MST3Promotes IL-17Induced Inflammation Through Enhancing The NF-κB Pathway

Interleukin-17A (IL-17A), the hallmark cytokine of the newly defined T helper17(Th17) cell subset, has important roles in protecting the host against extracellular pathogens. More recently, several innate immune cell populations have also been identified to produce IL-17and IL-17F. These distinctive cell populations, including γδT cells, iNKT cells, NK cells, LTi cells and neutrophils. IL-17has been shown to target various tissues under different inflammatory conditions and participate in the pathogenesis of multiple autoimmune diseases, allergic disorders, tumor formation and host defense. It has been reported that IL-17A activates NF-kB, a hallmark transcription factor associated with the induction of inflammation and apoptosis; how it signals remains poorly understood. Mammalian Ste20-like kinase (Mst), a serine/threonine kinase family member originally identified as a regulator of cell death. MST3may be involved in the regulation of cell motility and caspase-dependent or-independent apoptosis. Here we found Mammalian Ste20-like kinase MST3is a positive regulator of IL-17-mediated signaling and inflammation. Silencing of MST3can inhibit the phosphorylation of NF-kB after IL-17stimulation, as well as the expression of chemokines and cytokines. Consistent with that, MST3is highly expressed in tissue samples of ulcerative colitis patients. Mechanistically, we found that MST3modulates this pathway independent of its kinase activity, but acts as an adaptor to connect TAK1and IKK complex, then increase the phosphorylation of IKK|3. Our findings suggest that MST3plays an important role in controlling IL-17triggered NF-kB signaling, and provides new insight into the therapeutictarget of autoimmune disease.