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* Department of Microbiology and Immunology, College of Medicine,
Vascular System Research Center, and
Research Institute of Life Sciences, Kangwon National University, Chunchon, Korea; and
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
PGE2 inhibits mature T cell proliferation and protects T cells from activation-induced cell death (AICD). We have previously demonstrated that human follicular dendritic cells (FDC) strongly express PGI synthase. In this study, the hypothesis that FDC have regulatory roles on germinal center T cells by controlling production of PGE2 and PGI2 was tested. Confocal microscopic analyses of human tonsil tissues revealed that FDC indeed expressed PGE synthase in addition to PGIS. To confirm these results, we studied the regulation mechanism of PG production in FDC, using an established human FDC-like cell line, HK. Specifically in response to TNF-
, TGF-β, and LPS, protein expression of cyclooxygenase (COX)-2 and downstream PGE synthase was up-regulated with coordinate kinetics, whereas COX-1 and PGIS were constitutively expressed. The increase of these enzymes was reflected in actual production of PGE2 and PGI2. Interestingly, IL-4 almost completely abrogated the stimulatory activity of TNF-, TGF-β, and LPS in PG production. Furthermore, the up-regulation of PGE2 and PGI2 production was markedly down-regulated by indomethacin and a selective COX-2 inhibitor. PGI2 analog and PGE2 inhibited proliferation and AICD of T cells in dose- and time-dependent manners. Finally, coculture experiments revealed that HK cells indeed inhibit proliferation and AICD of T cells. Put together, these results show an unrecognized pathway of FDC and T cell interactions and differential mechanisms for PGE2 and PGI2 production, suggesting an important implication for development and use of anti-inflammatory drugs.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Korea Research Foundation grant funded by the Korean government (Ministry of Education and Human Resources Development, Basic Research Promotion Fund) (KRF-2005-041-E00123) and the Vascular System Research Center grant from the Korea Science and Engineering Foundation.
2 Current address: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602.
3 Address correspondence and reprint requests to Dr. Jongseon Choe, Department of Microbiology and Immunology, Kangwon National University College of Medicine, Chunchon, Kangwon 200-701, Republic of Korea. E-mail address: jchoe{at}kangwon.ac.kr
4 Abbreviations used in this paper: FDC, follicular dendritic cell; AICD, activation-induced cell death; COX, cyclooxygenase; GC, germinal center; mPGES-1, microsomal PGE synthase-1; PGES, PGE synthase; PGIS, PGI synthase; PI, propidium iodide; TXB2, thromboxane B2.
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