title: Activation-induced apoptosis and cell surface expression of Fas (CD95) ligand are reciprocally regulated by retinoic acid receptor alpha and gamma and involve nur77 in T cells.
abstract: It has been previously shown that CD4+ T cells enter the apoptotic suicide program via the Fas ligand (FasL)/Fas-mediated pathway upon T cell receptor (TCR) stimulation. In Jurkat cells TCR stimulation regulates the de novo synthesis of FasL, while in the influenza hemagglutinin-specific CD4+ murine T cell hybridoma (IP-12-7) the cell surface appearance of a preformed FasL is initiated. Both processes are dependent on new mRNA and protein synthesis, involve up-regulation of nur77, and can be inhibited by retinoic acids (RA). Two groups of nuclear receptors for RA have been identified: retinoic acid receptors (RAR) and retinoid X receptors (RXR). In this study various synthetic retinoids were used to define which receptors regulate TCR-mediated apoptosis. It is demonstrated that the inhibition is mediated via RARalpha, while RARgamma enhances TCR-mediated apoptosis, and when both receptors are stimulated, the costimulation by RXR will promote the effect of RARalpha. Evidence is presented that these receptors affect the transcriptional activity of nur77 and consequently the expression of FasL. Our data suggest a complex interaction between the various isoforms of retinoid receptors in regulating T cell death and demonstrate that the target through which retinoids regulate TCR-mediated apoptosis is nur77.
authors.affiliation: Department of Biochemistry, University Medical School of Debrecen, Hungary.
authors.forename: R
authors.initials: R
authors.lastname: Tóth
authors.forename: E
authors.initials: E
authors.lastname: Szegezdi
authors.forename: U
authors.initials: U
authors.lastname: Reichert
authors.forename: J M
authors.initials: JM
authors.lastname: Bernardon
authors.forename: S
authors.initials: S
authors.lastname: Michel
authors.forename: P
authors.initials: P
authors.lastname: Ancian
authors.forename: K
authors.initials: K
authors.lastname: Kis-Tóth
authors.forename: Z
authors.initials: Z
authors.lastname: Macsári
authors.forename: L
authors.initials: L
authors.lastname: Fésüs
authors.forename: Z
authors.initials: Z
authors.lastname: Szondy
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053222:Fas Ligand Protein; D006801:Humans; D006825:Hybridomas / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013816:Thermodynamics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D019014:fas Receptor; D014212:Tretinoin