The TSC-mTOR Signaling Pathway Regulates the Innate Inflammatory Response
| Autor: | Mathias Müller, Thomas M. Stulnig, Marko Poglitsch, Walter H. Hörl, Marcus D. Säemann, Margit Rosner, Karl M. Stuhlmeier, Thomas Kolbe, Giuseppina Costantino, Thomas Weichhart, Maximilian Zeyda, Markus Hengstschläger |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Lipopolysaccharides
STAT3 Transcription Factor Immunology Monocytes Proinflammatory cytokine 03 medical and health sciences Mice 0302 clinical medicine Immune system Tuberous Sclerosis Tuberous Sclerosis Complex 2 Protein Animals Humans Immunology and Allergy Listeriosis MOLIMMUNO STAT3 Transcription factor PI3K/AKT/mTOR pathway 030304 developmental biology Inflammation Mice Knockout Sirolimus 0303 health sciences Mice Inbred BALB C Innate immune system biology TOR Serine-Threonine Kinases Tumor Suppressor Proteins NF-kappa B Th1 Cells Listeria monocytogenes Immunity Innate 3. Good health Cell biology Anti-Bacterial Agents Transplantation Infectious Diseases Cancer research biology.protein Cytokines Female TSC2 Protein Kinases 030215 immunology Signal Transduction |
| Zdroj: | Immunity. 29(4):565-577 |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2008.08.012 |
| Popis: | Summary 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-κB but blocked the release of interleukin-10 via the transcription factor STAT3. Conversely, deletion of TSC2, the key negative regulator of mTOR, diminished NF-κB 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. |
| Databáze: | OpenAIRE |
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