title: A novel small compound SH-2251 suppresses Th2 cell-dependent airway inflammation through selective modulation of chromatin status at the Il5 gene locus.
abstract: IL-5 is a key cytokine that plays an important role in the development of pathological conditions in allergic inflammation. Identifying strategies to inhibit IL-5 production is important in order to establish new therapies for treating allergic inflammation. We found that SH-2251, a novel thioamide-related small compound, selectively inhibits the differentiation of IL-5-producing Th2 cells. SH-2251 inhibited the induction of active histone marks at the Il5 gene locus during Th2 cell differentiation. The recruitment of RNA polymerase II, and following expression of the Th2 cell-specific intergenic transcripts around the Il5 gene locus was also inhibited. Furthermore, Th2 cell-dependent airway inflammation in mice was suppressed by the oral administration of SH-2251. Gfi1, a transcriptional repressor, was identified as a downstream target molecule of SH-2251 using a DNA microarray analysis. The Gfi1 expression dramatically decreased in SH-2251-treated Th2 cells, and the SH-2251-mediated inhibition of IL-5-producing Th2 cell differentiation was restored by transduction of Gfi1. Therefore, our study unearthed SH-2251 as a novel therapeutic candidate for allergic inflammation that selectively inhibits active histone marks at the Il5 gene locus.
authors.affiliation: Department of Pharmacogenomics, Graduate School of Pharmaceutical Science, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Junpei
authors.initials: J
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuwahara
authors.forename: Soichi
authors.initials: S
authors.lastname: Tofukuji
authors.forename: Masashi
authors.initials: M
authors.lastname: Imamura
authors.forename: Fuminori
authors.initials: F
authors.lastname: Kato
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D007249:Inflammation / Q000188:drug therapy*; D015848:Interleukin-5 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012130:Respiratory Hypersensitivity / Q000188:drug therapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D002843:Chromatin; D015848:Interleukin-5