p38α senses environmental stress to control innate immune responses via mTOR

• Published in: The Journal of immunology (1950) 2013-01, Vol.190 (4), p.1519-1527
• Main Authors: Katholnig, Karl, Kaltenecker, Christopher C., Hayakawa, Hiroko, Rosner, Margit, Lassnig, Caroline, Zlabinger, Gerhard J., Gaestel, Matthias, Müller, Mathias, Hengstschläger, Markus, Hörl, Walter H., Park, Jin Mo, Säemann, Marcus D., Weichhart, Thomas
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1202683

The mitogen-activated protein kinase 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 interleukin (IL)-10 but inhibited IL-12 expression via mTOR and blocked the differentiation of proinflammatory CD4+ T helper 1 cells. Cellular stress induced p38α-mediated mTOR activation that was independent of phosphoinositide 3-kinase (PI3K) but dependent on the kinase MK2 and on the inhibition of TSC1/TSC2 (tuberous sclerosis gene 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 links p38α to mTOR signaling in myeloid immune cells that is decisive for tuning the immune response in dependence on the environmental milieu.