The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Akasaki, Y.
Right arrow Articles by Yu, J. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Akasaki, Y.
Right arrow Articles by Yu, J. S.
The Journal of Immunology, 2004, 173: 4352-4359.
Copyright © 2004 by The American Association of Immunologists

Induction of a CD4+ T Regulatory Type 1 Response by Cyclooxygenase-2-Overexpressing Glioma1

Yasuharu Akasaki, Gentao Liu, Nancy H. C. Chung, Moneeb Ehtesham, Keith L. Black and John S. Yu2

Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048

PGE2, synthesized by cyclooxygenase-2 (COX-2)-overexpressing tumor, is known to contribute to cellular immune suppression in cancer patients, but the mechanism remains unclear. We report the mechanism of a CD4+ T regulatory type 1 (Tr1) induction by CD11c+ mature dendritic cells (DCs) that phagocytose allogeneic and autologous COX-2-overexpressing glioma. A human glioma cell line, U-87MG, and primary cultured glioblastoma cells (MG-377) overexpressed COX-2. We did not detect IL-10R{alpha} expression in these gliomas, and rIL-10 did not suppress their COX-2 expression. Exposure to COX-2-overexpressing glioma induced mature DCs to overexpress IL-10 and decreased IL-12p70 production. These DCs induced a Tr1 response, which is characterized by robust secretion of IL-10 and TGF-{beta} with negligible IL-4 secretion by CD4+ T cells, and an inhibitory effect on admixed lymphocytes. Peripheral CD4+ T cell populations isolated from an MG-377 patient also predominantly demonstrated a Tr1 response against MG-377 cells. Selective COX-2 inhibition in COX-2-overexpressing gliomas at the time of phagocytic uptake by DCs abrogated this regulatory response and instead elicited Th1 activity. COX-2 stable transfectants in LN-18 (LN-18-COX2) also induced a Tr1 response. The effect of a COX-2 inhibition in LN-18-COX2 is reversible after administration of PGE2. Taken together, robust levels of PGE2 from COX-2-overexpressing glioma, which is unresponsive to IL-10 within the local microenvironment, may cause DCs to secrete high levels of IL-10. These results indicate that COX-2-overexpressing tumors induce a Tr1 response, which is mediated by tumor-exposed, IL-10-enhanced DCs.




This article has been cited by other articles:


Home page
 Cancer Res.Home page
M. Ahmadi, D. C. Emery, and D. J. Morgan
Prevention of Both Direct and Cross-Priming of Antitumor CD8+ T-Cell Responses following Overproduction of Prostaglandin E2 by Tumor Cells In vivo
Cancer Res., September 15, 2008; 68(18): 7520 - 7529.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. Bergmann, L. Strauss, R. Zeidler, S. Lang, and T. L. Whiteside
Expansion of Human T Regulatory Type 1 Cells in the Microenvironment of Cyclooxygenase 2 Overexpressing Head and Neck Squamous Cell Carcinoma
Cancer Res., September 15, 2007; 67(18): 8865 - 8873.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
Q. Ding, L. Lu, B. Wang, Y. Zhou, Y. Jiang, X. Zhou, L. Xin, Z. Jiao, and K.-Y. Chou
B7H1-Ig Fusion Protein Activates the CD4+ IFN-{gamma} Receptor+ Type 1 T Regulatory Subset through IFN-{gamma}-Secreting Th1 Cells
J. Immunol., September 15, 2006; 177(6): 3606 - 3614.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
G. Lizee, L. G. Radvanyi, W. W. Overwijk, and P. Hwu
Improving Antitumor Immune Responses by Circumventing Immunoregulatory Cells and Mechanisms.
Clin. Cancer Res., August 15, 2006; 12(16): 4794 - 4803.
[Abstract] [Full Text] [PDF]

Home page
 Neuro OncolHome page
S. F. Hussain, D. Yang, D. Suki, K. Aldape, E. Grimm, and A. B. Heimberger
The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses
Neuro-oncol, July 1, 2006; 8(3): 261 - 279.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Mahic, S. Yaqub, C. C. Johansson, K. Tasken, and E. M. Aandahl
FOXP3+CD4+CD25+ Adaptive Regulatory T Cells Express Cyclooxygenase-2 and Suppress Effector T Cells by a Prostaglandin E2-Dependent Mechanism
J. Immunol., July 1, 2006; 177(1): 246 - 254.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. S. von Bergwelt-Baildon, A. Popov, T. Saric, J. Chemnitz, S. Classen, M. S. Stoffel, F. Fiore, U. Roth, M. Beyer, S. Debey, et al.
CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition
Blood, July 1, 2006; 108(1): 228 - 237.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Akasaki, G. Liu, H. H. Matundan, H. Ng, X. Yuan, Z. Zeng, K. L. Black, and J. S. Yu
A Peroxisome Proliferator-activated Receptor-{gamma} Agonist, Troglitazone, Facilitates Caspase-8 and -9 Activities by Increasing the Enzymatic Activity of Protein-tyrosine Phosphatase-1B on Human Glioma Cells
J. Biol. Chem., March 10, 2006; 281(10): 6165 - 6174.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Website Copyright © 2004 by The American Association of Immunologists, Inc. All rights reserved.
All Contents Copyright © 2004 by The American Association of Immunologists, Inc. All rights reserved.