Role for nuclear interleukin-37 in the suppression of innate immunity

Significance Interleukin-1 family members are highly inflammatory, but member IL-37 is unique in broadly suppressing inflammation and specific immunity. IL-37 is a dual-function cytokine by binding in the nucleus and to cell surface receptors. We generated an IL-37 transgenic mouse carrying the aspartic acid (D) to alanine (A) mutation at amino acid 20 (D20A), which prevents the nuclear translocation of IL-37. In transgenic mice expressing native IL-37, inflammatory cytokines are reduced during systemic endotoxemia, but, in mice expressing the D20A mutation, protection is lost, consistent with a nuclear function of IL-37. Nevertheless, IL-37D20A released from cells binds to its receptors and initiates suppression of innate inflammation. These studies reveal a nuclear function of IL-37 in vivo.