Homodimerization attenuates the anti-inflammatory activity of interleukin-37

Andrew M. Ellisdon, Claudia A. Nold-Petry, Laura D'Andrea, Steven X. Cho, Jason C. Lao, Ina Rudloff, Devi Ngo, Camden Y. Lo, Tatiana P Soares da Costa, Matthew A. Perugini, Paul J. Conroy, James C. Whisstock, Marcel F. Nold

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

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 languageEnglish
Article numbereaaj1548
Number of pages12
JournalScience Immunology
Volume2
Issue number8
DOIs
Publication statusPublished - 10 Feb 2017

Cite this

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title = "Homodimerization attenuates the anti-inflammatory activity of interleukin-37",
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.",
author = "Ellisdon, {Andrew M.} and Nold-Petry, {Claudia A.} and Laura D'Andrea and Cho, {Steven X.} and Lao, {Jason C.} and Ina Rudloff and Devi Ngo and Lo, {Camden Y.} and {Soares da Costa}, {Tatiana P} and Perugini, {Matthew A.} and Conroy, {Paul J.} and Whisstock, {James C.} and Nold, {Marcel F.}",
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doi = "10.1126/sciimmunol.aaj1548",
language = "English",
volume = "2",
journal = "Science Immunology",
issn = "2470-9468",
publisher = "American Association for the Advancement of Science (AAAS)",
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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 journalArticleResearchpeer-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.

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