Receptor activator of NF-KB 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-Delta(12,14)-PGJ(2) (15d-PGJ(2)) is a cyclopentenone-type PG endowed with anti-inflammatory properties and produced by different cells, including those of the immune system. Although 15d-PGJ(2) has been studied as a natural ligand of the peroxisome proliferator-activated receptor-gamma nuclear receptor, relevant peroxisome proliferator-activated receptor-gamma-independent actions mediated by this prostanoid have been described. In this study, we describe the effect of 15d-PGJ(2) 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-PGJ(2) represses rankl activation by interfering with the expression and/or activity of the transcription factors NF-kappa 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-PGJ(2). The physiological and pharmacological implications of these observations are discussed.