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 IL‐1β 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‐1β and investigated the underlying mechanisms of its effects. Experimental Approach In vitro , the underlying mechanisms of ZFP91 at inhibiting the expression of IL‐1β 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 μg alum i.p. for 12 h. Key Results ZFP91 activated the non‐canonical caspase‐8 inflammasome, which resulted in robust IL‐1β 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‐1β 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. Conclusions and Implications Our research describes a mechanism by which ZFP91 promotes production of IL‐1β under physiological conditions and suggests that ZFP91 may be a promising therapeutic target for intervention in inflammatory, infectious and autoimmune‐related diseases.