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Retinoic Acid Enhances the Expression of Interferon-Induced Proteins: Evidence for Multiple Mechanisms of Action

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Retinoic Acid Enhances the Expression of Interferon-Induced Proteins: Evidence for Multiple Mechanisms of Action Oncogene (1997) 15, 2349 ± 2359 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Retinoic acid enhances the expression of interferon-induced proteins: evidence for multiple mechanisms of action Luis Pelicano1, Fengsheng Li2, Christian Schindler2 and Mounira K Chelbi-Alix1 1CNRS-UPR 9051; 1, avenue Claude Vellefaux, HoÃpital St Louis, 75010 Paris, France; 2Division of Molecular Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA Retinoic acid (RA) and interferons (IFNs) are negative Tyk2, phosphorylate Stat1, Stat2 and Stat3. The IFN- regulators of cell proliferation. In vitro and in vivo, their stimulated gene factor 3 (ISGF3) is formed between combination leads to a more potent growth inhibition. Stat1 and Stat2 (Stat1 : 2) in association with the DNA- However, the molecular mechanisms by which RA and binding protein, p48, a member of the interferon IFNs potentiate each other are not fully understood. As regulatory factor (IRF) family (Fu et al., 1992; some IFN-induced gene products regulate cell growth Schindler et al., 1992). This complex binds to the and/or antiviral activity, we analysed the eects of RA IFN-stimulated response element (ISRE) found in on their expressions. RA increases the level of promoters of IFNa/b-stimulated genes. In addition, 2'5'oligoadenylate synthetase, p68 kinase, the promyelo- homo- and heterodimers of Stat1 and Stat3 (Stat1 : 1, cytic leukemia protein (PML) and Sp100 in both HL-60 Stat3 : 3 and Stat1 : 3) bind to a palindromic version of and WISH cells. Moreover, RA and IFN act coopera- the IFNg-activated site (GAS), regulating the expres- tively to increase the expression of these proteins. RA sion of distinct ISGs (Kanno et al., 1993; Khan et al., also inhibits vesicular stomatitis virus replication and 1993; Pine et al., 1994). In response to IFNg, Jak1 and induces a higher antiviral state and growth inhibition Jak2, phosphorylate Stat1 which forms a homodimer when combined with IFN. RA stimulates the IFN and binds to the GAS motif. regulatory factor 1 (IRF-1) gene expression directly The diverse biological eects of IFNs are believed to through the GAS motif and causes the induction and be mediated by a speci®c set of more than 40 proteins secretion of IFNa. Additional mechanisms could be directly involved in response to IFN treatment. involved as RA increases the level of signal transducing However, only a few of these proteins, namely the activators of transcription (STAT) proteins, and en- p68 kinase (PKR) (Koromilas et al., 1992; Meurs et al., hances the IFN-induced STAT activation, suggesting 1992, 1993), the 2'5' oligoadenylate (2'5'A) synthetase that cooperative eects by RA and IFN are mediated (Chebath et al., 1987), certain forms of Mx proteins through multiple pathways. (Staeheli et al., 1993) and the promyelocytic leukemia (PML) protein (Mu et al., 1994; Chelbi-Alix et al., Keywords: interferon; retinoic acid; STAT; IRF-1; 1995, 1996; Koken et al., 1995; Liu et al., 1995; Stadler signalisation pathways et al., 1995) are implicated in the antiviral state and/or anti-tumor and anti-growth activities of IFNs. The enzymatic properties of PKR and 2'5'A synthetase have been well characterized (reviewed in Sen and Introduction Ransoho, 1993). In short, PKR, once phosphorylated, acquires the capacity to phosphorylate the a subunit of Interferons (IFNs) are a family of secreted cytokines the translation initiation factor eIF-2, leading to the with antiviral, antiproliferative and immunomodula- inhibition of protein synthesis. The 2'5'A synthetase tory activities (Pestka et al., 1987; Romeo et al., 1989; catalyses the synthesis, from ATP, of unusual 2'5' Sen and Ransoho, 1993). IFNs a and b (type I) are oligoadenylates, which in turn activate a latent produced by many types of cells in response to viral ribonuclease. The mechanism of action of Mx or infection, double stranded RNA treatment or other PML proteins remains to be elucidated. PML is a stimuli (Chelbi-Alix et al., 1994 and references within). nuclear matrix protein with growth suppressing IFNg (type II) is induced in T-lymphocytes and natural properties, whose expression is deregulated during killer cells in response to antigens or mitogens. These oncogenesis (Mu et al., 1994; Koken et al., 1995; Liu IFNs, after interacting with dierent speci®c high- et al., 1995). PML is associated to nuclear compart- anity receptors on the plasma membrane, activate ments called nuclear bodies where it colocalizes with dierent cascades of signal transduction reactions two IFN-induced proteins, Sp100 (an autoantigen leading to the transcriptional activation of IFN- detected in primary biliary cirrhosis, Guldner et al., stimulated genes (ISGs) (Schindler, 1995). IFN- 1992), and NDP52 (Korioth et al., 1995). induced signal transduction is mediated by the Retinoic acid (RA) is structurally related to vitamin phosphorylation-activation of the signal transducers A. RA exerts dierent eects such as inhibition of and activators of transcription (STAT) proteins proliferation, induction of dierentiation and immuno- (Schindler, 1995). In response to IFNa/b, Jak1 and modulation. RA modi®es gene expression by binding to speci®c nuclear receptors (Mangelsdorf et al., 1994). Both RA and IFNs exert antiproliferative eects on various cell types (Frey et al., 1991). Several groups Correspondence: MK Chelbi-Alix have reported a higher inhibition of cell proliferation Received 22 April 1997; revised 8 July 1997; accepted 9 July 1997 by a combination of RA with IFN, compared to Retinoic acid action on interferon system L Pelicano et al 2350 treatment by each agent alone (Lancillotti et al., 1995 the level of Stat1 in MCF-7, a breast tumor cell line and references within). However, the mechanism of this resistant to growth inhibition by IFNb (Kolla et al., collaborative eect is not yet fully elucidated. It is also 1996). not known whether these events are accompanied by In this report, we analysed the eect of RA, alone an enhancement of the IFN-induced antiviral state. It and in combination with IFNa, on the expression of has been recently shown that RA upregulates IRF-1 2'5'A synthetase, PKR, Sp100 and PML in dierent gene expression in myeloid cells (Matikainen et al., human cell lines. The capacity to inhibit cell 1996; Gianni' et al., 1997) and that RA also increases proliferation and vesicular stomatitis virus (VSV) a b C IFN RA PML Sp100 Figure 1 Capacity of RA to increase IFN-induced proteins. (a) Kinetics of increase of 2'5'A synthetase activity in HL-60 cells after 76 RA, IFNa and poly(I)-poly(C) treatments. HL-60 cells were untreated (&) or treated by RA (10 M)(*), 100 mg/ml of poly(I)- poly(C) (^) or IFNa (500 units/ml) (*). At the indicated times, 2'5'A synthetase activity was determined in cell extracts as described in Materials and methods. Values are an average of three experiments. (b) Increase of PML and Sp100 proteins by RA. 76 HL-60 cells were treated by RA (10 M) for 3 days. Immuno¯uorescence was revealed by monoclonal anti-PML antibodies followed by Texas red, and polyclonal anti-Sp100 antibodies were visualized with FITC Retinoic acid action on interferon system L Pelicano et al 2351 replication was also tested. We demonstrate that the cells treated with RA plus IFNa vs IFNa alone. In eects of RA could be mediated through multiple HeLa cells, we failed to detect an increase of 2'5'A mechanisms involving increase of STAT expression, synthetase activity by RA alone or RA-IFNa IFN-induced STAT activation, direct IRF-1 gene compared to IFNa alone (Table 1). induction and IFNa secretion. We then investigated the eects of RA and IFN on PML, Sp100 and PKR proteins expression. Equal amounts of total protein extracts from control and treated HL-60 cells for 24 h were analysed by Western Results blotting. At that time, RA per se had no eect and IFNa at 100 units/ml only slightly increased the Increase of 2'5'A synthetase, PML and Sp100 proteins expression by RA The 2'5'A synthetase activity induced by 1076 M RA Table 1 Induction of 2'5'A synthetase activity in HL-60, WISH and was studied in HL-60 cells and compared with that HeLa cells by RA, IFNa and their combination induced by 100 mg/ml of poly(I)-poly(C), a commonly Cells used IFN inducer. The basal level of 2'5'A synthetase HL-60 WISH HeLa activity remained constant in HL-60 cells for periods Treatment 2'5'A synthetase activity (units/mg) from 1 ± 7 days, whereas it increased in the presence of None 1+0.1 46+3 12+1 RA. The kinetics of enzyme activity for RA (Figure 1a) RA 8.1+0.3 100+5 13+1.5 shows a sixfold enhancement at day 1, reaching a IFNa 61+9 110+6 120+8 IFNa+RA 139+15 179+19 126+7 maximum at day 3 (50-fold), and a subsequent decline 76 75 Cells were treated for 24 h with 10 M RA (HL-60), 10 M RA of 80% at day 7. The maximal induction with poly(I)- (WISH and HeLa), IFNa (100 units/ml) or their combination. 2'5' A poly(C) was only fourfold after 3 days. Thus, clearly synthetase activity was measured in cell extracts as described in RA, compared to poly(I)-poly(C), is a better inducer of Materials and methods. Each value is the mean of three experiments 2'5'A synthetase activity in HL-60 cells. Note that, compared to IFN, RA induced enzyme activity with slower kinetics. In WISH cells, the maximum increase of RA-induced 2'5'A synthetase activity occurred at HL60 a 24 h at a concentration of 1075 M (Bourgeade and Besancon, 1984 and Table 1).
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