title: Tissue Non-specific Alkaline Phosphatase Expression is Needed for the Full Stimulation of T Cells and T Cell-Dependent Colitis.
abstract: OBJECTIVE
  Two alkaline phosphatase isoforms, intestinal [IAP] and tissue non-specific alkaline phosphatase [TNAP], are coexpressed in mouse colon, with the latter predominating in colitis. We aimed to examine the role of TNAP in T lymphocytes, using heterozygous TNAP+/- mice [as TNAP-/- mice are non-viable].
  
  
  METHODS
  In vitro primary cultures and in vivo T cell models using TNAP+/- mice were used.
  
  
  RESULTS
  Stimulated splenocytes [lipopolysaccharide and concanavalin A] and T lymphocytes [concanavalin A and a-CD3/a-CD28] showed a decreased cytokine production and expression when compared with wild-type [WT] cells. Decreased T cell activation was reproduced by the TNAP inhibitors levamisole, theophylline, and phenylalanine in WT cells. Intraperitoneal administration of anti-CD3 in vivo resulted in reduced plasma cytokine levels, and decreased activation of splenocytes and T cells ex vivo in TNAP+/- mice. We further tested the hypothesis that TNAP expressed in T lymphocytes is involved in T cell activation and inflammation, using the lymphocyte transfer model of colitis. Rag1-/- mice were transferred with T naïve cells [CD4+ CD62L+] from TNAP+/- or WT mice and developed colitis, which was attenuated in the group receiving TNAP+/- cells. Compared with WT, T cells from TNAP+/- mice showed a decreased capacity for proliferation, with no change in differentiation.
  
  
  CONCLUSIONS
  Our results offer clear evidence that TNAP modulates T lymphocyte function and specifically T cell-dependent colitis. This was associated with distinct changes in the type of TNAP expressed, probably because of changes in glycosylation.
authors.affiliation: Department of Biochemistry and Molecular Biology II, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Hernández-Chirlaque
authors.affiliation: Department of Pharmacology, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Reyes
authors.initials: R
authors.lastname: Gámez-Belmonte
authors.affiliation: Department of Pharmacology, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Ocón
authors.affiliation: Department of Biochemistry and Molecular Biology II, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martínez-Moya
authors.affiliation: Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.affiliation: Department of Pharmacology, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Fermín
authors.initials: F
authors.lastname: Sánchez de Medina
authors.affiliation: Department of Biochemistry and Molecular Biology II, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Martínez-Augustin
mesh_terms: D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D003092:Colitis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D007978:Levamisole / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010649:Phenylalanine / Q000494:pharmacology; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D012333:RNA, Messenger; C064658:RAG-1 protein; D007978:Levamisole; D010649:Phenylalanine; D013806:Theophylline; C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase
keywords: Alkaline phosphatase; Rag1-/-; T cells; anti-CD3; colitis