title: Human follicular dendritic cells interact with T cells via expression and regulation of cyclooxygenases and prostaglandin E and I synthases.
abstract: PGE(2) 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 PGE(2) and PGI(2) 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-alpha, TGF-beta, 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 PGE(2) and PGI(2). Interestingly, IL-4 almost completely abrogated the stimulatory activity of TNF-alpha, TGF-beta, and LPS in PG production. Furthermore, the up-regulation of PGE(2) and PGI(2) production was markedly down-regulated by indomethacin and a selective COX-2 inhibitor. PGI(2) analog and PGE(2) 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 PGE(2) and PGI(2) production, suggesting an important implication for development and use of anti-inflammatory drugs.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, Kangwon National University, Chunchon, Korea.
authors.forename: In Yong
authors.initials: IY
authors.lastname: Lee
authors.forename: Whajung
authors.initials: W
authors.lastname: Cho
authors.forename: Jini
authors.initials: J
authors.lastname: Kim
authors.forename: Chan-Sik
authors.initials: CS
authors.lastname: Park
authors.forename: Jongseon
authors.initials: J
authors.lastname: Choe
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D018920:Coculture Techniques; D051546:Cyclooxygenase 2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D020566:Dendritic Cells, Follicular / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D065607:Cytochrome P-450 Enzyme Inhibitors; D018793:Interleukin-13; D015847:Interleukin-4; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C022461:prostacyclin synthetase; D015232:Dinoprostone; D007213:Indomethacin