The Retinoic Acid Receptor-alpha mediates human T-cell activation and Th2 cytokine and chemokine production.
BACKGROUND
We have recently demonstrated that all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cis RA) promote IL-4, IL-5 and IL-13 synthesis, while decreasing IFN-gamma and TNF-alpha expression by activated human T cells and reduces the synthesis of IL-12p70 from accessory cells. Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-alpha (RAR-alpha)-selective agonist, AM580 but not with the RAR-beta/gamma ligand, 4-hydroxyphenylretinamide (4-HPR).


RESULTS
The increase in type 2 cytokine production by these retinoids correlated with the expression of the T cell activation markers, CD69 and CD38. The RAR-alpha-selective agonist, AM580 recapitulated all of the T cell activation and type 2 cytokine-inducing effects of ATRA and 9-cis-RA, while the RAR-alpha-selective antagonist, RO 41-5253, inhibited these effects.


CONCLUSIONS
These results strongly support a role for RAR-alpha engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production.
Dawson
Harry D
HD
Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, NIH, Baltimore, MD 21224, USA. harry.dawson@ars.usda.gov
Collins
Gary
G
Pyle
Robert
R
Key
Michael
M
Taub
Dennis D
DD
D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D002454:Cell Differentiation / Q000276:immunology; D002839:Chromans / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D003879:Dermatologic Agents / Q000494:pharmacology; D017313:Fenretinide / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014212:Tretinoin / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D001565:Benzoates; D002839:Chromans; D016207:Cytokines; D003879:Dermatologic Agents; D017313:Fenretinide; D037181:Lectins, C-Type; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes; D014212:Tretinoin; D000099192:CD69 Antigens; C000607071:RARA protein, human; C068073:Am 580; C084904:Ro 41-5253