interleukin-8 and Gigantism

In the member countries of the Organization for Economic Co-operation and Development (OECD), overweight and obesity affect the majority of the population. The use of environmental chemicals, such as the plasticizer DEHP, has largely increased simultaneously with this development. DEHP is an "obesogen" that interferes with normal adipocyte differentiation and energy homeostasis. Obesity in turn is accompanied by chronic low-grade adipose tissue inflammation, leading to metabolic disorders such as type II diabetes. The main actors in adipose tissue inflammation are adipocytes and macrophages. However, the impact of DEHP on adipose tissue inflammation and the crosstalk between adipocytes and macrophages are unknown and the subjects of the current study. The influence of DEHP on inflammation was investigated in human Simpson-Golabi-Behmel syndrome (SGBS)-derived adipocytes and human THP-1 macrophages. The proinflammatory markers IL8, MCP1, IL1β, TNFα and others were measured (qRT-PCR, ELISA) in SGBS-derived adipocytes treated with DEHP [day 0 (d0)-d4; 50 µg/ml] and THP-1 macrophages cultured with conditioned medium (CM) from DEHP-treated adipocytes (SGBS-CM) (from d4 and d8). DEHP exposure led to a proinflammatory state in SGBS-derived adipocytes (e.g., increased secretion of IL8 and MCP1). Surprisingly, exposure of THP-1 macrophages to SGBS-CM did not show DEHP-induced effects. However, we demonstrated that medium containing (pre)adipocyte-secreted factors had a significant impact on the expression and secretion of macrophage and inflammatory markers in THP-1 macrophages in general and led to the significantly increased accumulation of intracellular lipid droplets.

Topics: Adipocytes; Arrhythmias, Cardiac; Chemokine CCL2; Culture Media, Conditioned; Cytokines; Diethylhexyl Phthalate; Fluorescence; Gene Expression Regulation; Genetic Diseases, X-Linked; Gigantism; Heart Defects, Congenital; Humans; Inflammation; Intellectual Disability; Interleukin-8; Lipid Droplets; Macrophages; RNA, Messenger; THP-1 Cells

Adipocyte-macrophage crosstalk plays a critical role to regulate adipose tissue microenvironment and cause chronic inflammation in the pathogenesis of obesity. Interleukin-29 (IL-29), a member of type 3 interferon family, plays a role in host defenses against microbes, however, little is known about its role in metabolic disorders. We explored the function of IL-29 in the pathogenesis of obesity-induced inflammation and insulin resistance. We found that serum IL-29 level was significantly higher in obese patients. IL-29 upregulated IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) expression and decreased glucose uptake and insulin sensitivity in human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes through reducing glucose transporter 4 (GLUT4) and AKT signals. In addition, IL-29 promoted monocyte/macrophage migration. Inhibition of IL-29 could reduce inflammatory cytokine production in macrophage-adipocyte coculture system, which mimic an obese microenvironment. In vivo, IL-29 reduced insulin sensitivity and increased the number of peritoneal macrophages in high-fat diet (HFD)-induced obese mice. IL-29 increased M1/M2 macrophage ratio and enhanced MCP-1 expression in adipose tissues of HFD mice. Therefore, we have identified a critical role of IL-29 in obesity-induced inflammation and insulin resistance, and we conclude that IL-29 may be a novel candidate target for treating obesity and insulin resistance in patients with metabolic disorders.

Topics: Adipocytes; Adipose Tissue; Animals; Arrhythmias, Cardiac; Cell Differentiation; Cell Movement; Chemokine CCL2; Diet, High-Fat; Genetic Diseases, X-Linked; Gigantism; Glucose Transporter Type 4; Heart Defects, Congenital; Inflammation; Insulin Resistance; Intellectual Disability; Interferons; Interleukin-1beta; Interleukin-6; Interleukin-8; Interleukins; Lipopolysaccharides; Macrophages; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Interleukin; Up-Regulation

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.

Topics: Adipocytes; Adult; Arrhythmias, Cardiac; Cells, Cultured; Chemokine CCL2; Chemokine CCL20; Genetic Diseases, X-Linked; Gigantism; Heart Defects, Congenital; Humans; Inflammation; Intellectual Disability; Interleukin-6; Interleukin-8; Mitogen-Activated Protein Kinases; NF-kappa B; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand

The obesity-associated inflammation of white adipose tissue (WAT) is one of the factors leading to the development of related diseases such as insulin resistance and liver steatosis. Recently, microRNAs (miRNAs) were identified as important regulators of WAT functions. Herein, we cultured human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes with macrophage-conditioned medium (MacCM) and performed an Affimetrix miRNA array to identify miRNAs differentially expressed under inflammatory conditions. We identified 24 miRNAs differentially expressed upon inflammation in human adipocytes and miR-146a was the most up-regulated miRNA species. In subcutaneous WAT, miR-146a was elevated in both human and murine obesity. Transfection of miR-146a mimics prevented the MacCM-induced inflammatory response in SGBS adipocytes as seen by reduced levels of IL-8 and MCP-1 mRNA and protein. We identified IRAK1 and TRAF6 as targets of miR-146a in human adipocytes and detected a reduced inflammation-induced activation of JNK and p38 upon miR-146a transfection. Taken together, we could show that miR-146a reduces the inflammatory response in human adipocytes. In a negative feedback loop miR-146a might contribute to the regulation of inflammatory processes in WAT and possibly prevent an overwhelming inflammatory response.

Topics: Adipocytes, White; Adipose Tissue, White; Arrhythmias, Cardiac; Chemokine CCL2; Culture Media, Conditioned; Feedback, Physiological; Female; Gene Expression Regulation; Genetic Diseases, X-Linked; Gigantism; Heart Defects, Congenital; Humans; Inflammation; Intellectual Disability; Interleukin-1 Receptor-Associated Kinases; Interleukin-8; Intracellular Signaling Peptides and Proteins; Macrophages; MAP Kinase Kinase 4; MicroRNAs; Molecular Mimicry; Oligonucleotide Array Sequence Analysis; Oligoribonucleotides; p38 Mitogen-Activated Protein Kinases; Primary Cell Culture; RNA, Small Interfering; Signal Transduction; TNF Receptor-Associated Factor 6; Transfection