The TSC-mTOR pathway controls the innate inflammatory response of monocytes/macrophages.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mouse/human monocytes |
| Journal | Immunity |
| Year | 2008 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.immuni.2008.08.012 · PMID 18848473 |
The innate inflammatory immune response must be tightly controlled to avoid damage to the host. Here, we showed that the tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) pathway regulated inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Inhibition of mTOR by rapamycin promoted production of proinflammatory cytokines via the transcription factor NF-kappaB but blocked the release of interleukin-10 via the transcription factor STAT3. Conversely, deletion of TSC2, the key negative regulator of mTOR, diminished NF-kappaB but enhanced STAT3 activity and reversed this proinflammatory cytokine shift. Rapamycin-hyperactivated monocytes displayed a strong T helper 1 (Th1) cell- and Th17 cell-polarizing potency. Inhibition of mTOR in vivo regulated the inflammatory response and protected genetically susceptible mice against lethal Listeria monocytogenes infection. These data identify the TSC2-mTOR pathway as a key regulator of innate immune homeostasis with broad clinical implications for infectious and autoimmune diseases, vaccination, cancer, and transplantation.
| Intervention | Rapamycin (mTOR inhibition) |
| Target | TSC-mTOR / NF-κB |
| Model | Mouse/human monocytes |
| Effect | mTOR inhibition promotes pro-inflammatory cytokines via NF-κB – TSC-mTOR regulates the innate inflammatory response |