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...

The United Network for Organ Sharing (UNOS) implemented a policy that requires patients with hepatocellular carcinoma seeking liver transplantation to wait six months before being granted Model for End-Stage Liver Disease exception points. We investigated the difference in resource utilization between patients who underwent liver transplantation before and after the present policy. We conducted a retrospective cohort study of adult liver transplants from 2013 to 2018. Patients were classified into prepolicy or postpolicy groups based on 964 days before or after the wait-time policy. We also retrieved national survival outcome data from United Network for Organ Sharing. Differences across compared groups for continuous variables were assessed using the independent sample t test, and the chi-squared test was used for binary variables. We found statistical differences in recipient age ( P = 0.005), days on wait-list ( P = 0.001), sustained viro-logical response ( P < 0.001), and hepatocellular carcinoma recurrence one year posttransplant ( P = 0.04). There were statistically significant differences in the number of treatment days pretransplant and length of transplant admission stay, indicating an increase in resource utilization in the postpolicy group. No statistically significant differences were found between groups in one-year graft or patient survival despite an observed increase in resource utilization by the hepatocellular carcinoma postpolicy group.

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