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15-Deoxy-^12,14-Prostaglandin J₂ Negatively Regulates rankl Gene Expression in Activated T Lymphocytes: Role of NF-B and Early Growth Response Transcription Factors¹

Cinzia Fionda^2,*,, Filomena Nappi, Mario Piccoli^*, Luigi Frati^*,, Angela Santoni^3,*, and Marco Cippitelli^3,4,*,

^* Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Rome, Italy; Regina Elena Cancer Institute, Centro Ricerca Sperimentale, Rome, Italy; Istituto Mediterraneo di Neuroscienze Neuromed, Pozzilli, Italy; and National AIDS Centre, Istituto Superiore di Sanità, Rome, Italy

Receptor activator of NF-B ligand (RANKL) and its receptor RANK are cell surface proteins abundantly expressed in bone and lymphoid tissues, whose interaction triggers different signaling pathways leading to activation and differentiation of osteoclasts, pivotal actors of the normal bone remodeling cycle. Moreover, RANKL may act as an immunomodulator, representing an important dendritic cell survival factor produced by activated T cells. A large body of research has shown that not only does the RANKL/RANK system regulate the physiology of bone development but also plays an important pathological role in bone destruction mediated by inflammatory disorders or bone metastatic tumors. 15-Deoxy-^12,14-PGJ₂ (15d-PGJ₂) is a cyclopentenone-type PG endowed with anti-inflammatory properties and produced by different cells, including those of the immune system. Although 15d-PGJ₂ has been studied as a natural ligand of the peroxisome proliferator-activated receptor- nuclear receptor, relevant peroxisome proliferator-activated receptor--independent actions mediated by this prostanoid have been described. In this study, we describe the effect of 15d-PGJ₂ on the expression of the rankl gene in T lymphocytes. We show that 15d-PGJ₂ inhibits rankl mRNA expression, protein, and rankl promoter activity by mechanisms mediated by its chemically reactive cyclopentenone moiety. Our data also indicate that 15d-PGJ₂ represses rankl activation by interfering with the expression and/or activity of the transcription factors NF-B, early growth response-2, and early growth response-3, whose altered balancing and transactivation may contribute for the repression of this gene. These results place rankl as a novel molecular target for the different immunoregulatory activities mediated by 15d-PGJ₂. The physiological and pharmacological implications of these observations are discussed.

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 grants from the Italian Association for Cancer Research, Ministero della Salute, 60% Ateneo, Progetti di Interesse Nazionale, Fondo per gli Investimenti della Ricerca di Base.

² C.F. is recipient of a fellowship from the Italian Foundation for Cancer Research.

³ A.S. and M.C. contributed equally to this paper.

⁴ Address correspondence and reprint requests to Dr. Marco Cippitelli, Department of Experimental Medicine, University La Sapienza, Viale Regina Elena 324, Rome, Italy. E-mail address: marco.cippitelli{at}uniroma1.it or cippitelli{at}ifo.it

⁵ Abbreviations used in this paper: RANKL, receptor activator of NF-B ligand; CAY10410, 9,10-dihydro-15-deoxy-^12,14-prostaglandin J₂; CsA, cyclosporin A; cyPG, cyclopentenone-type PG; 15d-PGJ₂, 15-deoxy-^12,14-PGJ₂; EGR, early growth response; FLRE, fas-l regulatory element; MM, multiple myeloma; mRANKL, murine RANKL; PPAR, peroxisome proliferator-activated receptor; RSV, Rous sarcoma virus.

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