IL37

IL-37 (IL-1F7) is an anti-inflammatory IL-1 family cytokine that restrains pro-inflammatory responses through both receptor-dependent and intracellular mechanisms (PMID:12096920, PMID:12381835, PMID:12496389). It is synthesized as a precursor and processed by caspase-1 at a propeptide cleavage site to generate a mature form, with caspase-4 contributing inefficiently and other caspases unable to cleave it (PMID:12096920); this processing markedly increases its homodimerization affinity (PMID:12096920). Both pro- and mature IL-37 bind IL-18Rα but not IL-1R or ST2R, yet IL-37 fails to recruit IL-18Rβ into a functional ternary complex, accounting for its lack of IL-18-like agonist activity (PMID:12096920, PMID:12381835). IL-37 additionally forms a high molecular weight complex with IL-18-binding protein that enhances IL-18BP-mediated neutralization of IL-18-induced IFN-γ (PMID:12381835). In vivo, adenoviral delivery of IL-37 suppresses fibrosarcoma growth through an IL-12-, IFN-γ-, and Fas-ligand-dependent adaptive immune pathway (PMID:12496389), and transgenic expression of human IL-37 attenuates inflammation-driven sleep responses elicited by IL-1β or LPS (PMID:28070566).

1. 2002 High

   Established how the IL-37 precursor is converted to a mature cytokine, identifying caspase-1 as the principal processing enzyme and defining the maturation step that governs its activity.

   Evidence In vitro caspase cleavage assays against multiple caspases plus adenoviral expression in HEK293 cells

   PMID:12096920

   Open questions at the time

   • Physiological trigger and cellular context of caspase-1 processing not defined
   • Whether mature form is the dominant secreted species in vivo not established
2. 2002 High

   Defined IL-37's receptor selectivity, showing it engages IL-18Rα with affinity weaker than IL-18 and does not bind IL-1R or ST2R, framing it as an IL-18Rα-directed ligand without agonist output.

   Evidence Binding screen with soluble receptor-Fc fusions and IFN-γ induction assay in KG1a cells

   PMID:12096920 PMID:12381835

   Open questions at the time

   • Affinity for IL-18Rα is low, leaving physiological relevance of this binding open
   • No downstream signaling readout established for IL-37 binding
3. 2002 Medium

   Showed that caspase-1 processing dramatically increases homodimerization affinity, linking maturation to a defined biophysical state of the cytokine.

   Evidence Association constant measurement comparing pro- and mature forms

   PMID:12096920

   Open questions at the time

   • Functional consequence of homodimerization not resolved
   • Single-lab biophysical measurement without orthogonal structural confirmation
4. 2002 High

   Explained why IL-37 lacks IL-18 agonist activity by demonstrating its failure to recruit IL-18Rβ into the ternary signaling complex.

   Evidence Chemical cross-linking and SDS-PAGE analysis of receptor complex formation

   PMID:12381835

   Open questions at the time

   • Whether IL-18Rα engagement actively antagonizes IL-18 signaling not shown
   • Structural basis of failed co-receptor recruitment not resolved experimentally
5. 2002 High

   Identified a second anti-inflammatory mechanism in which IL-37 complexes with IL-18BP to cooperatively enhance IL-18 neutralization.

   Evidence Chemical cross-linking plus IFN-γ inhibition assays in an NK cell line and PBMCs

   PMID:12381835

   Open questions at the time

   • Enhancement is modest (~25-30%) and concentration-dependent
   • Stoichiometry and architecture of the IL-37/IL-18BP complex not determined
6. 2003 Medium

   Placed IL-37 in an in vivo anti-tumor pathway, showing its effect requires IL-12, IFN-γ, Fas-ligand, and intact adaptive immunity.

   Evidence Genetic epistasis across IL-12-/-, IFN-γ-/-, FasL-/-, NKT-deficient, nude, and SCID mice with intratumoral adenoviral gene transfer

   PMID:12496389

   Open questions at the time

   • Mechanistic link between IL-37 expression and IL-12/IFN-γ/FasL induction not defined
   • Reliance on adenoviral overexpression rather than endogenous IL-37
7. 2011 Low

   Raised the possibility of a receptor-independent intranuclear role for IL-37 by reporting nuclear localization analogous to IL-1α and IL-33.

   Evidence Nuclear localization described in a review citing prior experimental work

   PMID:22047735

   Open questions at the time

   • Reported in review without primary method detail
   • No nuclear transcriptional target or partner identified
8. 2016 Medium

   Demonstrated an in vivo anti-inflammatory function by showing IL-37 attenuates inflammation-driven sleep responses triggered by IL-1β or LPS.

   Evidence Sleep recording in human IL-37b transgenic versus wild-type mice with LPS, IL-1β, and influenza challenge

   PMID:28070566

   Open questions at the time

   • Molecular pathway connecting IL-37 to dampened NREMS responses not mapped
   • Relies on human transgene in mouse background
9. 2024 Low

   Proposed a structural rationale for IL-37's failure to recruit IL-18Rβ, implicating the N-terminal loop and an N297 glycan steric block, and a distinct IL-37/IL-18BP binding mode.

   Evidence Homology modeling, AlphaFold2 multimer prediction, and molecular dynamics simulations (preprint)

   PMID:bio_10.1101_2024.09.21.613817

   Open questions at the time

   • Computational prediction with no experimental validation
   • Predicted N-terminal loop and glycan roles not tested by mutagenesis

• The signaling output of IL-37 engagement of IL-18Rα and the molecular basis of its proposed intranuclear transcriptional role remain undefined.
• No intracellular signaling effector identified for IL-37 receptor binding
• No nuclear binding partner or target gene established
• Endogenous (non-overexpression) anti-inflammatory mechanism not resolved