Abstract
Th17 cells promote inflammatory reactions, whereas regulatory T (Treg) cells inhibit them. Thus, the Th17/Treg cell balance is critically important in inflammatory diseases. However, the molecular mechanisms underlying this balance are unclear. Here, we demonstrate that casein kinase 2 (CK2) is a critical determinant of the Th17/Treg cell balance. Both the inhibition of CK2 with a specific pharmacological inhibitor, CX-4945, and its small hairpin RNA (shRNA)-mediated knockdown suppressed Th17 cell differentiation but reciprocally induced Treg cell differentiation in vitro. Moreover, CX-4945 ameliorated the symptoms of experimental autoimmune encephalomyelitis and reduced Th17 cell infiltration into the central nervous system. Mechanistically, CX-4945 inhibited the IL-6/STAT3 and Akt/mTOR signaling pathways. Thus, CK2 has a crucial role in regulating the Th17/Treg balance.
Highlights
Autoimmune diseases are regulated by the balance between T helper 17 (Th17) cells, which promote inflammatory reactions by secreting interleukin (IL)-17A, IL-17F, IL-21 and IL-22,1–4 and regulatory T (Treg) cells, which suppress effector T cells and regulate self-tolerance.[5,6] Despite their conflicting roles, Th17 and Treg cells share a precursor cell and an inducing signal (transforming growth factor β (TGFβ))
Casein kinase 2 (CK2) determines the severity of EAE Since our data showed that CX-4945 suppresses Th17 cell differentiation in favor of Treg cell differentiation in vitro, we examined whether it affects Th17-mediated inflammation in a mouse model of EAE
Here, we showed that CK2 controls the differentiation of CD4 T cells
Summary
Autoimmune diseases are regulated by the balance between T helper 17 (Th17) cells, which promote inflammatory reactions by secreting interleukin (IL)-17A, IL-17F, IL-21 and IL-22,1–4 and regulatory T (Treg) cells, which suppress effector T cells and regulate self-tolerance.[5,6] Despite their conflicting roles, Th17 and Treg cells share a precursor cell (naive CD4 T cells) and an inducing signal (transforming growth factor β (TGFβ)). Depending on other environmental conditions, such as the presence of specific antigens, T cell receptor (TCR) binding, and the amount of IL-2, IL-6, IL-21 and IL-23, naive CD4 T cells differentiate into either Th17 or Treg cells.[7,8,9,10]. The differentiation of Th17 and Treg cells is controlled reciprocally, and the balance between them has a critical role in autoimmune responses. Th17 cells by inducing retinoid-related orphan receptor (ROR)-γt, the key transcription factor that determines Th17 lineage.[11,12] STAT3, which is phosphorylated and activated by IL-6, is an important component of IL-6-mediated Th17 cell differentiation. STAT3-deficient T cells fail to produce IL-17 and instead induce Foxp[3], even in the presence of IL-6 and TGF-β.13,14. The PI3K–Akt axis works downstream of the TCR and CD28 in
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