Human NK Cell Subset Functions Are Differentially Affected by Adipokines

Lena Huebner,Heike Kielstein,Lilia Goudeva,Christiane D Wrann,Stefan Engeli,Tobias Laue,Golo Ahlenstiel

doi:10.1371/journal.pone.0075703

Abstract

BackgroundObesity is a risk factor for various types of infectious diseases and cancer. The increase in adipose tissue causes alterations in both adipogenesis and the production of adipocyte-secreted proteins (adipokines). Since natural killer (NK) cells are the host’s primary defense against virus-infected and tumor cells, we investigated how adipocyte-conditioned medium (ACM) affects functions of two distinct human NK cell subsets.MethodsIsolated human peripheral blood mononuclear cells (PBMCs) were cultured with various concentrations of human and murine ACM harvested on two different days during adipogenesis and analyzed by fluorescent-activated cell sorting (FACS).ResultsFACS analyses showed that the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), granzyme A (GzmA) and interferon (IFN)-γ in NK cells was regulated in a subset-specific manner. ACM treatment altered IFN-γ expression in CD56dim NK cells. The production of GzmA in CD56bright NK cells was differentially affected by the distinct adipokine compositions harvested at different states of adipogenesis. Comparison of the treatment with either human or murine ACM revealed that adipokine-induced effects on NK cell expression of the leptin receptor (Ob-R), TRAIL and IFN-γ were species-specific.ConclusionConsidering the growing prevalence of obesity and the various disorders related to it, the present study provides further insights into the roles human NK cell subsets play in the obesity-associated state of chronic low-grade inflammation.

Highlights

Obesity, defined as a body-mass-index (BMI) $30 kg/m2, is one of today’s leading health threats in most industrialized countries [1]
Previous in vitro and in vivo studies conducted by our group demonstrated an impaired leptin-dependent signal transduction in natural killer (NK) cells in diet-induced obesity (DIO) which could be ameliorated by transfer of NK cells to a normal-weight metabolic environment [18,19]
peripheral blood mononuclear cells (PBMCs) incubated for 24 hours with medium only served as controls

Summary

Introduction

Obesity, defined as a body-mass-index (BMI) $30 kg/m2, is one of today’s leading health threats in most industrialized countries [1]. Obesity increases the susceptibility to infections and the risk to develop multiple types of cancer (e.g. colon and postmenopausal breast cancer) [4,5]. These findings led to the suggestion of obesity being an immunodeficient state [6]. Among the secreted adipokines with relevance for immunological processes are tumor necrosis factor (TNF)-a, interleukin (IL)-6, leptin, adiponectin, resistin and visfatin [8,9]. Resistin and visfatin are considered pro-inflammatory adipokines They induce pro-inflammatory cytokines [12,13] and their plasma concentrations are elevated during inflammatory conditions [14]. Since natural killer (NK) cells are the host’s primary defense against virus-infected and tumor cells, we investigated how adipocyte-conditioned medium (ACM) affects functions of two distinct human NK cell subsets

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