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 neutralizing monoclonal 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., previously known as IL-1 family member 7, broadly reduces innate inflammation as well as acquired immune responses (1). In human peripheral blood mononuclear cells (PBMCs), a knockdown of endogenous IL-37 results in increased production of LPS-as well as IL-1β-induced cytokines (2). Mice transgenic for full-length human IL-37 (IL-37tg) are protected against LPS-induced systemic inflammation (2), chemical colitis (3), metabolic syndrome (4), and acute myocardial infarction (5). IL-37tg mice also have suppressed immune responses following challenge by specific antigen (6). We believe that full-length IL-37 expressed in the transgenic mice is processed extracellularly.In mouse macrophages stably transfected with human IL-37, ∼20% of IL-37 translocates to the nucleus (7), which is associated with decreased cytokine production (2, 7). However, in the presence of a caspase-1 inhibitor, there is no translocation to the nucleus and no reduction in LPS-induced cytokines (7). Mutation of aspartic acid at the caspase-1 cleavage position 20 to alanine also results in failure to translocate to the nucleus and loss of the suppression of cytokine production (8). Thus, as with IL-1α and IL-33, IL-37 is the third member of the IL-1 family that translocates to the nucleus and affects cellular responses. Nevertheless, it remains unclear whether the reduction in cytokin...
