibitable ferricytochrome c reduction, respectively. Western analysis of eNOS immunoprecipitates was used to determine effects of LDL and L-4F on heat shock protein 90 (hsp90)

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NCX-1015, a nitric-oxide derivative of prednisolone, enhances regulatory T cells in the lamina propria and protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice

Cited by 68 publications

References 43 publications

Prednisolone Treatment Induces Tolerogenic Dendritic Cells and a Regulatory Milieu in Myasthenia Gravis Patients

Prednisolone Treatment Induces Tolerogenic Dendritic Cells and a Regulatory Milieu in Myasthenia Gravis Patients

Enhanced Anti-Inflammatory Potency of a Nitric Oxide-Releasing Derivative of Flunisolide: Role of Nuclear Factor-κB

L-4F, an Apolipoprotein A-1 Mimetic, Restores Nitric Oxide and Superoxide Anion Balance in Low-Density Lipoprotein-Treated Endothelial Cells

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