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Cutting Edge: Inhibition of NF-B-Mediated TSLP Expression by Retinoid X Receptor¹

Hai-Chon Lee^*, Mark B. Headley, Masanori Iseki^*, Koichi Ikuta and Steven F. Ziegler^2,*,

^* Immunology Program, Benaroya Research Institute, Seattle, WA 98101; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195; and Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan

	Abstract

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The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) has important roles in the initiation of allergic airway inflammation and the activation of dendritic cells. We have shown that the human TSLP gene is regulated in a NF-B-dependent manner; however the factors that negatively regulate TSLP expression are not known. In this study we demonstrate that 9-cis-retinoic acid (9-cis-RA) is a negative regulator of TSLP expression in airway epithelial cells. This inhibition is manifested as a block in the IL-1β-mediated recruitment of NF-B to the human TSLP promoter. 9-cis-RA-mediated inhibition is not restricted to TSLP gene expression but rather reflects a general inhibition of NF-B activation, as other NF-B-regulated-genes were also inhibited in a similar manner by 9-cis-RA treatment. Taken as a whole, these data demonstrate that inhibition of IL-1β-dependent genes by active retinoid X receptors involves antagonism of NF-B signaling.

	Introduction

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Thymic stromal lymphopoietin (TSLP)³ is an IL-7-like cytokine implicated in airway inflammatory diseases such as asthma. For example, mice that express a lung-specific TSLP transgene develop a spontaneous airway inflammatory disease with characteristic features found in human asthma, and human asthmatics display elevated TSLP levels in the lung (1, 2). In addition, mice that lack the TSLP receptor fail to develop inflammation in an Ag-driven model of asthma (1). TSLP is expressed primarily by epithelial cells and is induced in airway epithelial cells exposed to proinflammatory mediators, including IL-1β, TNF-, and selected TLR agonists, and activation of NF-B is a critical regulator for inflammation-induced expression of TSLP (3).

Nuclear receptors (NR) are members of a superfamily of ligand-dependent transcription factors that regulate diverse aspects of reproduction, development, homeostasis, and immune responses by both positively and negatively regulating gene expression (4, 5, 6). Responses to retinoic acid and its isomers are mediated by two members of this family, the retinoic acid receptors (RAR) and the retinoid X receptors (RXR), for which 9-cis-retinoic acid (9-cis-RA) acts as a high-affinity ligand (7). There are three RXR genes, coding for RXR, RXRβ, and RXR, which are obligate heterodimerization partners for many members of the nuclear receptor family, including RAR (5). In vivo studies using knockout animals showed that disruption of RXR lead to embryonic lethality, while deficiencies in RXRβ or RXR were less severe (8, 9, 10, 11). Studies using conditional knockouts showed that keratinocyte-selective ablation of RXR and RXRβ (referred to as RXRβ^ep–/–) triggered an inflammatory response similar to human atopic dermatitis. Interestingly, TSLP expression was rapidly induced in keratinocytes of RXRβ^ep–/– mice (12). This study supported previous work showing that TSLP is important in the initiation of skin inflammation and suggested that RXR and RXRβ are involved in regulating TSLP expression in the skin.

In this study, we have used IL-1β signaling as a model system to investigate mechanisms by which different members of the NR superfamily repress TSLP gene expression. The RXR agonist 9-cis-RA was found to repress IL-1β-mediated TSLP gene expression through inhibition of NF-B, not through direct binding to the TSLP gene promoter. These findings demonstrate that inhibition of NF-B-dependent genes by RXR involves direct antagonism of NF-B signaling.

	Materials and Methods

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Cells and chemicals

The 16HBEo^– cell line was a gift from D. C. Gruenert (California Pacific Medical Research Institute, San Francisco, CA) and the cells were grown in bronchial/tracheal epithelial cell basal medium (Lonza). The HEK293 cell line was grown in DMEM with 10% FCS, penicillin, and streptomycin (100 U/ml). Recombinant human IL-1β was purchased from R&D Systems. Abs to normal rabbit IgG, NF-B p50 (catalog no. sc-114), NF-B p65 (catalog no. sc-109), RXR (D-20) and RXR (N 197) were purchased from Santa Cruz Biotechnology. Anti-FLAG M2 mAb, RXR agonist 9-cis-RA, liver X receptor (LXR) agonist GW3965, peroxisome proliferator-activated receptor (PPAR) agonist GW7647, PPAR agonist GW0742, PPAR agonist GW1929, and dexamethasone were purchased from Sigma-Aldrich. Anti-hemagglutinin (HA) mAb was purchased from Roche.

Transfection assay

16HBEo^– cells (3 x 10⁵) were seeded into 6-well plates and transfected 24 h later with Mirus transfection reagent (Mirus Bio). Each well was transfected with 1 µg of reporter plasmid and 1 µg of a β-galactosidase plasmid (pRSV-β-Gal). After transfection, cells were cultured for 19 h and then treated with 1 ng/ml IL-1β in the absence or presence of nuclear receptor agonists. Cells were harvested 5 h after stimulation, lysed in 100 µl of lysis buffer (Promega), and luciferase activity was measured. Relative luciferase activity was given as the ratio of relative light units to relative β-galactosidase units. In each experiment, samples were analyzed in triplicate, and each experiment was repeated in at least three independent experiments.

Real-time quantitative PCR

Total RNA and cDNA synthesis was prepared as previous described (3). The primers used were as follows: human (h)TSLP, 5'-TAGCAATCGGCCACATTGCC-3' and 5'-CTGAGTTTCCGAATAGCCTG-3'; and hGAPDH, 5'-ATGGCACCGTCAAGGCTGAG-3' and 5'-GCTAAGCAGTTGGTGGTGCA-3'. Real-time PCR was conducted using Platinum SYBR Green quantitative PCR SuperMix-UDG with ROX (Invitrogen). Amplification was performed on an ABI 7700 sequence detector (Applied Biosystems). The levels of TSLP mRNA were normalized with GAPDH mRNA as previously described (3).

EMSA

Nuclear extracts were prepared as previously described (13). The sequences of double strand oligonucleotides used as probes were as follows: NF-B consensus motif, 5'-AGAGGATCTGTACAGGATGTTCTAGAT-3' (consensus NFB site underlined); and hTSLP NF-B motif, 5'-CTGCTAGGGAAACTCCATTATTAC-3'.

Coimmunoprecipitation and Western blot analysis

HA-tagged RXR and FLAG-tagged p65 were transiently cotransfected into HEK293 cells using a Mirus transfection reagent. Cells were cultured for 24 h and then treated with either or both 1 ng/ml IL-1β and 1 µM 9-cis-RA for 30 min. After centrifugation, cell lysates were immunoprecipitated with anti-FLAG or anti-HA mAbs and resolved by electrophoresis on 10% SDS-polyacrylamide gels and transferred to membrane. The membranes were incubated with anti-FLAG or anti-HA mAbs and visualized with Western blotting luminal reagent (Santa Cruz Biotechnology).

Chromatin immunoprecipitation (ChIP) assay

ChIP assay was performed as previously described (14). Two and one-half micrograms of anti-NF-B (catalog no. sc-114; Santa Cruz Biotechnology), anti-RXR (catalog no. sc-553, Santa Cruz Biotechnology), or normal rabbit IgG (Upstate Biotechnology) Abs were used in immunoprecipitation experiments. Purified ChIP DNA was measured by real-time quantitative PCR using Platinum SYBR Green qPCR SuperMix-UDG with ROX. The PCR condition was 95°C for 10 min followed by 40 cycles consisting of 95°C for 30 s, 55°C for 30 s, and 72°C for 30 s. The level of ChIP DNA was normalized with that of input DNA. In each experiment, samples were analyzed in triplicate. The primers used were as follows: hTSLP/NF-B, 5'-GAGGGTCCAGAGCAATACAC-3' and 5'-CCTCTCTGATATCCCTTCCA-3'; hTSLP/RXR, 5'-CACTAGCCACTTCTCCTTAC-3' and 5'-CCAAAGAACACCCTTCTGCT-3'; human inducible NO synthase (iNOS)/NF-B, 5'-CCTGTAGCAGTGACGTCTGT-3' and 5'-CTCAATGAGTGATGCTCTGG; and hDef-2/NF-B, 5'-CTCACTCCATTCACACACTG-3' and 5'-CACCAGGTAAGTGGCTGAAT.

	Results and Discussion

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RXR inhibits IL-1β-induced TSLP expression

The increased TSLP expression in the skin of RXRβ^ep–/– mice suggested the possibility that TSLP gene expression was directly regulated by nuclear receptors. To test the effect of nuclear receptor agonists on TSLP gene expression, the human bronchial epithelial cell line 16HBEo^– was stimulated with agonists for RXR (9-cis-RA), LXR (GW3965), PPAR (GW1929), and glucocorticoid receptor (GR; dexamethasone), as well as the inflammatory cytokine IL-1β. As previously shown, IL-1β treatment lead to an increase in TSLP mRNA levels (3). However, basal TSLP mRNA levels were not affected by treatment with RXR, LXR, PPAR, or GR agonists (Fig. 1a). Next, we determined the effect on TSLP gene expression of cotreatment with IL-1β and these NR agonists, including three distinct classes of PPAR agonists (PPAR, PPAR, and PPAR). 16HBEo^– cells were stimulated with IL-1β in the absence or presence of NR agonists for 2 and 4 h, and TSLP gene expression was measured. Cotreatment with IL-1β plus each NR agonist affected TSLP gene expression to varying degrees. Interestingly, treatment with 9-cis-RA had the most dramatic effect, significantly reducing TSLP mRNA level at both time points (Fig. 1b).

View larger version (17K): [in this window] [in a new window]   FIGURE 1. Selective NR agonists inhibit the induction of human TSLP mRNA in response to IL-1β. a, IL-1β but not NR agonists, induce expression of TSLP mRNA. 16HBEo– cells were stimulated with 1 µM RXR (9-cis-RA), LXR (GW3965), PPAR (GW1929), and GR (dexamethasone (Dex)) or 1 ng/ml IL-1β for the indicated time course, respectively. **, p < 0.01 comparing TSLP mRNA levels in IL-1β-treated cells as compared with NR agonists alone. b, The RXR agonist 9-cis-RA suppresses IL-1β-induced TSLP mRNA expression. Cells were treated with IL-1β in the absence or presence of 1 µM RXR, LXR, PPAR, PPAR, PPAR, and GR agonists for the indicated time course, respectively. Cells were harvested and measured for mRNA level by real-time quantitative PCR. TSLP mRNA levels were normalized to GAPDH. Data are the mean ± SD of triplicate data points from a representative experiment. *, p < 0.05, statistically significant difference compared with IL-1β treatment.

Activation of RXR agonist inhibits NF-B signaling

We next investigated the mechanism by which RXR inhibits TSLP expression using reporter plasmids containing the human TSLP gene promoter (3). 16HBEo^– cells were transfected with a luciferase reporter plasmid containing 4 kb of the human TSLP promoter, which contains the IL-1β-responsive NF-B site (3), and stimulated with IL-1β in the absence or presence of 9-cis-RA. IL-1β treatment led to a 5-fold increase in TSLP promoter activity, whereas treatment with 9-cis-RA alone had no effect. However, in a dose-dependent fashion, 9-cis-RA was capable of reducing the IL-1β-mediated activation of the human TSLP promoter (Fig. 2a). Li et al. (12, 15) identified a putative RXR binding site in the human TSLP gene promoter at positions –3912 –3900 (relative to the start of transcription). To determine whether this site was involved in the 9-cis-RA-dependent repression of TSLP expression, site-directed mutagenesis was used to eliminate it in the human TSLP gene reporter. No difference was found in the ability of 9-cis-RA to inhibit IL-1β-mediated activation of the mutated reporter (Fig. 2b). These data demonstrate that this site is not required for RXR-mediated inhibition of IL-1β-induced TSLP gene expression. As we had previously shown that activation of the human TSLP promoter was NF-B dependent, this result led us to determine whether NF-B signaling was affected by 9-cis-RA treatment. To test this hypothesis, we evaluated the effect of 9-cis-RA on the IL-1β-mediated activation of an NF-B reporter plasmid (pNFB-Luc; Ref. 16). As shown in Fig. 2c, 9-cis-RA effectively inhibited the IL-1β-mediated activation of this reporter in a dose-dependent fashion. These results demonstrate that the effect of RXR on TSLP gene expression is mediated through inhibition of NF-B, not by direct action on the TSLP gene promoter.

View larger version (16K): [in this window] [in a new window]   FIGURE 2. 9-cis-RA inhibition of NF-B activation. a, 9-cis-RA-mediated, dose-dependent inhibition of a luciferase (Luc) reporter containing the hTSLP promoter. b, 9-cis-RA inhibition of a luciferase reporter containing hTSLP promoter with a putative RARE site deleted. c, Dose-dependent inhibition by 9-cis-RA of a luciferase reporter containing multiple NF-B binding sites. For each set of experiments 16HBEo– cells were transiently transfected with the indicated luciferase constructs and, 19 h after transfection, cells were incubated for 5 h in 1 ng/ml IL-1β in the absence (–) or presence of 9-cis-RA at the indicated concentration. At that time, cells were harvested and lysates prepared for the determination of luciferase activity. Luciferase activity in the whole cell lysate was normalized to β-galactosidase activity. Data are the mean ± SD of triplicate data points from a representative experiment.

RXR activation inhibits DNA binding by NF-B

We next analyzed whether the binding of NF-B to the human TSLP promoter was inhibited by the effect of 9-cis-RA. 16HBEo^– cells were treated with IL-1β in the absence or presence of 9-cis-RA and analyzed for NF-B transactivation by EMSA by using oligonucleotide probes corresponding to either the NF-B consensus or to the NF-B site in the TSLP promoter (3). Binding of NF-B to both probes was markedly increased in nuclear extracts from IL-1β-treated cells. In contrast, nuclear extracts from cells cotreated with IL-1β and increasing amounts of 9-cis-RA showed reduced NF-B DNA binding activity to each probe that correlated with increasing concentration of 9-cis-RA (Fig. 3a). Similar results were obtained using extract from a second human lung epithelial cell line (A549) treated in the same fashion (data not shown). These results demonstrate that IL-1β-mediated NF-B binding to the human TSLP gene promoter is abrogated by cotreatment with the RXR agonist 9-cis-RA.

View larger version (77K): [in this window] [in a new window]   FIGURE 3. 9-cis-RA inhibits DNA-binding activity of NF-B in response to IL-1β. a, 16HBEo– cells were stimulated with 1 ng/ml IL-1β in the absence or presence of 9-cis-RA at the indicated concentration. Nuclear extracts were incubated with labeled oligonucleotide probes containing the NF-B consensus or the NF-B binding site in the TSLP promoter and subjected to EMSA. Arrow indicates specific binding activity. b, Interaction of NF-B with RXR in vitro. 16HBEo– cells were transfected with the HA-tagged RXR and FLAG-tagged p65 or p50 and stimulated with either or both 1 ng/ml IL-1β and 1 µM 9-cis-RA for 30 min. Coimmunoprecipitation assays were performed using anti-FLAG Abs and blotted with anti-HA or anti-FLAG Abs. IP, Immunoprecipitation; WB, Western blot.

9-cisRA inhibits NF-B binding to the human TSLP gene promoter in vivo

We next investigated whether NF-B is recruited to the TSLP promoter following IL-1β treatment and whether this recruitment is affected by cotreatment with 9-cis-RA. ChIP assays were performed using 16HBEo^– cells stimulated with IL-1β in the absence or presence of the RXR agonist 9-cis-RA. The chromatin fraction was isolated, and binding to the human TSLP promoter was determined following immunoprecipitation using Abs against NF-B (anti-p50), RXR, or isotype control. As expected, NF-B was recruited to the TSLP promoter in response to IL-1β. However, recruitment of NF-B was inhibited at both time points in the presence of the RXR agonist 9-cis-RA (Fig. 4a). These results show that RXR acts to repress IL-1β-mediated induction of the TSLP gene by preventing the recruitment of NF-B to its promoter. Recently, Li et al. (15) identified putative RXR binding sites in the human and mouse TSLP gene promoters and suggested that RXR may be involved in directly repressing transcription of the TSLP gene through RXR/RAR heterodimers. To determine whether RXR is recruited to the retinoic acid response element (RARE) in the human TSLP gene promoter (–3912 –3900), we examined recruitment of RXR in the absence or presence of 9-cis-RA. RXR binding to the putative RARE in the TSLP promoter was not detected (Fig. 4b). However, lack of RXR binding was not due to the inability to analyze RXR binding by ChIP, as binding to the human BLR1 promoter was seen (Fig. 4b). This result indicates that inhibition of NF-B activation by 9-cis-RA occurs at the level of NF-B, and not at the TSLP promoter. To extend these findings, we examined the effect of 9-cis-RA treatment on the binding of NF-B to the IL-1β-inducible genes iNOS and defensin-2 (17, 18). ChIP experiments revealed that NF-B was recruited to the promoters of each of these genes in response to IL-1β at 1 and 2 h, but treatment with the RXR agonist 9-cis-RA significantly inhibited this recruitment (Fig. 4, c and d). These results suggest that an RXR agonist inhibits inflammatory responses by transrepression of NF-B target genes.

View larger version (40K): [in this window] [in a new window]   FIGURE 4. 9-cis-RA blocks recruitment of NF-B to endogenous TSLP promoter and NF-B-dependent genes in response to IL-1β. a, c, and d, Recruitment of NF-B was inhibited at the NF-B binding site of TSLP gene promoter (a), human iNOS gene (c), and human defensin-2 gene (d) by 9-cis-RA. b, RXR was not recruited to the RXR binding site at the TSLP promoter despite RXR agonist stimulation but was recruited to the BLR1 promoter. 16HBEo– cells were stimulated with 1 ng/ml IL-1β in the absence or presence of 1 µM 9-cis-RA for 1 h, and soluble chromatin preparation was immunoprecipitated with anti-NF-B, anti-RXR Ab, or control normal rabbit IgG. Purified ChIP and input DNA were analyzed by real-time quantitative PCR with the primers, respectively. The amount of ChIP DNA was normalized to that of input DNA. The mean value of control Ab before stimulation was arbitrarily defined as 1. Data are the mean ± SD of triplicate data points from a representative experiment.

Ligand deprivation and pharmacological studies in vivo have suggested that RXR homodimers and heterodimers are physiologically involved in epidermis development and keratinocyte differentiation (20, 21, 22). Interestingly, mice with targeted deletion of RXR and RXRβ in the epidermis develop an inflammatory disease of the skin similar to atopic dermatitis (12). This disease development is accompanied by increased TSLP expression in the epidermis, suggesting that RXRs are involved in repressing transcription of the TSLP gene. The data presented herein support this study and provide a mechanistic framework for RXR-mediated inhibition of TSLP gene expression. Rather than direct binding of RXR to the TSLP promoter, as suggested by Li et al. (12), our data show that RXR acts through inhibition of NF-B activation. These data are supported by work in this report showing no direct binding of RXR to the TSLP promoter and by our previous work showing that mutation of putative RXR binding sites in the human and mouse TSLP promoters had no effect on IL-1β-mediated gene induction (3). However, it remains to be determined whether RXR is functioning as a homodimer or heterodimer with other NRs.

In conclusion, 9-cis-RA inhibits the induction of TSLP gene expression via RXR. This inhibition is due to a direct effect of RXR on NF-B. Because TSLP has been linked to allergic inflammatory diseases (23), these data suggest that the use of RXR agonists may be useful as a therapeutic modality in treating allergy.

	Acknowledgments

 
We thank Theingi Aye, Weihui Shih, and Xiaocui Sun for excellent technical assistance, Drs. Jessica Hamerman and Daniel Campbell for critical discussion of manuscript before submission, and members of the Ziegler laboratory for helpful discussions throughout the course of this work. We thank Matt Warren for administrative support.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was partially supported by National Institutes of Health Grants AI44259, AI50864, AI68731, and AI71130 to S.F.Z.

² Address correspondence and reprint requests to Dr. Steven F. Ziegler, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101. E-mail address: sziegler{at}benaroyaresearch.org

³ Abbreviations used in this paper: TSLP, thymic stromal lymphopoietin; ChIP, chromatin immunoprecipitation; 9-cis-RNA, 9-cis-retioic acid; GR, glucocorticoid receptor; h, human; HA, hemagglutinin; iNOS, inducible NO synthase; LXR, liver X receptor; NR, nuclear receptor; PPAR, peroxisome proliferator-activated receptor; RAR, retinoic acid receptor; RARE, retinoic acid response element; RXR, retinoid X receptor; RXRβ^ep–/–, keratinocyte-selective ablation of RXR and RXRβ.

Received for publication June 13, 2008. Accepted for publication August 17, 2008.

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