Zinc finger protein 91 positively regulates the production of IL-1β in macrophages by activation of MAPKs and non-canonical caspase-8 inflammasome

Background and Purpose Experimental Approach IL-1 beta is a cytokine of critical importance in inflammatory, infectious and autoimmune diseases. Zinc finger protein 91 (ZFP91) has been reported to be involved in multiple biological processes. Here, we identified a previously unknown role for ZFP91 in the production of biologically active IL-1 beta and investigated the underlying mechanisms of its effects. In vitro, the underlying mechanisms of ZFP91 at inhibiting the expression of IL-1 beta were investigated by ELISA, RT-PCR, Western blotting, immunoprecipitation and immunofluorescence assays. In vivo, colitis was induced by giving 4% dextran sulfate sodium (DSS) p.o. in drinking water for 5 days. Peritonitis was induced by injecting 700 mu g alum i.p. for 12 h. Key Results Conclusions and Implications ZFP91 activated the non-canonical caspase-8 inflammasome, which resulted in robust IL-1 beta secretion. Using an immunoprecipitation assay and immunofluorescence assay, we found that ZFP91 promoted the assembly of the non-canonical caspase-8 inflammasome complex. Moreover, ZFP91 enhanced the activation of ERK, p38 MAPK and JNK in macrophages. In addition, our data demonstrate that the synthesis of pro-IL-1 beta is dependent on activation of these MAPK signalling pathways. In vivo experiments, the symptoms and colonic inflammation associated with DSS-induced colitis were ameliorated in mice deficient in ZFP91. Furthermore, the inflammation in alum-induced peritonitis was also attenuated in mice deficient in ZFP91. Our research describes a mechanism by which ZFP91 promotes production of IL-1 beta under physiological conditions and suggests that ZFP91 may be a promising therapeutic target for intervention in inflammatory, infectious and autoimmune-related diseases.