Cyclin-dependent kinase (CDK) 8 and its paralog CDK19 develop group 2 innate lymphoid cell–related lung fibrosis by activating STAT5

Abstract Group 2 innate lymphoid cells (ILC2s) produce large amounts of IL-5, IL-13, and amphiregulin, which are involved in the development of lung fibrosis. Activation of ILC2s is mediated by phosphorylation of STAT5. Although STAT5 has tyrosine and serine phosphorylation sites, the mechanisms responsible for phosphorylating serine residues and their significance in ILC2s remain unclear. The present study demonstrated that cyclin-dependent kinase (CDK) 8 and its paralog CDK19 (CDK8/19) were crucial for the activation of ILC2s in OVA-induced asthmatic BALB/c mice by phosphorylating serine residues of STAT5, leading to lung fibrosis. The following results were obtained: (1) The development of lung fibrosis and the number of ILC2s were significantly ameliorated by the CDK8/19 inhibitor, AS3334366, in OVA-induced asthmatic mice. Consistently, lung fibrosis did not develop in OVA-induced asthmatic ILC2-deficient (Il7rCre/+ Rorafl/fl) mice. (2) IL-33 markedly up-regulated the expression of IL-2 receptor chains, CD25 and CD132, in lung ILC2s. IL-2 significantly augmented the expression of ST2, the high-affinity receptor for IL-33. Furthermore, simultaneous stimulation with IL-33 and IL-2 resulted in the upregulation of CDK8/19 expression in ILC2s. (3) The combined treatment with IL-33 and IL-2 synergistically enhanced the proliferation and cytokine production of ILC2s. Conversely, both these effects, along with the phosphorylation of serine residues in STAT5, were suppressed by AS3334366 in a concentration-dependent manner. The present study is the first to report the involvement of CDK8/19 in the activation of ILC2s via the phosphorylation of STAT5, which led to the development of lung fibrosis.