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

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