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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. The IL-1 family member IL-37 broadly suppresses innate inflammation and acquired immunity. Similar to IL-1α and IL-33, IL-37 is a dual-function cytokine in that IL-37 translocates to the nucleus but also transmits a signal via surface membrane receptors. The role of nuclear IL-37 remains unknown on the ability of this cytokine to inhibit innate inflammation. Here, we compared suppression of innate inflammation in transgenic mice expressing native human IL-37 (IL-37Tg) with those of transgenic mice carrying the mutation of aspartic acid (D) to alanine (A) at amino acid 20 (IL-37D20ATg). The mutation D20A prevents cleavage of caspase-1, a step required for IL-37 nuclear translocation. In vitro, peritoneal macrophages from IL-37Tg mice reduced LPS-induced IL-1β, IL-6, TNFα and IFNγ by 40–50% whereas in macrophages from IL-37D20ATg mice this suppression was not observed, consistent with loss of nuclear function. Compared with macrophages from IL-37Tg mice, significantly less or no suppression of LPS-induced MAP kinase and NFκB activation was also observed in macrophages from IL-37D20ATg mice. In vivo, levels of IL-1β, IL-6, and TNFα in the lungs and liver were markedly reduced during endotoxemia in IL-37Tg mice but not observed in IL-37D20ATg mice. However, suppression of innate inflammation remains intact in the IL-37D20A mice once the cytokine is released from the cell and binds to its receptor. These studies reveal a nuclear function for suppression of innate inflammation and are consistent with the dual function of IL-37 and a role for caspase-1 in limiting inflammation.