Abstract
Dysregulation of the inflammatory response underlies numerous diseases. Although most interleukin-1 family cytokines are proinflammatory, human interleukin-37 (IL-37) is a powerful, broad-spectrum inhibitor of inflammation and immunity. We determined the crystal structure of IL-37 to establish the anti-inflammatory mechanism of this key cytokine in view of developing IL-37-based therapies. We found that two β-trefoil fold IL-37 molecules form a head-to-head dimer that is stable in solution. IL-37 variants mutated to convert the cytokine into an obligate monomer were up to 13-fold more effective than the dimer in suppressing proinflammatory events both in primary human blood cells and in vivo in murine endotoxic shock. Therapeutic exploitation of the powerful anti-inflammatory properties of monomeric IL-37 may prove beneficial in treating a wide range of inflammatory and autoimmune disorders.
| Original language | English |
|---|---|
| Article number | eaaj1548 |
| Number of pages | 12 |
| Journal | Science Immunology |
| Volume | 2 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 10 Feb 2017 |
Cite this
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Homodimerization attenuates the anti-inflammatory activity of interleukin-37. / Ellisdon, Andrew M.; Nold-Petry, Claudia A.; D'Andrea, Laura; Cho, Steven X.; Lao, Jason C.; Rudloff, Ina; Ngo, Devi; Lo, Camden Y.; Soares da Costa, Tatiana P; Perugini, Matthew A.; Conroy, Paul J.; Whisstock, James C.; Nold, Marcel F.
In: Science Immunology, Vol. 2, No. 8, eaaj1548, 10.02.2017.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Homodimerization attenuates the anti-inflammatory activity of interleukin-37
AU - Ellisdon, Andrew M.
AU - Nold-Petry, Claudia A.
AU - D'Andrea, Laura
AU - Cho, Steven X.
AU - Lao, Jason C.
AU - Rudloff, Ina
AU - Ngo, Devi
AU - Lo, Camden Y.
AU - Soares da Costa, Tatiana P
AU - Perugini, Matthew A.
AU - Conroy, Paul J.
AU - Whisstock, James C.
AU - Nold, Marcel F.
PY - 2017/2/10
Y1 - 2017/2/10
N2 - Dysregulation of the inflammatory response underlies numerous diseases. Although most interleukin-1 family cytokines are proinflammatory, human interleukin-37 (IL-37) is a powerful, broad-spectrum inhibitor of inflammation and immunity. We determined the crystal structure of IL-37 to establish the anti-inflammatory mechanism of this key cytokine in view of developing IL-37-based therapies. We found that two β-trefoil fold IL-37 molecules form a head-to-head dimer that is stable in solution. IL-37 variants mutated to convert the cytokine into an obligate monomer were up to 13-fold more effective than the dimer in suppressing proinflammatory events both in primary human blood cells and in vivo in murine endotoxic shock. Therapeutic exploitation of the powerful anti-inflammatory properties of monomeric IL-37 may prove beneficial in treating a wide range of inflammatory and autoimmune disorders.
AB - Dysregulation of the inflammatory response underlies numerous diseases. Although most interleukin-1 family cytokines are proinflammatory, human interleukin-37 (IL-37) is a powerful, broad-spectrum inhibitor of inflammation and immunity. We determined the crystal structure of IL-37 to establish the anti-inflammatory mechanism of this key cytokine in view of developing IL-37-based therapies. We found that two β-trefoil fold IL-37 molecules form a head-to-head dimer that is stable in solution. IL-37 variants mutated to convert the cytokine into an obligate monomer were up to 13-fold more effective than the dimer in suppressing proinflammatory events both in primary human blood cells and in vivo in murine endotoxic shock. Therapeutic exploitation of the powerful anti-inflammatory properties of monomeric IL-37 may prove beneficial in treating a wide range of inflammatory and autoimmune disorders.
UR - http://www.scopus.com/inward/record.url?scp=85057409737&partnerID=8YFLogxK
U2 - 10.1126/sciimmunol.aaj1548
DO - 10.1126/sciimmunol.aaj1548
M3 - Article
VL - 2
JO - Science Immunology
JF - Science Immunology
SN - 2470-9468
IS - 8
M1 - eaaj1548
ER -