Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner.
Interleukin 6 (IL-6) is a pleiotropic cytokine and a strong activator of Mammalian Target of Rapamycin (mTOR). In contrast, mTOR activity is negatively regulated by Regulated in Development and DNA Damage Responses 1 (REDD1). Expression of REDD1 is induced by cellular stressors such as glucocorticoids and DNA damaging agents. We show that the expression of basal as well as stress-induced REDD1 is reduced by IL-6. The reduction of REDD1 expression by IL-6 is independent of proteasomal or caspase-mediated degradation of REDD1 protein. Instead, induction of REDD1 mRNA is reduced by IL-6. The regulation of REDD1 expression by IL-6 is independent of Phosphatidylinositide-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signalling but depends on the expression and activation of Signal Transducer and Activator of Transcription 3 (STAT3). Furthermore, the reduction of basal REDD1 expression by IL-6 correlates with IL-6-induced activation of mTOR signalling. Inhibition of STAT3 activation blocks IL-6-induced mTOR activation. In summary, we present a novel STAT3-dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress-induced inhibition of mTOR activity.
Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28, 39106 Magdeburg, Germany. Electronic address: jessica.pinno@st.ovgu.de.
Jessica
J
Pinno
Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28, 39106 Magdeburg, Germany. Electronic address: hannes.bongartz@ovgu.de.
Hannes
H
Bongartz
Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28, 39106 Magdeburg, Germany. Electronic address: oliver.klepsch@ovgu.de.
Oliver
O
Klepsch
Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28, 39106 Magdeburg, Germany. Electronic address: nicole.wundrack@ovgu.de.
Nicole
N
Wundrack
Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza 52, 10126 Turin, Italy. Electronic address: valeria.poli@unito.it.
Valeria
V
Poli
Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28, 39106 Magdeburg, Germany. Electronic address: fred.Schaper@ovgu.de.
Fred
F
Schaper
Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28, 39106 Magdeburg, Germany. Electronic address: anna.dittrich@ovgu.de.
Anna
A
Dittrich
D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C469991:DDIT4 protein, human
Interleukin 6; REDD1; STAT3; Stress signalling; mTOR