title: Peroxisome proliferator-activated receptor-gamma and its ligands attenuate biologic functions of human natural killer cells.
abstract: Interferon-gamma (IFN-gamma) production and cytolytic activity are 2 major biologic functions of natural killer (NK) cells that are important for innate immunity. We demonstrate here that these functions are compromised in human NK cells treated with peroxisome proliferator-activated-gamma (PPAR-gamma) ligands via both PPAR-gamma-dependent and -independent pathways due to variation in PPAR-gamma expression. In PPAR-gamma-null NK cells, 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), a natural PPAR-gamma ligand, reduces IFN-gamma production that can be reversed by MG132 and/or chloroquine, and it inhibits cytolytic activity of NK cells through reduction of both conjugate formation and CD69 expression. In PPARgamma-positive NK cells, PPAR-gamma activation by 15d-PGJ(2) and ciglitazone (a synthetic ligand) leads to reduction in both mRNA and protein levels of IFN-gamma. Overexpression of PPAR-gamma in PPAR-gamma-null NK cells reduces IFN-gamma gene expression. However, PPAR-gamma expression and activation has no effect on NK cell cytolytic activity. In addition, 15d-PGJ(2) but not ciglitazone reduces expression of CD69 in human NK cells, whereas CD44 expression is not affected. These results reveal novel pathways regulating NK cell biologic functions and provide a basis for the design of therapeutic agents that can regulate the function of NK cells within the innate immune response.
authors.affiliation: Laboratory of Experimental Immunology, Center for Cancer Reseach, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702-1201, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Rodriguez-Galán
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Subleski
authors.forename: John R
authors.initials: JR
authors.lastname: Ortaldo
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Hodge
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Wang
authors.forename: Osamu
authors.initials: O
authors.lastname: Shimozato
authors.forename: Della A
authors.initials: DA
authors.lastname: Reynolds
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
mesh_terms: D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008024:Ligands; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology
chemical_list: C477819:15-deoxyprostaglandin J2; D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D007371:Interferon-gamma; D015230:Prostaglandin D2; C039671:ciglitazone