Interleukin‐17–induced proliferation of fibroblast‐like synovial cells is mTOR dependent

Saxena, Ankit; Raychaudhuri, Smriti K.; Raychaudhuri, S. P.

doi:10.1002/art.30278

Cited by 39 publications

(27 citation statements)

References 6 publications

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“…In synovial fibroblast of RA patients, rapamycin inhibited growth factor-induced fibroblast proliferation and reduced the invasive properties of fibroblast via inhibition of actin reorganization and lamellipodia formation [14,15]. In addition, recent report showed that IL-17 induces the proliferation of fibroblast derived from patients with RA and this proliferation is mediated through the mTOR pathway [16]. These findings provide the possibility that mTOR inhibitors may become important therapeutic agents in RA.…”

Section: Introductionmentioning

confidence: 87%

Combined therapeutic application of mTOR inhibitor and vitamin D3 for inflammatory bone destruction of rheumatoid arthritis

et al. 2012

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Section: Introductionmentioning

confidence: 87%

Combined therapeutic application of mTOR inhibitor and vitamin D3 for inflammatory bone destruction of rheumatoid arthritis

et al. 2012

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“…In support of this notion, rapamycin decreased the invasive properties of RA FLS 133 . Additional evidence of the benefits of mTORC1 inhibition in RA includes the ability of IL-17 to induce mTORC1-dependent proliferation of RA FLS 134 , the increase in mTORC1 activity in osteoclasts from patients with RA and in arthritic transgenic mice 7 , and the downregulation of extracellular matrix digestive enzymes and induction of apoptosis in osteoclasts elicited by mTOR inhibition 7 (FIG. 3).…”

Section: Mtor — Biomarker and Pathogenetic Factormentioning

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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“…Components of the nutrient-sensing machinery, found to be important in aging, such as Akt (protein kinase B), Foxo and mTOR, have been implicated in the local inflammatory process in RA and were studied mostly in joint-derived FLS [171-176]. In RA circulating T-cells, expression of nutrient-sensing proteins (AMPK and mTOR) was not different compared with controls [154].…”

Section: The Nine Hallmarks Of Aging and Ramentioning

confidence: 99%

Rheumatoid Arthritis, Immunosenescence and the Hallmarks of Aging

Chalan¹,

Berg²,

Kroesen

et al. 2015

CAS

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Age is the most important risk factor for the development of infectious diseases, cancer and chronic inflammatory diseases including rheumatoid arthritis (RA). The very act of living causes damage to cells. A network of molecular, cellular and physiological maintenance and repair systems creates a buffering capacity against these damages. Aging leads to progressive shrinkage of the buffering capacity and increases vulnerability. In order to better understand the complex mammalian aging processes, nine hallmarks of aging and their interrelatedness were recently put forward.RA is a chronic autoimmune disease affecting the joints. Although RA may develop at a young age, the incidence of RA increases with age. It has been suggested that RA may develop as a consequence of premature aging (immunosenescence) of the immune system. Alternatively, premature aging may be the consequence of the inflammatory state in RA. In an effort to answer this chicken and egg conundrum, we here outline and discuss the nine hallmarks of aging, their contribution to the pre-aged phenotype and the effects of treatment on the reversibility of immunosenescence in RA.

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Interleukin‐17–induced proliferation of fibroblast‐like synovial cells is mTOR dependent

Cited by 39 publications

References 6 publications

Combined therapeutic application of mTOR inhibitor and vitamin D3 for inflammatory bone destruction of rheumatoid arthritis

Combined therapeutic application of mTOR inhibitor and vitamin D3 for inflammatory bone destruction of rheumatoid arthritis

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

Rheumatoid Arthritis, Immunosenescence and the Hallmarks of Aging

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