Hye Ryung Kim

Abstract C38: Immunosuppression by indoleamine 2,3‐dioxygenase in mesenchymal stem cells derived from adult human tissues

Mesenchymal stem cells (MSCs), which evoke only minimal immune reactivity, may have anti‐inflammatory and immunomodulatory effects. In this study, we conducted a comparative analysis of the immunomodulatory properties of MSCs derived from adult human tissues including bone marrow (BM), adipose tissues (AT), umbilical cord blood (CB), and cord Wharton9s jelly (WJ). Using a multiple cytokine detection assay, we showed that there were no significant differences in levels of secreted factors from non‐stimulated MSCs. We compared the immunosuppressive effect of BM‐MSCs, AT‐MSCs, CB‐MSCs, and WJ‐MSCs on phytohemagglutinin (PHA)‐induced T‐cell proliferation. AT‐MSCs, CB‐MSCs, and WJ‐MSCs effectively suppressed PHA‐induced T‐cell proliferation as effectively as did BM‐MSCs. Levels of interferon (IFN)‐γ secreted from activated T‐cells increased over time, but these levels were significantly reduced when cocultured with each type of MSCs. In addition, the expression of hepatocyte growth factor, interleukin‐10, transforming growth factor‐β1, cyclooxygenase (COX)‐1, and COX‐2 were unchanged in MSCs treated with IFN‐γ, while that of indoleamine 2,3‐dioxygenase (IDO) increased. Use of an antagonist, 1‐methyl‐L‐tryptophan, restored T‐cell proliferation and confirmed an IDO contribution to IFN‐γ‐induced immunosuppression by MSCs. Addition of tryptophan catabolite, such as kynurenine, 3‐hydroxykynurenine, or quinolinic acid, significantly decreased PHA‐induced T‐cell proliferation. These data indicate that IFN‐γ produced by activated T‐cells were correlated with induction of IDO expression by MSCs, which, in turn, suppressed T‐cell proliferation through tryptophan depletion and the local accumulation of tryptophan catabolites. Our findings suggest that MSCs derived from AT, CB, or WJ could be substituted for BM‐MSCs for treatment of allogeneic conflicts. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C38.

Abstract A150: Ciglitazone, PPAR agonist, induces cell death independent of peroxisome proliferator‐activated receptor γ (PPARγ) in glioma

Ciglitazone (CGZ), peroxisome proliferator‐activated receptor γ (PPARγ) agonist, is recognized to regulate multiple signal pathways and induce apoptosis in various cancer cells. CGZ induces apoptotic cell death through binding to PPARγ, but interdependence between CGZ and PPARγ is not clear. In this study, over 30 eM CGZ observed significant cytotoxicity in T98G cell line, but not below 25 µM. Cotreatment with 20 µM CGZ and 30 µM GW9662, an antagonist of PPARγ, synergistically induced apoptotic cell death. However, treatment with 30 µM GW9662 not significantly induced cell death and cell‐cycle arrest on T98G cells pre‐treated with 20 µM CGZ. These results indicate that CGZ may induce cell death independent of PPARγ in T98G cells. In addition, only treatment with 20 µM CGZ in T98G cells induced the activation of Akt. However, cotreatment with 20 µM CGZ and 30 µM GW9662 gradually decreased the activation of Akt. These data indicate that CGZ enhance the antiapoptotic effects by PPARγ binding, while free CGZ on cotreatment with GW9662 PPARγ‐independently activates cell death signaling pathway through Akt inactivation. We suggest that combination of CGZ and GW9662 could be therapeutic application for the treatment of glioma. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A150.