Vitamin A enhances in vitro Th2 development via retinoid X receptor pathway.
Vitamin A deficiency diminishes Th2-mediated Ab responses, and high-level dietary vitamin A or treatment with the vitamin A metabolite retinoic acid (RA) enhances such responses. To identify a potential mechanism(s) underlying this in vivo activity of vitamin A, we examined the effects of all-trans and 9-cis RA on development of Th1 and Th2 cell populations using in vitro stimulation of Ag-naive Th0 cells from the DO11.10 TCR-transgenic mouse. Treatment with 9-cis, but not with all-trans RA, at primary stimulation strongly enhanced Th2 development. IL-4-neutralizing Ab blocked this activity, but IL-12- and IFN-gamma-neutralizing Ab did not. Because 9-cis RA regulates gene transcription via either RA receptors or retinoid X receptors (RXRs), we tested the Th2-enhancing activities of the RXR- and RA receptor-selective agonists AGN194204 and 4-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid (TTNPB). AGN194204 strongly enhanced Th2 development, whereas TTNPB did not. This RXR agonist also enhanced Th2 development when purified, naive Th0 cells (L-selectin(high)/CD4(+)) were stimulated with CD3 and CD28 Abs in the absence of APCs. During primary antigenic stimulation of naive Th0 cells from DO11.10 mice, AGN194204 increased IL-4 and IL-5 production, decreased IFN-gamma production, increased mRNA in responding T cells for genes involved in Th2 development (IL-4, GATA-3, and c-maf), and decreased mRNA for genes involved in Th1 development (IFN-gamma, T-bet, and IL-12R). These data show that stimulation of the RXR pathway enhances Th2 development, perhaps by affecting the relative expression of pertinent transcription factors, cytokines, and cytokine receptors.
Stephensen
Charles B
CB
U.S. Department of Agriculture Western Human Nutrition Research Center and Nutrition Department, University of California, Davis, CA 95616, USA. cstephenson@ucdavis.edu
Rasooly
Reuven
R
Jiang
Xiaowen
X
Ceddia
Michael A
MA
Weaver
Casey T
CT
Chandraratna
Roshantha A S
RA
Bucy
R Patterson
RP
D000077556:Alitretinoin; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000502:physiology; D015847:Interleukin-4 / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism*; D047488:Retinoid X Receptors; D015398:Signal Transduction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000494:pharmacology*
C430898:AGN 194204; D016207:Cytokines; D005231:Fatty Acids, Unsaturated; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D014801:Vitamin A; D018664:Interleukin-12; D000077556:Alitretinoin; D015847:Interleukin-4; D014212:Tretinoin