p38α senses environmental stress to control innate immune responses via mechanistic target of rapamycin

J Immunol. 2013 Feb 15;190(4):1519-27. doi: 10.4049/jimmunol.1202683. Epub 2013 Jan 11.

Abstract

The MAPK p38α senses environmental stressors and orchestrates inflammatory and immunomodulatory reactions. However, the molecular mechanism how p38α controls immunomodulatory responses in myeloid cells remains elusive. We found that in monocytes and macrophages, p38α activated the mechanistic target of rapamycin (mTOR) pathway in vitro and in vivo. p38α signaling in myeloid immune cells promoted IL-10 but inhibited IL-12 expression via mTOR and blocked the differentiation of proinflammatory CD4(+) Th1 cells. Cellular stress induced p38α-mediated mTOR activation that was independent of PI3K but dependent on the MAPK-activated protein kinase 2 and on the inhibition of tuberous sclerosis 1 and 2, a negative regulatory complex of mTOR signaling. Remarkably, p38α and PI3K concurrently modulated mTOR to balance IL-12 and IL-10 expression. Our data link p38α to mTOR signaling in myeloid immune cells that is decisive for tuning the immune response in dependence on the environmental milieu.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Transformed
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Environmental Exposure* / adverse effects
  • Humans
  • Immunity, Innate* / genetics
  • Interleukin-10 / biosynthesis
  • Interleukin-12 Subunit p40 / biosynthesis
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 14 / genetics
  • Mitogen-Activated Protein Kinase 14 / physiology*
  • Monocytes / immunology
  • Monocytes / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • TOR Serine-Threonine Kinases / physiology*

Substances

  • Interleukin-12 Subunit p40
  • Interleukin-10
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mitogen-Activated Protein Kinase 14