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Prostaglandin D₂ Suppresses Human NK Cell Function via Signaling through D Prostanoid Receptor¹

Yingying Chen^*, Bice Perussia^* and Kerry S. Campbell^2,

^* Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; and Division of Basic Science, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111

NK cells play critical roles in immune responses against tumors or virus infections by generating type 1 cytokine and cytotoxicity responses. In contrast, during type 2 dominant immune responses, such as allergic diseases, activities of NK cells are often impaired. These type 2 immune-mediated diseases have been reported to be closely associated with local production of PGD₂. PGD₂ is an eicosanoid primarily synthesized by mast cells and alveolar macrophages, and it functions through two major receptors, D prostanoid receptor (DP) and chemoattractant receptor-like molecule on the Th2 cell. Within the immune system, PGD₂ binding to DP generally leads to suppression of cellular functions. In the current study, we show that: 1) DP is expressed in human NK cells as detected by mRNA analysis and Western blot; 2) PGD₂ inhibits cytotoxicity, chemotaxis, and type 1 cytokine production of human NK cells via signaling through DP; 3) PGD₂ signaling via DP elevates intracellular cAMP levels and the inhibitory effects on NK cells are cAMP dependent; 4) PGD₂ binding to DP suppresses Ca²⁺ mobilization triggered by the cross-linking of the activating receptor, CD16. Together, these data uncover a novel mechanism by which PGD₂ functions through DP to suppress type 1 and cytolytic functions of human NK cells, thus contributing to the promotion of a type 2 immune response.

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 supported by U.S. Public Health Service Grant AI055842 (to B.P.) and National Institutes of Health Centers of Research Excellence Grant CA06927 (Fox Chase Cancer Center).

² Address correspondence and reprint requests to Dr. Kerry S. Campbell, Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail address: kerry.campbell{at}fccc.edu

³ Abbreviations used in this paper: DP, D prostanoid receptor; CRTH2, chemoattractant-receptor-like molecule on the Th2 cell; DC, dendritic cell; SA, streptavidin; rh, recombinant human; PI, propidium iodide; Fluo-3/AM, fluro-3-penta-acetoxymethylester; [Ca²⁺]i, cytosolic Ca²⁺ concentration; PKA, protein kinase A.

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The JI 2007 179: 2665-2666. [Full Text]  

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