title: Prostaglandin E2 suppressed IL-15-mediated human NK cell function through down-regulation of common gamma-chain.
abstract: NK cell function is regulated by cytokines and certain biochemical mediators in a positive or negative manner. This study was performed to investigate the suppressive effects of PGE(2) on IL-15-activated human NK cell function. Purified NK cells were cultured with 200 ng/ml IL-15 for 2 days in the presence or absence of 10-200 ng/ml PGE(2). PGE(2) significantly suppressed NK cell-mediated cytotoxicity and IFN-gamma production at the secretional and the transcriptional levels. We also evaluated the effect of PGE(2) on the IL-15R complex that consists of IL-2Rbeta, common gamma-chain (gamma(c)-chain), and a specific chain IL-15Ralpha. Percentage of positive cells and number of binding sites for gamma(c)-chain were significantly increased after IL-15 treatment; however, a substantial decrease was observed with PGE(2) cotreatment. In contrast, constitutive expression of IL-2Rbeta was significantly decreased after IL-15 treatment, with no change detected in the presence of PGE(2.) At the transcriptional level, neither IL-15 nor PGE(2) had significant effects on the expression of beta- or gamma(c)-chains. There was a 3-fold increase in the expression of IL-15Ralpha at the transcriptional level that peaked at 8 h after IL-15 treatment; however, PGE(2) had no significant effect. Suppression of NK function by PGE(2) was not due to the endogenous production of IL-4, IL-10, or TGF-beta(1) by NK cells. These results suggest that down-regulation of surface expression of gamma(c)-chain on NK cells may be one mechanism through which PGE(2) mediates suppression of IL-15-activated NK cell function.
authors.affiliation: Departments of. Surgery and Microbiology, University of Mississippi Medical Center, Jackson, MS 39216, USA. pjoshi@surgery.umsmed.edu
authors.forename: P C
authors.initials: PC
authors.lastname: Joshi
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Cuchens
authors.forename: Q
authors.initials: Q
authors.lastname: Jones
mesh_terms: D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: C508024:IL15RA protein, human; C507941:IL2RG protein, human; D007166:Immunosuppressive Agents; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7; D007371:Interferon-gamma; D015232:Dinoprostone