A synthetic derivative of bioactive constituents from Isatis indigotica ameliorates hypersensitivity and arthritis by inhibiting JAK2-STAT3 pathway in mice

The JAK-STAT pathway plays a crucial role in the signaling cascade associated with various cytokines that have been implicated in the pathogenesis of inflammatory diseases and myeloproliferative neoplasms (MPN). Among the isoforms of JAKs, the JAK2 subtype is primarily responsible for the function of hematopoietic system cells, making it a significant target in the treatment of MPN. However, the precise regulatory role of JAK2 in inflammatory diseases requires further investigation and confirmation. The current study employed a selective JAK2 inhibitor, ZT55, derived from Isatis indigotica roots, to examine its regulatory effects on inflammatory and immune responses in delayed-type hypersensitivity (DTH) and arthritis in mice. To evaluate the efficacy of ZT55 treatment, DNFB-induced DTH and collagen-induced arthritis (CIA) mouse models were utilized. T cells were cultured and subsequently analyzed for proliferation and activation using flow cytometry and EdU assay. Additionally, the maturation and function of dendritic cells were assessed through flow cytometry and ELISA. Our findings indicate that ZT55 significantly reduced DNFB-induced DTH and attenuated inflammation, cartilage degradation, and bone destruction in CIA mice. Moreover, ZT55 was found to inhibit the proliferation and activation of T cells and the maturation of dendritic cells by regulating the JAK2-STAT3 signaling pathway. These results suggest that selectively targeting the JAK2 isoform could have anti-inflammatory and immunosuppressive effects by regulating the adaptive and innate immune responses via the JAK2-STAT3 signaling pathway. Therefore, ZT55 has the potential to be a promising pharmaceutical candidate for the treatment of inflammatory and autoimmune diseases.