IL-37a, an Anti-Inflammatory Molecule and a Nuclear Cytokine: Linking Alternative Splicing, Nuclear Trafficking, and Epigenetic Regulation of Inflammation

Interleukin-37 (IL-37) is an anti-inflammatory member of interleukin-1 family. Alternative splicing generates five isoforms (IL-37a–e) with distinct exon compositions. IL-37a has recently attracted increasing attention because it uniquely retains exon 3. Exon 3 encodes an N-terminal nuclear localization sequence (NLS) that enables autonomous nuclear translocation and harbors an elastase cleavage site at L21/R22. Elastase cleavage produces N-terminal IL-37a (NIL-37a) and mature IL-37a (mIL-37a). Full-length IL-37a and NIL-37a can exert IL-1R8-independent nuclear regulatory and anti-inflammatory effects in the endotoxemic shock model. Nuclear IL-37a recruits a WDR5/MLL4/C/EBPβ-associated complex to promote PPARG transcription, thereby linking cytokine signaling with chromatin regulation and PPARγ-mediated inflammatory control. These findings highlight IL-37a as a mechanistically distinct isoform and illustrate how isoform-specific sequence composition, proteolytic processing, and subcellular localization can diversify cytokine functions. This review synthesizes available evidence regarding the molecular basis of IL-37a nuclear activity, compartmentalized signaling and receptor-independent epigenetic regulation, in the context of nuclear cytokine biology and immunometabolic control. Collectively, IL-37a is a mechanistically distinct isoform whose alternative splicing, proteolytic processing, and nuclear trafficking shape compartment-specific signaling. In LPS-induced endotoxic shock, nuclear IL-37a acts independently of IL-1R8 to upregulate PPARγ through WDR5/MLL4/C/EBPβ-associated chromatin regulation; however, isoform-specific evidence requires further validation, particularly in humans.