文摘
IL-1 family member IL-37 functions to suppress innate inflammation in models of colitis, LPS-induced shock and ischemic myocardial injury. In the present study, we examined a role for IL-37 in the adaptive immune response, namely the development of skin contact hypersensitivity (CHS) to specific antigen. We generated a strain of transgenic mice expressing human IL-37 (IL-37Tg). Not expressed in the resting state, IL-37 was induced in the skin of IL-37Tg mice 6 h following application of the hapten antigen 2,4-dinitrofluorobenzene. Mice were challenged by local application of antigen five days later and we observed a marked reduction in ear swelling in IL-37Tg mice compared to wild-type (WT) mice at 48 h (?60 % ; p < 0.001). Although the distribution, phagocytic activity and migration of skin dendritic cells (DCs) to regional lymph nodes in IL-37Tg mice were comparable to those from sensitized WT mice, LPS induction of a costimulatory molecule, CD40, was reduced (?51 % ; p < 0.01) in IL-37-DCs. Also, LPS-induced secretion of IL-1b, IL-6 and IL-12 was significantly suppressed (?30 % , ?43 % and ?36 % with p < 0.01, p < 0.05 and p < 0.01, respectively), whereas the secretion of IL-10 was enhanced (1.37-fold; p < 0.001) in IL-37-DCs compared to WT-DCs. Consistent with these data, IL-37-DCs exhibited reduced ability to stimulate na?ve T cells (p < 0.001) and induced 86 % more T regulatory cells (p < 0.001) in vitro. Lastly, when sensitized DCs were adoptively transferred to WT mice, CHS responses to antigen challenge were impaired in mice receiving IL-37-DCs compared to those receiving WT-DCs (?57 % ; p < 0.01 at 48 h after the challenge). Histological analysis revealed decreased CD8+ T cells (?73 % ; p < 0.01) and increased T regulatory cells (2.60-fold; p < 0.01) in CHS skin in mice receiving sensitized IL-37-DCs. These findings provide evidence that DCs expressing IL-37 are tolerogenic, thereby impairing activation of T effector responses and inducing T regulatory cells. IL-37 thus emerges as an inhibitor of adaptive immunity.
