Journal
IMMUNITY
Volume 29, Issue 4, Pages 565-577Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2008.08.012
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Funding
- Else-Kroner Fresensius Stiftung
- Austrian Ministry of Education, Science, and Culture [SFB F28, BM_WFa, GZ200.112/1VI/l/2004]
- Austrian Science Fund [P18776-B11, P18894-B12]
- European Community's 7th Framework [201608]
- Austrian Science Fund (FWF) [F 2808] Funding Source: researchfish
- Austrian Science Fund (FWF) [P18894, P18776] Funding Source: Austrian Science Fund (FWF)
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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-kappa B but blocked the release of interleukin-10 via the transcription factor STAT3. Conversely, deletion of TSC2, the key negative regulator of mTOR, diminished NF-kappa B 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.
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