The TSC-mTOR signaling pathway regulates the innate inflammatory response

Immunity. 2008 Oct 17;29(4):565-77. doi: 10.1016/j.immuni.2008.08.012. Epub 2008 Oct 9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Cytokines / biosynthesis
  • Cytokines / immunology*
  • Female
  • Humans
  • Immunity, Innate*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Lipopolysaccharides / immunology
  • Listeria monocytogenes / immunology
  • Listeriosis / immunology*
  • Listeriosis / microbiology
  • Listeriosis / prevention & control
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Monocytes / metabolism
  • NF-kappa B / metabolism
  • Protein Kinases / immunology
  • Protein Kinases / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Tuberous Sclerosis
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Anti-Bacterial Agents
  • Cytokines
  • Lipopolysaccharides
  • NF-kappa B
  • STAT3 Transcription Factor
  • TSC2 protein, human
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus

Associated data

  • GEO/GSE6002