A novel small compound SH-2251 suppresses Th2 cell-dependent airway inflammation through selective modulation of chromatin status at the Il5 gene locus

IL-5 is a key cytokine that plays an important role in the development of pathological conditions in chronic allergic inflammation. Identification of a strategy to inhibit IL-5 production is important for establishment of new therapies for allergic inflammation. We found that SH-2251, a novel thioamide-related compound, selectively inhibits the differentiation of IL-5-producing Th2 cells. SH-2251 inhibited the formation of the active histone modifications (H3K4me3, H3K9ac, H3K27ac) at the Il5 gene locus during Th2 cell differentiation. The recruitment of RNA polymerase II and the induction of Th2 cell-specific intergenic transcription between the Rad50 and Il5 gene locus was also inhibited. Furthermore, Th2 cell-driven airway inflammation in mice was suppressed by oral administration of SH-2251. We identified Gfi1 as a downstream target molecule of SH-2251 treatment. The expression of Gfi1 was dramatically decreased in SH-2251-treated Th2 cells. SH-2251-mediated inhibition of the IL-5-producing Th2 cell generation was restored by transduction of Gfi1. Thus, our study unearths SH-2251 as a novel therapeutic candidate for allergic inflammation that selectively inhibits IL-5 production. Gene expression in SH-2251-treated and untreated Th2 cells