Retinoids induce Fas(CD95) ligand cell surface expression via RARγ and nur77 in T cells

Abstract

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 upregulation 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 RAR § and RAR + . 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 RAR + . Despite the induced expression of cell surface FasL, only two structurally related RAR + -selective compounds, CD437 and CD2325, initiated apoptosis in these cells. The lack of apoptosis induction by natural RA was related to the inability of RAR + 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 T cells.

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

“…It is possible that our Western blot analysis was not sensitive enough to detect RAR-␥, although RNA levels for RAR-␣ and RAR-␥ were similar. Other investigators report the presence of RAR-␥ mRNA in T lymphocytes and biological activity for RAR-␥-selective ligands (24). To our knowledge, RAR-␥ protein has not been identified in T lymphocytes by Western blot analysis, thus the significance of RAR-␥ RNA levels in these cells remains uncertain.…”

“…For example, retinoic acid and RAR-selective ligands can inhibit Fas-mediated apoptosis by diminishing cell surface Fas ligand expression in T cell hybridomas activated via the TCR (19 -22). This antiapoptotic effect is mediated via RAR-␣/ RXR heterodimers (23), whereas RAR-␥ agonists can up-regulate FAS-ligand and thus facilitate apoptosis in T cell hybridomas (24) as well as thymocytes (25). Thymocyte apoptosis has also been reduced by retinoic acid treatment (26).…”

Retinoic acid regulates Fas-induced apoptosis in Jurkat T cells: reversal of mitogen-mediated repression of Fas DISC assembly

“…In the second case, RA counteracts the ability of mitogens to induce FasL and thereby, Fas-induced apoptosis. In the absence of mitogens or other T cell-stimulatory agents, however, it was reported that RA rather enhances than reduces FasL cell-surface expression in hybridoma and preactivated T cells [74]. Thus, it appears that depending on the conditions and the type of T cell, RA will act to repress or promote Fas-induced apoptosis.…”

CD437, a synthetic retinoid, induces apoptosis in human respiratory epithelial cells via caspase-independent mitochondrial and caspase-8-dependent pathways both up-regulated by JNK signaling pathway

“…Conversely, CD437 increased the levels of death receptors, such as TRAIL receptors, DR4, DR5 and Fas, in human tumor cell lines [19,21,23,35]. CD437 increased the expression of FasL at cell surface of T cells [32], but apoptosis was only partially blocked by FasFc which inhibits Fas-FasL interaction or by an RARg antagonist. As a result, the authors concluded that CD437-induced apoptosis was not correlated to the Fas pathway.…”

“…The nur77 gene was shown to be induced by CD437 in a study of CD437-induced changes in gene expression carried out by cDNA array screening in human lung carcinoma cells [31]. The up-regulation of nur77 and FasL induced by CD437 in murine T cells was mediated by RARg [32]. However, these authors also showed that CD437 induced apoptosis via an alternative pathway, which was independent of RARg, nur77 and FasL.…”