Prevention of murine lupus disease in (NZB×NZW)F1 mice by sirolimus treatment

Ramos-Barron, M.A.; Piñera-Haces, Celestino; Gómez-Alamillo, C.; Santiuste-Torcida, I.; Ruiz, J.C.; Buelta-Carrillo, L.; Merino, Ramón; Francisco, Ángel; Arias, Manuel

doi:10.1177/0961203307081401

Cited by 48 publications

(27 citation statements)

References 23 publications

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“…By studying the models of lupus mice (NZB Â NZW F1 lupus mice and female MLR/lpr lupus mouse), it was found that rapamycin can effectively reduce the production of autoantibody, decrease vascular immune complex deposition and proteinuria, significantly prolong the survival [32,33]. In clinical terms, rapamycin not only suppresses the SLE activity, also reduces the dose corticosteroids [34].…”

Section: Mtor Signaling Pathwaymentioning

confidence: 99%

Update on the role of autophagy in systemic lupus erythematosus: A novel therapeutic target

Gao

Chen

Feng

et al. 2015

Biomedicine & Pharmacotherapy

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Section: Mtor Signaling Pathwaymentioning

confidence: 99%

Update on the role of autophagy in systemic lupus erythematosus: A novel therapeutic target

Gao

Chen

Feng

et al. 2015

Biomedicine & Pharmacotherapy

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“…Rapamycin has shown great potency in blocking the development of SLE in the MRL/lpr 5 and NZB/W F1 animal models 41,175 , in which autoimmunity, T-cell hyper-reactivity, titres of ANA and anti-DNA antibodies, glomerular immunoglobulin deposition, proteinuria, nephritis, and overall survival were all improved. Importantly, rapamycin also attenuates the severity of established nephritis 176 .…”

Section: Mtor As a Therapeutic Target In Rheumatic Diseasementioning

confidence: 99%

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

2015

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Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4−CD8− (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4+CD25+FoxP3+ T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of Tfollicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.

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“…Rapamycin has been used as an immunosuppressive agent and several reports have shown that rapamycin decreased the development of glomerulonephritis in NZB/W and MRL/lpr mice. [70][71][72][73] Although inhibition of mTOR has been shown to exert beneficial effects in lupus mice, other reports have suggested a negative outcome with the use of rapamycin in regulating anti-GBM glomerulonephritis, depending on timing of administration. 74 mTOR blockage by rapamycin has also been shown to induce proteinuria and renal deterioration and induce focal segmental glomerulonephritis.…”

Section: Egcg Inhibits Inflammation In Lupus Mesangial Cells a Peairsmentioning

confidence: 99%

Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells

et al. 2010

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Epigallocatechin-3-gallate (EGCG), a bioactive component of green tea, has been reported to exert anti-inflammatory effects on immune cells. EGCG is also shown to activate the metabolic regulator, adenosine 5'-monophosphate-activated protein kinase (AMPK). Reports have also indicated that EGCG inhibits the immune-stimulated phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. The PI3K/Akt/mTOR pathway has been implicated in mesangial cell activation in lupus. Mesangial cells from MRL/lpr lupus-like mice are hyper-responsive to immune stimulation and overproduce nitric oxide (NO) and other inflammatory mediators when stimulated. In our current studies, we sought to determine the mechanism by which EGCG attenuates immune-induced expression of pro-inflammatory mediators. Cultured mesangial cells from MRL/lpr mice were pre-treated with various concentrations of EGCG and stimulated with lipopolysaccharide (LPS)/interferon (IFN)-c. EGCG activated AMPK and blocked LPS/ IFN-c-induced inflammatory mediator production (iNOS expression, supernatant NO and interleukin-6). Interestingly, EGCG attenuated inflammation during AMPK inhibition indicating that the anti-inflammatory effect of EGCG may be partially independent of AMPK activation. Furthermore, we found that EGCG effectively inhibited the immune-stimulated PI3K/Akt/mTOR pathway independently of AMPK, by decreasing phosphorylation of Akt, suggesting an alternate mechanism for EGCG-mediated anti-inflammatory action in mesangial cells. Taken together, these studies show that EGCG attenuated inflammation in MRL/lpr mouse mesangial cells via the PI3K/Akt/mTOR pathway. Our findings suggest a potential therapeutic role for the use of EGCG to regulate inflammation and control autoimmune disease.

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Prevention of murine lupus disease in (NZB×NZW)F1 mice by sirolimus treatment

Cited by 48 publications

References 23 publications

Update on the role of autophagy in systemic lupus erythematosus: A novel therapeutic target

Update on the role of autophagy in systemic lupus erythematosus: A novel therapeutic target

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells

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