Background: Obesity is tightly associated with adipose tissue inflammation. Tumor necrosis factor-alpha (TNFα) has been identified as a key player in this inflammatory process and has been linked to the development of obesity-associated insulin resistance. Our group studies the involvement of TNF superfamily members in obesity-induced alterations in adipose tissue.
Objective and hypotheses: Here, we aimed to identify the effects of the TNF superfamily member TNF-related apoptosis-inducing ligand (TRAIL) on cytokine production in human adipocytes.
Method: SGBS adipocytes on day 8 of adipogenic differentiation were treated with increasing doses of TRAIL for 6, 12, and 24 h. The production of several pro-inflammatory cytokines (IL6, IL8, and MCP1) was analyzed by qPCR and ELISA.
Results: In SGBS adipocytes, TRAIL increased the expression of IL6, IL8, and MCP1 in a dose-dependent manner. After 6 h of treatment, we observed a 3.7-fold increase in IL6, a 15-fold increase of IL8 and 3.8-fold increase of MCP1 mRNA compared to vehicle-treated control cells. Comparable results were observed on the protein level. We next sought to identify the molecular events causing these changes in gene expression. Upon TRAIL stimulation, we observed a rapid cleavage of caspases. Treatment with the pan-caspase inhibitor zVAD.fmk abolished the upregulation of IL6, but not that of IL8 or MCP1. In contrast, genetic ablation of caspase-8 by shRNA negated the TRAIL-induced upregulation of all three cytokines. This suggests that the presence and activation of caspase-8 is important for the TRAIL-induced upregulation of IL6, whereas only the presence of caspase-8 is necessary for mediating TRAILs effect on IL8 and MCP1 expression.
Conclusion: TRAIL increases the production of pro-inflammatory cytokines in human adipocytes in a caspase-dependent manner. Our findings suggest that in the context of obesity, TRAIL might be an important player modulating the adipocyte secretion profile.
Nominated for a Presidential Poster Award.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology