Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans

Wei Ching Huang, Jie Liang, Masayuki Nagahashi, Dorit Avni, Akimitsu Yamada, Michael Maceyka, Aaron Wolen, Tomasz Kordula, Sheldon Milstien, Kazuaki Takabe, Tamas Oravecz, Sarah Spiegel

Research output: Contribution to journalArticle

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Abstract

The bioactive sphingolipid sphingosine-1-phosphate (S1P) and the kinase that produces it have been im plicated in inflammatory bowel diseases in mice and humans; however, little is known about the role of the 2S1P-specific phosphohy drolase 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-nullmice failed tomount aDSS-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.

Original languageEnglish (US)
Pages (from-to)2945-2958
Number of pages14
JournalFASEB Journal
Volume30
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Dextran Sulfate
Colitis
Ulcerative Colitis
Tissue
STAT3 Transcription Factor
Sphingolipids
Sphingosine
Cadherins
Interleukin-1
Inflammatory Bowel Diseases
Infiltration
Interleukin-6
Protein Isoforms
Transcription Factors
Phosphotransferases
Chemical activation
Cells
Apoptosis
Cytokines
Adherens Junctions

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans. / Huang, Wei Ching; Liang, Jie; Nagahashi, Masayuki; Avni, Dorit; Yamada, Akimitsu; Maceyka, Michael; Wolen, Aaron; Kordula, Tomasz; Milstien, Sheldon; Takabe, Kazuaki; Oravecz, Tamas; Spiegel, Sarah.

In: FASEB Journal, Vol. 30, No. 8, 01.08.2016, p. 2945-2958.

Research output: Contribution to journalArticle

Huang, WC, Liang, J, Nagahashi, M, Avni, D, Yamada, A, Maceyka, M, Wolen, A, Kordula, T, Milstien, S, Takabe, K, Oravecz, T & Spiegel, S 2016, 'Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans', FASEB Journal, vol. 30, no. 8, pp. 2945-2958. https://doi.org/10.1096/fj.201600394R
Huang, Wei Ching ; Liang, Jie ; Nagahashi, Masayuki ; Avni, Dorit ; Yamada, Akimitsu ; Maceyka, Michael ; Wolen, Aaron ; Kordula, Tomasz ; Milstien, Sheldon ; Takabe, Kazuaki ; Oravecz, Tamas ; Spiegel, Sarah. / Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans. In: FASEB Journal. 2016 ; Vol. 30, No. 8. pp. 2945-2958.
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