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.
Subject(s)
Adipocytes/drug effects , Inflammation/physiopathology , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Adult , Arrhythmias, Cardiac , Cells, Cultured , Chemokine CCL2/metabolism , Chemokine CCL20 , Genetic Diseases, X-Linked , Gigantism , Heart Defects, Congenital , Humans , Intellectual Disability , Interleukin-6/metabolism , Interleukin-8/metabolism , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Signal TransductionABSTRACT
Tumor necrosis factor-α (TNFα) and other ligands of the TNF superfamily are potent regulators of adipose tissue metabolism and play a crucial role in the obesity-induced inflammation of adipose tissue. Adipose tissue expression levels of TRAIL (TNF-related apoptosis-inducing ligand) and its receptor were shown to be upregulated by overfeeding and decreased by fasting in mice. In the present study we aimed to elucidate the impact of TRAIL on adipogenesis. To this end, human Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes as well as stromal-vascular cells isolated from human white adipose tissue were used as model systems. Human recombinant TRAIL inhibited adipogenic differentiation in a dose-dependent manner. It activated the cleavage of caspase-8 and -3, which in turn resulted in a downregulation of the key adipogenic transcription factors C/EBPα, C/EBPδ, and PPARγ. The effect was completely blocked by pharmacological or genetic inhibition of caspases. Taken together we discovered a so far unrecognized function of TRAIL in the regulation of adipogenesis. Targeting the TRAIL/TRAIL receptor system might provide a novel strategy to interfere with adipose tissue homeostasis.
Subject(s)
Adipocytes/cytology , Adipocytes/enzymology , Adipogenesis/drug effects , Caspases/metabolism , Cell Differentiation/drug effects , Down-Regulation/drug effects , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Transcription Factors/metabolism , Adipocytes/drug effects , Adult , Arrhythmias, Cardiac/pathology , Enzyme Activation/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Genetic Diseases, X-Linked/pathology , Gigantism/pathology , Heart Defects, Congenital/pathology , Humans , Intellectual Disability/pathology , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Signal Transduction/drug effects , Stromal Cells/drug effects , Stromal Cells/metabolism , Stromal Cells/pathologyABSTRACT
Irritable bowel syndrome is a disorder of the gastrointestinal tract with unknown etiology. Recent clinical data support a link between changes in fecal microbiota with decreased biodiversity and the development of irritable bowel syndrome. Whether these changes of the microbiota are caused by the disease or whether they develop during the course of the disease remains unclear. Several studies demonstrated that fecal microbiota transfer (FMT) successfully attenuates Clostridium difficile infection by restoring the disturbed bacterial flora of the gut and case reports suggest that FMT may relief symptoms in patients with irritable bowel syndrome (IBS). Here we report a 47-year-old male patient with longstanding refractory diarrhea predominant IBS, who was successfully treated with a single FMT. The beneficial effect on the patient's symptoms was associated with changes of the stool microbiome. Post-FMT the recipient's microbiome resembled the donor's microbiome.
Subject(s)
Biological Therapy/methods , Feces/microbiology , Irritable Bowel Syndrome/therapy , Colonoscopy , Diagnosis, Differential , Follow-Up Studies , Humans , Irritable Bowel Syndrome/diagnosis , Male , Middle AgedABSTRACT
Upon obesity, adipose tissue is excessively expanded and characterized by pathologic processes like hypoxia, fibrosis, and inflammation. Death ligands belonging to the TNF superfamily such as TNF-α are important contributors to these derangements and exert a pronounced influence on the metabolic and cellular homeostasis of adipose tissue. Here, we sought to identify the effect of the death ligand TNF-related apoptosis-inducing ligand (TRAIL) on the adipose tissue precursor cell pool and therefore investigated its influence on preadipocyte proliferation. Treatment of human preadipocytes with TRAIL resulted in a time- and dose-dependent increase in proliferation (EC50 3.4 ng/ml) comparable to IGF-1. Although no apoptosis was observed, TRAIL triggered a rapid cleavage of caspase-8 and -3. Neither inhibition of caspase activity by zVAD.fmk (20 µM) nor ablation of caspase-8 expression by lentivirus-delivered small hairpin RNA (shRNA) abolished the proliferative response. TRAIL triggered a delayed and sustained activation of ERK1/2, leaving Akt, p38, JNK, and NF-κB unaffected. Importantly, inhibition of ERK1/2 activation by PD0325901 (300 nM) or AZD6244 (5 or 10 µM) completely abolished the proliferative response. We thus reveal a hitherto unknown function of TRAIL in regulating adipose tissue homeostasis by promoting the proliferation of tissue-resident precursor cells.