title: Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans.
abstract: The bioactive sphingolipid sphingosine-1-phosphate (S1P) and the kinase that produces it have been implicated in inflammatory bowel diseases in mice and humans; however, little is known about the role of the 2 S1P-specific phosphohydrolase isoforms, SGPP1 and SGPP2, which catalyze dephosphorylation of S1P to sphingosine. To elucidate their functions, we generated specific knockout mice. Deletion of Sgpp2, which is mainly expressed in the gastrointestinal tract, significantly reduced dextran sodium sulfate (DSS)-induced colitis severity, whereas deletion of ubiquitously expressed Sgpp1 slightly worsened colitis. Moreover, Sgpp1 deletion enhanced expression of multifunctional proinflammatory cytokines, IL-6, TNF-α, and IL-1β, activation of the transcription factor signal transducer and activator of transcription 3, and immune cell infiltration into the colon. Conversely, Sgpp2-null mice failed to mount a DSS-induced systemic inflammatory response. Of interest, Sgpp2 deficiency suppressed DSS-induced intestinal epithelial cell apoptosis and improved mucosal barrier integrity. Furthermore, down-regulation of Sgpp2 attenuated LPS-induced paracellular permeability in cultured cells and enhanced expression of the adherens junction protein E-cadherin. Finally, in patients with ulcerative colitis, SGPP2 expression was elevated in colitis tissues relative to that in uninvolved tissues. These results indicate that induction of SGPP2 expression contributes to the pathogenesis of colitis by promoting disruption of the mucosal barrier function. SGPP2 may represent a novel therapeutic target in inflammatory bowel disease.-Huang, W.-C., Liang, J., Nagahashi, M., Avni, D., Yamada, A., Maceyka, M., Wolen, A. R., Kordula, T., Milstien, S., Takabe, K., Oravecz, T., Spiegel, S. Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA;
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA;
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA;
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA;
authors.forename: Dorit
authors.initials: D
authors.lastname: Avni
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA;
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA;
authors.forename: Michael
authors.initials: M
authors.lastname: Maceyka
authors.affiliation: Center for Clinical and Translational Research, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA;
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Wolen
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA;
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kordula
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA;
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA;
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
authors.affiliation: Lexicon Pharmaceuticals, The Woodlands, Texas, USA.
authors.forename: Tamas
authors.initials: T
authors.lastname: Oravecz
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine and the Massey Cancer Center, Richmond, Virginia, USA; sarah.spiegel@vcuhelath.org.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
mesh_terms: D000818:Animals; D015820:Cadherins; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate / Q000633:toxicity; D015536:Down-Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016264:Dextran Sulfate; C498527:SGPP1 protein, human; C498526:SGPP2 protein, human; D010744:Phosphoric Monoester Hydrolases; C000612430:Sgpp2 protein, mouse
keywords: S1P; SGPP1; SGPP2; inflammatory bowel disease