title: Human adipose tissue-derived mesenchymal stem cells facilitate the immunosuppressive effect of cyclosporin A on T lymphocytes through Jagged-1-mediated inhibition of NF-κB signaling.
abstract: OBJECTIVE
  Cyclosporine A (CsA), known as an effective immunosuppressive agent, is widely used in clinical fields. Mesenchymal stem cells may exert immunomodulatory effects on the immune system, but the exact mechanisms underlying them remain controversial. Here we investigated whether human adipose tissue-derived mesenchymal stem cells (AMSCs) facilitate in vitro the immunomodulatory effects of CsA and we explored the molecule mechanisms that may be involved.
  
  
  METHODS
  Proliferation of T lymphocytes was measured by uptake of (3)H-thymidine. Transcription and production of interleukin-2 and interferon-γ were evaluated by real-time quantitative polymerase chain reaction, reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay. Nuclear factor-κB (NF-κB) was assayed by Western blotting and electrophoretic mobility shift assay. Expression of Jagged-1, Jagged-2, and Delta-1 of AMSCs were surveyed by flow cytometric analysis and Western blotting.
  
  
  RESULTS
  The combination of moderate-dose AMSCs and low-dose CsA was significantly more powerful than moderate-dose AMSCs or large-dose CsA alone in suppressing transcription and production of interleukin-2 and interferon-γ, activation of NF-κB, and proliferation of T lymphocytes. In addition, AMSCs expressed a high level of Jagged-1, which induced activation of Notch signaling in T lymphocytes, thus reducing NF-κB activity. Anti-Jagged-1 neutralizing antibody and N [N-(3, 5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester could reverse this trend.
  
  
  CONCLUSIONS
  Human AMSCs facilitate the immunosuppressive effect of CsA on T lymphocytes through Jagged-1/Notch-related inhibition of NF-κB signaling. The combination of AMSCs and CsA represents a rationale therapeutic approach aimed to prevent adverse effects of CsA while maintaining its adequate immunosuppressive effect. Expression of Jagged-1 on AMSCs may provide an effective mechanism for the immunomodulatory activity of AMSCs via direct cell-cell interaction.
authors.affiliation: Institute of Basic Medical Sciences and School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Shi
authors.forename: Lianming
authors.initials: L
authors.lastname: Liao
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Dou
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Xishan
authors.initials: X
authors.lastname: Zhu
authors.forename: Limei
authors.initials: L
authors.lastname: Yu
authors.forename: Daixiong
authors.initials: D
authors.lastname: Chen
authors.forename: Robert C H
authors.initials: RC
authors.lastname: Zhao
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D011485:Protein Binding; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D016328:NF-kappa B; D000072099:Serrate-Jagged Proteins; D016572:Cyclosporine