Abstract
Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.
| Original language | English |
|---|---|
| Pages (from-to) | 354-365 |
| Number of pages | 12 |
| Journal | Nature Immunology |
| Volume | 16 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Mar 19 2015 |
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ASJC Scopus subject areas
- Immunology
- Medicine(all)
Cite this
IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. / Nold-Petry, Claudia A.; Lo, Camden Y.; Rudloff, Ina; Elgass, Kirstin D.; Li, Suzhao; Gantier, Michael P.; Lotz-Havla, Amelie S.; Gersting, Søren W.; Cho, Steven X.; Lao, Jason C.; Ellisdon, Andrew M.; Rotter, Björn; Azam, Tania; Mangan, Niamh E.; Rossello, Fernando J.; Whisstock, James C.; Bufler, Philip; Garlanda, Cecilia; Mantovani, Alberto; Dinarello, Charles A.; Nold, Marcel F.
In: Nature Immunology, Vol. 16, No. 4, 19.03.2015, p. 354-365.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction
AU - Nold-Petry, Claudia A.
AU - Lo, Camden Y.
AU - Rudloff, Ina
AU - Elgass, Kirstin D.
AU - Li, Suzhao
AU - Gantier, Michael P.
AU - Lotz-Havla, Amelie S.
AU - Gersting, Søren W.
AU - Cho, Steven X.
AU - Lao, Jason C.
AU - Ellisdon, Andrew M.
AU - Rotter, Björn
AU - Azam, Tania
AU - Mangan, Niamh E.
AU - Rossello, Fernando J.
AU - Whisstock, James C.
AU - Bufler, Philip
AU - Garlanda, Cecilia
AU - Mantovani, Alberto
AU - Dinarello, Charles A.
AU - Nold, Marcel F.
PY - 2015/3/19
Y1 - 2015/3/19
N2 - Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.
AB - Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.
UR - http://www.scopus.com/inward/record.url?scp=84925671141&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84925671141&partnerID=8YFLogxK
U2 - 10.1038/ni.3103
DO - 10.1038/ni.3103
M3 - Article
C2 - 25729923
AN - SCOPUS:84925671141
VL - 16
SP - 354
EP - 365
JO - Nature Immunology
JF - Nature Immunology
SN - 1529-2908
IS - 4
ER -