Human Breast Adipocytes Express Interleukin-6 (IL-6) and Its Receptor System: Increased IL-6 Production by β-Adrenergic Activation and Effects of IL-6 on Adipocyte Function

Abstract

Adipocytes produce the inflammatory cytokine interleukin-6 (IL-6); however, it is not known whether these cells express the IL-6 receptor system, how the secretion of this cytokine is regulated, and whether it has a function within adipose tissue. Using cultured human breast adipocytes, we investigated the expression of IL-6 and its receptor system, the effects of IL-6 on main adipocyte functions, and the regulation of IL-6 secretion by catecholamines and glucocorti-coids. In the culture system, immunohistochemistry demonstrated expression of IL-6 and its receptor system, consisting of the ligand-binding IL-6 receptor and the signal-transducing protein gp130, in mature adipocytes, but not in undifferentiated adipocyte precursor cells. In freshly isolated adipocytes, RT-PCR detected messenger ri-bonucleic acids encoding the above proteins. Chronic incubation of adipocytes with 1 nmol/L IL-6 during adipose differentiation reduced glycero-3-phosphate dehydrogenase (GPDH) activity, a marker of adi-pocyte differentiation, and triglyceride synthesis to 67 9% of the basal level (mean SEM; P 0.05) only on day 21. Incubation of differentiated adipocytes with 10 nmol/L IL-6 for 24 h also resulted in a reduction of GPDH activity to 81 5% (P 0.05). On the other hand, 24-h exposure to 10 nmol/L IL-6 increased basal glycerol release by 42 12% (P 0.01) and isoproterenol-induced glycerol release by 21 6% (P 0.05). The same concentration of IL-6, however, did not alter basal or insulin-stimulated glucose transport. IL-6 secretion was acutely and chronically stimulated by 1 mol/L isoproterenol (peak of 6.2-fold after 3 h; P 0.001) and only moderately suppressed by 100 nmol/L cortisol (36 10%; P 0.001). In conclusion, human breast adipocytes release substantial amounts of IL-6 and express IL-6 receptor and gp130. The secretion of IL-6 by adipocytes is strongly stimulated by-adrenergic activation and is modestly suppressed by glucocorticoids. IL-6 reduces GPDH activity and stimulates lipolysis, suggesting an autocrine/paracrine role of this cytokine in human adipose breast tissue. (J Clin Endocrinol Metab 86: 2281-2288, 2001) H UMAN ADIPOSE TISSUE secretes a large number of hormones that act either locally or at distant sites (1). Among them is the ubiquitous and multifunctional cytokine interleukin-6 (IL-6) (2-5), which is involved in immune responses , inflammation, hemopoiesis, and many endocrine and metabolic functions (6, 7). Measurement of arterio-venous differences in IL-6 concentrations across an sc adi-pose tissue bed showed that this cytokine is released by human adipose tissue in vivo, indicating that peripheral fat contributes to circulating IL-6 concentrations in man (3). This is in line with the finding that circulating IL-6 levels are elevated in obesity and are positively correlated with the body mass index (BMI) (8). The capacity of human adipo-cytes to release IL-6 was demonstrated in a recent study that reported substantial amounts of IL-6 in the supernatants of freshly isolated human adipocytes (4). In addition, high levels of IL-6 were found in the interstitial fluid of sc abdominal adipose tissue in normal volunteers (5). Catecholamines are known as powerful lipolytic hormones in humans (9), whereas glucocorticoids increase the expression and activity of lipoprotein lipase (LPL), the key enzyme for fatty acid uptake (10-12). Regarding IL-6, a positive correlation was observed between exercise-induced peak plasma epinephrine or norepinephrine and IL-6 levels in humans (13), whereas glucocorticoids suppress IL-6 production in vitro and in vivo (13-17). In rodents, IL-6 levels are closely related to psychological and physiological stress, which induces catecholamine release (18, 19). Administration of epinephrine to rats in vivo resulted in a dose-dependent increase in plasma IL-6 concentrations (20). In vitro, norepinephrine and-adrenergic agonists stimulated IL-6 release from murine brown adipocytes (21). On the other hand, treatment with IL-6 is known to influence energy metabolism ; IL-6 reduces the production and activity of LPL in adipose tissue of mice in vivo and in murine 3T3-L1 adipo-cytes in vitro (10, 12) and increases hepatic de novo fatty acid synthesis (20, 23). Administration of IL-6 to mice resulted in weight loss, which was prevented by pretreatment with monoclonal antibodies against IL-6 (24). As adipose tissue is innervated by postganglionic sympathetic nerves releasing norepinephrine, the regulation of adipocyte IL-6 production via-adrenergic receptor activation is of interest concerning the hypothesis that some of the catecholamine-induced cat-abolic effects could be mediated or potentiated by IL-6.