Peroxisome proliferator-activated receptor-γ and its ligands attenuate biologic functions of human natural killer cells

Abstract

AbstractInterferon-γ (IFN-γ) 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-γ (PPAR-γ) ligands via both PPAR-γ-dependent and -independent pathways due to variation in PPAR-γ expression. In PPAR-γ-null NK cells, 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2), a natural PPAR-γ ligand, reduces IFN-γ 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 PPARγ-positive NK cells, PPAR-γ activation by 15d-PGJ2 and ciglitazone (a synthetic ligand) leads to reduction in both mRNA and protein levels of IFN-γ. Overexpression of PPAR-γ in PPAR-γ-null NK cells reduces IFN-γ gene expression. However, PPAR-γ expression and activation has no effect on NK cell cytolytic activity. In addition, 15d-PGJ2 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. (Blood. 2004;104:3276-3284)