title: Selective sequestration of STAT1 in the cytoplasm via phosphorylated SHP-2 ameliorates murine experimental colitis.
abstract: The side effects of current immunosuppressive drugs have impeded the development of therapies for immune diseases. Selective regulation of STAT signaling is an attractive strategy for treating immune disorders. In this study, we used a small-molecule compound to explore possible means of targeting STAT1 for the treatment of Th1-mediated inflammation. Selective regulation of STAT1 signaling in T cells from C57BL/6 mice was accomplished using fusaruside, a small-molecule compound that triggers the tyrosine phosphorylation of Src homology 2-containing protein tyrosine phosphatase 2 (SHP-2). The interaction of tyrosine phosphorylated SHP-2 (pY-SHP-2) with cytosolic STAT1 prevented the recruitment of STAT1 to IFN-γR and specifically inhibited STAT1 signaling, resulting in a reduction in Th1 cytokine production and an improvement in 2, 4, 6-trinitrobenzene sulfonic acid-induced colitis in mice. Blocking the pY-SHP-2-STAT1 interaction, with SHP-2 inhibitor NSC-87877 or using T cells from conditional SHP-2 knockout mice, reversed the effects of fusaruside, resulting in STAT1 activation and worsened colitis. The fusaruside-induced ability of pY-SHP-2 to selectively sequestrate STAT1 from recruitment to the receptor is independent of its function as a phosphatase, demonstrating a novel role for SHP-2 in regulating both STAT1 signaling and Th1-type immune responses. These findings could lead to increased options for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Xingxin
authors.initials: X
authors.lastname: Wu
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.forename: Limei
authors.initials: L
authors.lastname: Wu
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
authors.forename: Liyun
authors.initials: L
authors.lastname: Gu
authors.forename: Suhai
authors.initials: S
authors.lastname: Xu
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Ke
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002554:Cerebrosides / Q000378:metabolism / Q000502:physiology; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D003600:Cytosol / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D005670:Fusarium / Q000737:chemistry; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D002554:Cerebrosides; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse