title: Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors.
abstract: The vitamin A metabolite, retinoic acid (RA), affects Th1 and Th2 development. The effect is partly exerted through the modulation of antigen-presenting cell functions, but it remains unclear whether RA directly exerts its effect on T cells to influence Th1/Th2 development. To clarify this problem, we used two experimental systems with isolated T cells in vitro. In one system, isolated CD4+CD8+ thymocytes differentiated into Th1 and Th2 by two transient stimulations with defined combinations of ionomycin and phorbol myristate acetate followed by treatment with IL-2 and IL-4 and/or IL-12. In the second system, functional differentiation was induced in purified naive CD4 T cells from DO-11.10 TCR-transgenic and RAG-2-deficient mice with cytokines and antibodies to CD3 and CD28. In both systems, all-trans-RA at > or = 1 nM concentrations suppressed Th1 development, but enhanced Th2 development. 9-cis-RA elicited similar effects. The optimal enhancement of Th2 development in the second system, however, was achieved with a delayed addition of RA. The presence of RA during the initial stimulation period often suppressed Th2 development. The RA receptor (RAR) antagonists, LE540 and LE135, but not the retinoic X receptor (RXR) antagonist, PA452, inhibited the effect of RA on Th1/Th2 development. Accordingly, the RAR agonists, Am80 and Tp80, but not the RXR agonists, HX600 and TZ335, mimicked the effect of RA. The RXR agonists enhanced the effect of the RAR agonists only slightly, if at all. These results indicate that, via RAR, RA directly suppresses Th1 development and directly enhances Th2 development with its timely addition.
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida-shi, Tokyo 194-8511, Japan. iwata@libra.Is.m-kagaku.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Iwata
authors.forename: Yuko
authors.initials: Y
authors.lastname: Eshima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation / Q000187:drug effects; D006649:Histocompatibility Antigens / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D015848:Interleukin-5 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051257:Proto-Oncogene Proteins c-maf; D018123:Receptors, Interleukin / Q000235:genetics; D053707:Receptors, Interleukin-12; D019948:Receptors, Interleukin-4 / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors; D047488:Retinoid X Receptors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*; D014801:Vitamin A / Q000494:pharmacology; D000098815:T-bet Transcription Factor
chemical_list: D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006649:Histocompatibility Antigens; D007376:Interleukin-2; D015848:Interleukin-5; C495608:Maf protein, mouse; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; C499308:Rag2 protein, mouse; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D019948:Receptors, Interleukin-4; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; C064655:V(D)J recombination activating protein 2; D014801:Vitamin A; D016753:Interleukin-10; D018664:Interleukin-12; D000077556:Alitretinoin; D015847:Interleukin-4; D014212:Tretinoin; D007371:Interferon-gamma