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

Abstract

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 Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase/Ribosomal S6 Protein Kinase 1 Cascade Phosphorylates cAMP Response Element-binding Protein to Induce MUC5B Gene Expression via d-Prostanoid Receptor Signaling

“…Likewise, Shaywitz and Greenberg (58) have demonstrated that a variety of kinase signaling pathways can differentially contribute to Ca 2ϩ influx-mediated phosphorylation of CREB in pheochromocytoma (PC12) cells. Notably, a recent paper reported that treatment of human NK cells with PGD 2 does not directly increase intracellular Ca 2ϩ (59). Our data showed that PGD 2 does not induce changes in the intracellular Ca 2ϩ content in NCI-H292 cells, and we observed similar results in both BEAS-2B and A549 cells.…”

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

“…This study suggested that the role of IL-18 depends on its capacity to induce the production of IFN-γ. In IL-18-deficient mice injected with Propionibacterium acnes, IFN-γ production in response to LPS was markedly reduced and NK cell activity was significantly impaired (127 (136) and glucocorticoids (137,138). In mice, in vivo blocking of IL-10 reverted the hyporesponsive status of NK cells in the lungs or the liver (139,140).…”

Killing of Avian and Swine Influenza Virus by Natural Killer Cells

“…The monoclonal antibodies (MAbs) used in the present study included anti-NKp46 MAbs, 461-G1 (IgG1) (4), and clone 9E2 (IgG1) (11), as well as anti-influenza virus type A (H1), H17-L2, and H28-E23 anti-H1 (kindly provided by Jonathan W. Yewdell). As negative controls, we used anti-CD3 MAb T3D and the anti-CD99 antibody, 12E7 (IgG1).…”