title: Phosphatase Wip1 Masters IL-17-producing Neutrophil-mediated Colitis in Mice.
abstract: Wild-type p53-induced phosphatase 1 (Wip1) is currently believed to be a promising drug target for cancer therapy. Our recent studies showed that deletion of Wip1 remarkably promoted neutrophil inflammatory response. Whether Wip1 is involved in the regulation of inflammatory bowel disease is unknown. In the present study, we found that Wip1 knockout (KO) mice were more susceptible to colitis induced by dextran sulphate sodium (DSS) than wild-type mice as substantiated by the lower mouse survival ratio, rapid bodyweight loss, increased disease activity index, shorter colon length, and more severe pathology of colons in Wip1KO mice. Using full bone marrow chimera mouse models, we demonstrated that Wip1 intrinsically controls inflammatory response of immune cells. Deletion of IL-17 (Wip1/IL-17 double KO mice) significantly rescued the pathology in Wip1KO mice. Neutrophils of DSS-treated wild-type and Wip1KO mice expressed significantly higher IL-17. After adoptive transfer of sorted Wip1KO or double KO neutrophils into IL-17KO mice, mice receiving double KO neutrophils were more resistant to DSS-induced colitis than mice receiving Wip1KO neutrophils. These data collectively indicate that Wip1 modulates host sensitivity to colitis by intrinsically regulating immune cells. The enhanced IL-17 expression in neutrophils contributed to the increased sensitivity and severity of colitis in Wip1KO mice. Thus, Wip1 may be used as a drug target to treat colitis.
authors.affiliation: *State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; †Department of General Surgery, General Hospital of Beijing Military Command, Beijing, China; and ‡Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Hu
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Junfeng
authors.initials: J
authors.lastname: Du
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Shen
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics; D054426:Chemokine CXCL2 / Q000235:genetics; D003092:Colitis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D020022:Genetic Predisposition to Disease; D018664:Interleukin-12 / Q000235:genetics; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D000071636:Protein Phosphatase 2C / Q000235:genetics* / Q000276:immunology*; D012313:RNA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D018664:Interleukin-12; D012313:RNA; D016264:Dextran Sulfate; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C