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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

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.

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.