DUSP8 induces TGF-beta-stimulated IL-9 transcription and Th9-mediated allergic inflammation by promoting nuclear export of Pur-alpha repressor
Dual-specificity phosphatase 8 is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T-cell-specific DUSP8 conditional knockout (T-DUSP8 cKO) mice, mass spectrometry analysis, chromatin-immunoprecipitation sequencing, and immune analysis, we found that DUSP8 interacted with Pur-alpha, stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-alpha upon TGF-beta signaling, leading to the nuclear export of Pur-alpha and subsequent IL-9 transcriptional activation. Furthermore, IL-9 mRNA levels were induced in Pur-alpha-deficient T cells. In addition, T-DUSP8 cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in the allergic asthma model. Reduction of IL-9 mRNA levels in T cells and allergic responses of T-DUSP8 cKO mice was reversed by Pur-alpha knockout. Remarkably, DUSP8 protein levels and the DUSP8-Pur-alpha interaction were indeed increased in the cytoplasm of T cells from human asthma patients and atopic dermatitis patients. Collectively, DUSP8 induces TGF-beta-stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-alpha. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis.