Retinoids induce Fas(CD95) ligand cell surface expression via RARgamma and nur77 in T cells.
Cells from the CD4+ murine T hybridoma line IP-12-7 enter the apoptotic suicide program via the Fas ligand (FasL)/Fas-mediated pathway upon TCR stimulation. This stimulus regulates the sensitization of the Fas death pathway and the cell surface appearance of preformed FasL. The apoptosis is dependent on new mRNA and protein synthesis and involves up-regulation of nur77. Two groups of nuclear receptors for retinoic acids (RA) have been identified: retinoic acid receptors (RAR) and retinoid X receptors. IP-12-7 cells express RARalpha and RARgamma. Here we show that,in the IP-12-7 T cells, RA also induced the expression and DNA binding of nur77, and the cell surface appearance of FasL. The induction was mediated via RARgamma. Despite the induced expression of cell surface FasL, only two structurally related RARgamma-selective compounds, CD437 and CD2325, initiated apoptosis in these cells. The lack of apoptosis induction by natural RA was related to the inability of RARgamma to sensitize the Fas death-pathway. Cell surface FasL, however, was able to induce cell death in Fas-bearing target cells. Natural RA also induced the expression of FasL in phytohemagglutinin-activated peripheral murine T cells. It is proposed that therapeutically administered RA might induce apoptosis in Fas-sensitive cells via induction of FasL expression in activated Tcells.
Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University Medical School of Debrecen, Debrecen, Hungary.
Beáta
B
Tóth
Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University Medical School of Debrecen, Debrecen, Hungary.
Katalin
K
Ludányi
Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University Medical School of Debrecen, Debrecen, Hungary.
Ildikó
I
Kiss
Galderma Research and Development Center, Sophia Antipolis, France.
Uwe
U
Reichert
Galderma Research and Development Center, Sophia Antipolis, France.
Serge
S
Michel
Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University Medical School of Debrecen, Debrecen, Hungary.
László
L
Fésüs
Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University Medical School of Debrecen, Debrecen, Hungary.
Zsuzsa
Z
Szondy
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D053222:Fas Ligand Protein; D006825:Hybridomas; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000378:metabolism; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D000097768:Retinoic Acid Receptor gamma
D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D000097768:Retinoic Acid Receptor gamma; C099555:CD 437; C505658:Fasl protein, mouse; C539818:Nr4a1 protein, mouse