Curcumin and resveratrol inhibit nuclear factor-kappaB-mediated cytokine expression in adipocytes

Abstract

BackgroundAdipocytes express inflammatory mediators that contribute to the low-level, chronic inflammation found in obese subjects and have been linked to the onset of cardiovascular disorders and insulin resistance associated with type 2 diabetes mellitus. A reduction in inflammatory gene expression in adipocytes would be expected to reverse this low-level, inflammatory state and improve cardiovascular function and insulin sensitivity. The natural products, curcumin and resveratrol, are established anti-inflammatory compounds that mediate their effects by inhibiting activation of NF-κB signaling. In the present study, we examined if these natural products can inhibit NF-κB activation in adipocytes and in doing so reduce cytokine expression.MethodsCytokine (TNF-α, IL-1β, IL-6) and COX-2 gene expression in 3T3-L1-derived adipocytes was measured by quantitative real-time PCR (qRT-PCR) with or without TNFα-stimulation. Cytokine protein and prostaglandin E2 (PGE2) expression were measured by ELISA. Effects of curcumin and resveratrol were evaluated by treating TNFα-stimulated adipocytes with each compound and 1) assessing the activation state of the NF-κB signaling pathway and 2) measuring inflammatory gene expression by qRT-PCR and ELISA.ResultsBoth preadipocytes and differentiated adipocytes express the genes for TNF-α, IL-6, and COX-2, key mediators of the inflammatory response. Preadipocytes were also found to express IL-1β; however, IL-1β expression was absent in differentiated adipocytes. TNF-α treatment activated NF-κB signaling in differentiated adipocytes by inducing IκB degradation and NF-κB translocation to the nucleus, and as a result increased IL-6 (6-fold) and COX-2 (2.5-fold) mRNA levels. TNF-α also activated IL-1β gene expression in differentiated adipocytes, but had no effect on endogenous TNF-α mRNA levels. No detectable TNFα or IL-1β was secreted by adipocytes. Curcumin and resveratrol treatment inhibited NF-κB activation and resulted in a reduction of TNF-α, IL-1β, IL-6, and COX-2 gene expression (IC50 = 2 μM) and a reduction of secreted IL-6 and PGE2 (IC50 ~ 20 μM).ConclusionCurcumin and resveratrol are able to inhibit TNFα-activated NF-κB signaling in adipocytes and as a result significantly reduce cytokine expression. These data suggest that curcumin and resveratrol may provide a novel and safe approach to reduce or inhibit the chronic inflammatory properties of adipose tissue.

Curcumin and its allied analogues: epigenetic and health perspectives - a review

“…Another study supported previous findings; they determined that the phospholipid lecithin formulation of standardised curcuminoids (Meriva ® ) increased the curcuminoid absorption up to 29 times as compared to an unformulated curcuminoid mixture, but on the other side with demethoxycurcumin they attained the maximum systemic bioavailability and absorption (Garcea et al 2004). Nevertheless, µg of curcuminoid in plasma remained appreciably less than that required for the inhibition of anti-inflammatory targets identified by curcumin (Gonzales & Orlando 2008). Likewise, Shao et al (2011) synthesised curcumin-loaded spherical core-shell structure nanoparticles composed of methoxy poly(ethylene glycol)-poly block copolymers (mPEG-PCL) in a laboratory.…”

Resveratrol reduces chronic inflammation and improves insulin action in the myocardium of high-fat diet-induced obeserats

“…The IKK/NF-κB inflammatory pathway and TNFα have a critical role in the development of insulin resistance in pathophysiological conditions like obesity 14 . Highfat diet-induced obese rodents presented a significant increase in insulin resistance and expression of inflammatory cytokines, such as IL-1β, IL-6, TNFα, and NF-κB 13 . In states such as insulin resistance, cytokines such as TNFα activate IKKα and IKKβ by intermediate signaling pathways.…”

“…Some nutrients increase insulin action significantly 13,14 , such as resveratrol (3,5,4'-trihydroxystilbene), a phytoalexin found in plants and some foods, including peanuts, mulberries, and grapes 15 . Resveratrol provides cardiovascular protection 16 , inhibits platelet aggregation 17 , reduces inflammatory factors 18 , and improves glucose homeostasis 19 .…”

Anti-Inflammatory Role of Natural Polyphenols and Their Degradation Products

“…The release of various cytokines after various stimuli from macrophages and lymphocytes, such as IL-6 (Feng et al, 2002;Zhong et al, 1999), IFN , IL-2, TNF-, and IL-12 (Gao et al, 2001), has been shown to be inhibited by resveratrol. Resveratrol was also reported to suppress the activity of T-and B-cells, and macrophages the major cell types responsible for producing cytokines by decreasing the production of proinflammatory proteins, (Sharma et al, 2007) and it was able to reduce TNF-, IL-1 , IL-6, and COX-2 gene expression and to reduce the secretion of IL-6 and PGE2 in TNF--stimulated adipocytes (Gonzales & Orlando, 2008). In an age-related diseases study, mice treated with resveratrol had decreased expression of the inflammatory markers TNF-, IL-1 , IL-6, intercellular adhesion molecule (ICAM)-1 and iNOS (Pearson et al, 2008).…”