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

Abstract

Interferon-␥ (IFN-␥) 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-␥ (PPAR-␥) ligands via both PPAR-␥-dependent and -independent pathways due to variation in PPAR-␥ expression. In PPAR-␥-null NK cells, 15-deoxy-⌬ 12,14 prostaglandin J 2 (15d-PGJ 2 ), a natural PPAR-␥ ligand, reduces IFN-␥ 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 PPAR␥-positive NK cells, PPAR-␥ activation by 15d-PGJ 2 and ciglitazone (a synthetic ligand) leads to reduction in both mRNA and protein levels of IFN-␥. Overexpression of PPAR-␥ in PPAR-␥-null NK cells reduces IFN-␥ gene expression. However, PPAR-␥ 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. IntroductionNatural killer (NK) cells are bone marrow-derived cytotoxic lymphocytes with a granular morphology and account for up to 15% of peripheral blood lymphocytes. 1,2 They are important cellular components of innate immune defense against infection and immune surveillance against malignancies and transplanted organs. 3,4 NK cells are also implicated in the regulation of hematopoiesis and adaptive immune responses. 2,5 The biologic activity of NK cells includes not only cytokine production (eg, interferon-␥ [IFN-␥]) to regulate the type 1 T-cell immune response but also cytolytic activity, because NK cells can destroy target cells prior to sensitization and without restriction by major histocompatibility complex (MHC) antigens (natural killing activity). Imbalance of NK biologic functions has been implicated in the pathogenesis of autoimmune diseases such as diabetes. 6 Removal of NK cells abrogates cyclophosphamide-induced diabetes in nonobese diabetic (NOD) mice and prevents streptozotocin-induced diabetes in CD-1 mice. 7,8 Furthermore, IFN-␥ promotes the penetration of diabetogenic cells into pancreatic islets, and depletion of IFN-␥ delays the development of autoimmune diabetes in NOD mice. 9,10 Whereas the role of NK cells in pathogenesis has been extensively studied, the mechanisms involved in the regulation of NK functions remain to be defined. Many agents like cytokines, prostaglandins, and drugs regulate NK cell function. Interleukin-2 (IL-2) enhances intrinsic killing activity of NK cells and also induces a rapid expression of In contrast, interleukin-4 (IL-4) inhibits IFN-␥ production by human NK cells and regulates growth factor-dependent proliferation and differentiation of thes...

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