Caffeic Acid Phenethyl Ester Suppresses the Production of Pro-inflammatory Cytokines in Hypertrophic Adipocytes through Lipopolysaccharide-Stimulated Macrophages

Abstract

Obesity is a condition in which excess body fat accumulates due to lipids producing adipocytes and an increased number of differentiated mature cells. Recently, new findings have shown that macrophages infiltrate into adipose tissues and produce various pro-inflammatory cytokines in obese subjects. The inflammatory changes induced by the cross-talk between adipocytes and macrophages are critical for the pathophysiology of obesity and thus of metabolic syndrome. Caffeic acid phenethyl ester (CAPE) is known to have many functions, including antibacterial, anticancer and anti-inflammatory properties, but there is no evidence of its effect on the inflammatory responses in hypertrophic adipocytes through stimulation by macrophages. We investigated the effect of CAPE on macrophages and hypertrophic adipocytes in this study. CAPE significantly suppressed the levels of lipopolysaccharide (LPS)-induced interleukin (IL)-1-beta, tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1 from a macrophage cell line, RAW264.7. Supernatants of stimulated RAW264.7 macrophages drastically increased mRNA levels of pro-inflammatory cytokines such as IL-6, MCP-1 and TNF-alpha in 3T3-L1 hypertrophic adipocytes. CAPE also significantly and dose-dependently reduced the gene expression of these cytokines. Our findings indicate that CAPE has inhibitory effects on the production of pro-inflammatory cytokines from LPS-stimulated RAW264.7 macrophages. In addition, CAPE suppressed gene expressions of cytokines under inflammatory conditions of hypertrophic adipocytes, suggesting that it may have the potential to suppress inflammation by macrophage infiltration into adipose tissue in obese patients.Key words caffeic acid phenethyl ester; hypertrophic adipocyte; macrophage; pro-inflammatory cytokine Obesity is a major risk factor for metabolic syndrome, which includes a number of disorders, such as hypertension, heart diseases and diabetes.1,2) Obesity is a condition in which excess body fat accumulates due to lipids producing hypertrophic adipocytes and an increased number of differentiated mature cells. This process is regulated by genetic and environmental factors, such as nutrient intake.3,4) It is known that adipocytes in obese individuals show cell hypertrophy and chronic inflammation. The inflammatory changes induced by the cross-talk between adipocytes and macrophages are critical for the pathophysiology of obesity and thus of metabolic syndrome. 5,6) Recent studies have demonstrated that obese adipose tissue is characterized by increased infiltration of macrophages, 7,8) which produce various inflammatory proteins. The inflammation process is associated with the activation of macrophages and the release of pro-inflammatory cytokines, such as interleukin (IL)-1-beta, tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6. 9,10) MCP-1, known to play a pivotal role in macrophage trafficking and activation, is produced by macrophages and adipocytes. Several reports suggest t...

Caffeic acid phenethyl ester suppresses oxidative stress in 3T3-L1 adipocytes

“…The addition of CAPE during adipocyte differentiation caused a reduction in intercellular lipid accumulation as compared with the control. CAPE did not changed the growth of 3T3-L1 cells [14,16]. …”

Therapeutic potential of caffeic acid phenethyl ester and its anti-inflammatory and immunomodulatory effects (Review)

“…In another in vitro study, CAPE significantly suppressed the levels of lipopolysaccharide (LPS)-induced IL-1β, TNF-α and MCP-1 from a macrophage cell line, RAW264.7 (35). Furthermore, in a recent study of RAW264.7 murine macrophage in vivo models, CAPE reduced the production of cytotoxic molecules, such as NO and peroxynitrite, and thus suppressed the inflammatory responses that could have resulted in cell damage and, potentially, cell death.…”

“…Several proposed molecular anti-inflammatory mechanisms of CAPE have been suggested by in vivo and in vitro studies. Table I (22,23,30,34,35,(46)(47)(48)(49)(50) summarizes the anti-inflammatory effects of CAPE.…”

Caffeic Acid Phenethyl Ester: Consequences of Its Hydrophobicity in the Oxidative Functions and Cytokine Release by Leukocytes

“…Hence, there are numerous demonstrations of the beneficial effect of natural compounds that, besides antioxidative effects, also decrease the production of TNF-α and other proinflammatory cytokines [10, 45, 46]. C2 is included in this class of natural antioxidants that are able to inhibit the release of TNF in many experimental models and using different cell/tissue models [2, 47, 48]. Indeed, C2 was described as a potent and a specific inhibitor of NF-kappa B in the human U937 cell lineage [49].…”