Trail (TNF-related apoptosis-inducing ligand) induces an inflammatory response in human adipocytes

Verena Zoller,Meike Dahlhaus,Martin Wabitsch,Julian Roos,Pamela Fischer-Posovszky,Klaus-Michael Debatin,Muad Abd El Hay,Ralf Marienfeld,Jan-Bernd Funcke,Karlheinz Holzmann,Thomas Kietzmann

doi:10.1038/s41598-017-05932-7

Abstract

High serum concentrations of TNF-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor protein family, are found in patients with increased BMI and serum lipid levels. In a model of murine obesity, both the expression of TRAIL and its receptor (TRAIL-R) is elevated in adipose tissue. Accordingly, TRAIL has been proposed as an important mediator of adipose tissue inflammation and obesity-associated diseases. The aim of this study was to investigate if TRAIL regulates inflammatory processes at the level of the adipocyte. Using human Simpson-Golabi-Behmel syndrome (SGBS) cells as a model system, we found that TRAIL induces an inflammatory response in both preadipocytes and adipocytes. It stimulates the expression of interleukin 6 (IL-6), interleukin 8 (IL-8) as well as the chemokines monocyte chemoattractant protein-1 (MCP-1) and chemokine C-C motif ligand 20 (CCL-20) in a time- and dose-dependent manner. By using small molecule inhibitors, we found that both the NFκB and the ERK1/2 pathway are crucial for mediating the effect of TRAIL. Taken together, we identified a novel pro-inflammatory function of TRAIL in human adipocytes. Our findings suggest that targeting the TRAIL/TRAIL-R system might be a useful strategy to tackle obesity-associated adipose tissue inflammation.

Highlights

Obesity as defined by a body mass index (BMI) >30 kg/m2 is a disease with increasing prevalence[1, 2]
tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces a pro-inflammatory response in preadipocytes and adipocytes
In Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes, 38 genes showed a differential expression profile upon TRAIL treatment when compared to the control

Summary

Introduction

Obesity as defined by a body mass index (BMI) >30 kg/m2 is a disease with increasing prevalence[1, 2]. Receptor binding leads to the recruitment of Fas-associated death domain (FADD), caspase-8 and -10 as well as cellular FLICE inhibitory protein (cFLIP) to the receptor[13, 14] The formation of this death inducing signaling complex (DISC, primary complex) leads to the activation of the initiator caspases, i.e. caspase-8 or -10, by proximity-induced dimerization and subsequent self-cleavage[15]. Based on the overall data, we hypothesized that TRAIL might contribute to obesity-induced adipose tissue inflammation by triggering kinase pathways that lead to cytokine and chemokine expression. It has not been investigated whether and to which extent TRAIL promotes an inflammatory response in human adipocytes. We studied the impact of TRAIL on the production of inflammatory cytokines and chemokines as well as the signaling pathways underlying this effect in human preadipocytes and adipocytes

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