Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8

Suzhao Li, C. Preston Neff, Kristina Barber, Jaewoo Hong, Yuchun Luo, Tania Azam, Brent E. Palmer, Mayumi Fujita, Cecilia Garlanda, Alberto Mantovani, Soohyun Kim, Charles Anthony Dinarello

Research output: Contribution to journalArticlepeer-review


Similar to IL-1α and IL-33, IL-1 family member IL-37b translocates to the nucleus and is associated with suppression of innate and adaptive immunity. Here we demonstrate an extracellular function of the IL-37 precursor and a processed form. Recombinant IL-37 precursor reduced LPS-induced IL-6 by 50% (P <0.001) in highly inflammatory human blood-derived M1 differentiated macrophages derived from selective subjects but not M2 macrophages. In contrast, a neutralizingmonoclonal anti-IL-37 increased LPS-induced IL-6, TNFα and IL-1β (P <0.01). The suppression by IL-37 was consistently observed at low picomolar but not nanomolar concentrations. Whereas LPS induced a 12-fold increase in TNFα mRNA, IL-37 pretreatment decreased the expression to only 3-fold over background (P <0.01). Mechanistically LPS-induced p38 and pERK were reduced by IL-37. Recombinant IL-37 bound to the immobilized ligand binding α-chain of the IL-18 receptor as well as to the decoy receptor IL-1R8. In M1 macrophages, LPS increased the surface expression of IL-1R8. Compared with human blood monocytes, resting M1 cells express more surface IL-1R8 as well as total IL-1R8; there was a 16-fold increase in IL-1R8 mRNA levels when pretreated with IL-37. IL-37 reduced LPS-induced TNFα and IL-6 by 50-55% in mouse bone marrow-derived dendritic cells, but not in dendritic cells derived from IL-1R8-deficient mice. In mice subjected to systemic LPSinduced inflammation, pretreatment with IL-37 reduced circulating and organ cytokine levels. Thus, in addition to a nuclear function, IL-37 acts as an extracellular cytokine by binding to the IL-18 receptor but using the IL-1R8 for its anti-inflammatory properties.

Original languageEnglish
Pages (from-to)2497-2502
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number8
Publication statusPublished - Feb 24 2015


  • Endotoxemia
  • Immunity
  • Inflammasome

ASJC Scopus subject areas

  • General


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