title: Retinoid x receptor agonists increase bcl2a1 expression and decrease apoptosis of naive T lymphocytes.
abstract: Vitamin A affects many aspects of T lymphocyte development and function. The vitamin A metabolites all-trans- and 9-cis-retinoic acid regulate gene expression by binding to the retinoic acid receptor (RAR), while 9-cis-retinoic acid also binds to the retinoid X receptor (RXR). Naive DO11.10 T lymphocytes expressed mRNA and protein for RAR-alpha, RXR-alpha, and RXR-beta. DNA microarray analysis was used to identify RXR-responsive genes in naive DO11.10 T lymphocytes treated with the RXR agonist AGN194204. A total of 128 genes was differentially expressed, including 16 (15%) involved in cell growth or apoptosis. Among these was Bcl2a1, an antiapoptotic Bcl2 family member. Quantitative real-time PCR analysis confirmed this finding and demonstrated that Bcl2a1 mRNA expression was significantly greater in nonapoptotic than in apoptotic T lymphocytes. The RXR agonist 9-cis-retinoic acid also increased Bcl2a1 expression, although all-trans-retinoic acid and ligands for other RXR partner receptors did not. Treatment with AGN194204 and 9-cis-retinoic acid significantly decreased apoptosis measured by annexin V staining but did not affect expression of Bcl2 and Bcl-xL. Bcl2a1 promoter activity was examined using a luciferase promoter construct. Both AGN194204 and 9-cis-retinoic acid significantly increased luciferase activity. In summary, these data demonstrate that RXR agonists increase Bcl2a1 promoter activity and increase expression of Bcl2a1 in naive T lymphocytes but do not affect Bcl2 and Bcl-xL expression in naive T lymphocytes. Thus, this effect on Bcl2a1 expression may account for the decreased apoptosis seen in naive T lymphocytes treated with RXR agonists.
authors.affiliation: U.S. Department of Agriculture (USDA) Western Human Nutrition Research Center and Nutrition Department, University of California, Davis, CA, 95616, USA.
authors.forename: Reuven
authors.initials: R
authors.lastname: Rasooly
authors.forename: Gertrud U
authors.initials: GU
authors.lastname: Schuster
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Gregg
authors.forename: Jia-Hao
authors.initials: JH
authors.lastname: Xiao
authors.forename: Roshantha A S
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: Charles B
authors.initials: CB
authors.lastname: Stephensen
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D047488:Retinoid X Receptors / Q000819:agonists*; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics
chemical_list: C430898:AGN 194204; C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; D005231:Fatty Acids, Unsaturated; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D051020:bcl-X Protein; D000077556:Alitretinoin; D014212:Tretinoin