Abstract
Interleukin 17 (IL-17) is a key inflammatory cytokine that plays a critical role in tissue inflammation and autoimmune diseases. However, its signaling remains poorly understood. In this study, we identified serine/threonine kinase 24 (Stk24) as a positive modulator of IL-17-mediated signaling and inflammation. Stk24 deficiency or knockdown markedly inhibited IL-17-induced phosphorylation of NF-κB and impaired IL-17-induced chemokines and cytokines expression. Stk24 overexpression greatly enhanced IL-17-induced NF-κB activation and expression of chemokines and cytokines in a kinase activity-independent manner. The IL-17-induced inflammatory response was significantly reduced in Stk24-deficient mice. In addition, the severity of experimental autoimmune encephalomyelitis was markedly reduced in mice with a deficiency of Stk24 in non-hematopoietic cells. We further demonstrated that Stk24 directly interacts with TAK1 and IKKβ and promotes the formation of TAK1/IKK complexes, leading to enhanced IKKβ/NF-κB activation and downstream cytokines and chemokines induction. Collectively, our findings suggest that Stk24 plays an important role in controlling IL-17-triggered inflammation and autoimmune diseases and provides new insight into the therapeutic targets of IL-17-mediated inflammatory disease.
Highlights
The interleukin 17 (IL-17) family is a recently emerged subset of cytokines secreted by innate and adaptive immune cells, including iNKT cells, δγ T cells, LTi-like cells, NK cells, and myeloid cells, and participate in both acute and chronic inflammatory responses [1]
We examined the effect of serine/threonine kinase 24 (Stk24) deficiency on the expression of Interleukin 17 (IL-17)-induced pro-inflammatory cytokines and chemokines in mouse embryo fibroblasts (MEFs)
Stk24 deficiency in primary astrocytes resulted in lower expression of IL-6, CXCL1, CXCL2, and CCL20 compared with WT astrocytes (Figure 1E)
Summary
The interleukin 17 (IL-17) family is a recently emerged subset of cytokines secreted by innate and adaptive immune cells, including iNKT cells, δγ T cells, LTi-like cells, NK cells, and myeloid cells, and participate in both acute and chronic inflammatory responses [1]. This family contains six members: IL-17A, IL-17B, IL-17C, IL-17 D, IL-17E ( named IL-25), and IL-17F. IL-17A (commonly referred to as IL-17), a founding member of the IL-17 family, is the most widely investigated cytokine of this family and its biological function and regulation are best understood.
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