Polyphenol-rich grape powder extract (GPE) attenuates inflammation in human macrophages and in human adipocytes exposed to macrophage-conditioned media

Abstract

Background: Obesity-associated inflammation is characterized by an increased abundance of macrophages (MFs) in white adipose tissue (WAT), leading to the production of inflammatory cytokines, chemokines and prostaglandins (PGs) that can cause insulin resistance. Grape powder extract (GPE) is rich in phenolic phytochemicals that possess anti-oxidant and antiinflammatory properties. Objective: We examined the ability of GPE to prevent lipopolysaccharide (LPS)-mediated inflammation in human MFs and silence the cross-talk between human MFs and adipocytes. Design: We investigated the effect of GPE pretreatment on LPS-mediated activation of mitogen activated protein kinases (MAPKs), nuclear factor kappa B (NF-kB) and activator protein-1 (AP-1), and induction of inflammatory genes in human MFs (that is, differentiated U937 cells). In addition, we determined the effect of GPE pretreatment of MFs on inflammation and insulin resistance in primary human adipocytes incubated with LPS-challenged MF-conditioned medium (MF-CM). Methods and Results: Pretreatment of MFs with GPE attenuated LPS-induction of inflammatory cytokines, such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) and IL-1b; chemokines, such as IL-8 and interferon-g inducible protein-10 (IP-10); and a marker of PG production, cyclooxygenase-2 (COX-2). Grape powder extract also attenuated LPS activation of MAPKs, NF-kB and AP-1 (c-Jun), as evidenced by decreased (1) phosphorylation of c-Jun NH 2 -terminal kinase (JNK) and p38; (2) degradation of IkBa and activation of an NF-kB reporter construct; and (3) phosphorylation of c-Jun and Elk-1. Using LPSchallenged MF-CM, GPE pretreatment attenuated MF-mediated inflammatory gene expression, activation of an NF-kB reporter and suppression of insulin-stimulated glucose uptake in human adipocytes. Conclusion:Collectively, these data demonstrate that GPE attenuates LPS-mediated inflammation in MFs, possibly by decreasing the activation of MAPKs, NF-kB and AP-1, and that GPE decreases the capacity of LPS-stimulated MFs to inflame adipocytes and cause insulin resistance.

Quercetin attenuates inflammation in human macrophages and adipocytes exposed to macrophage-conditioned media

“…16 Consistent with these data, we recently found that a grape powder extract (GPE) made from table grapes from the California Table Grape Commission attenuated inflammatory signaling, such as MAPKs and transcription factors NFkB and activator protein (AP)-1 in human MFs, and cross-talk with adipocytes. 18 Furthermore, we found that this GPE had relatively high levels of quercetin (QUE). However, the ability of QUE alone to prevent inflammation in human MFs, and block inflammation and insulin resistance in human adipocytes treated with MF-conditioned media (CM) is unknown.…”

“…13,[38][39][40] Consistent with these findings, we previously reported that LPS increased the activation of MAPK, NFkB and AP-1 in human MFs, increasing their capacity to cause inflammation and insulin resistance in primary human adipocytes. 18 Pretreatment of human MFs with GPE, which is rich in QUE, attenuated inflammation in MFs and adipocytes, and MF-mediated insulin resistance in adipocytes. 18 Mechanisms by which polyphenols like QUE have been reported to reduce inflammation include: (1) serving as an antioxidant or inducing the expression of antioxidant genes, (2) interfering with inflammatory signaling pathways, (3) blocking inflammatory gene expression by preventing histone acetylation, or (4) increasing the activation of transcription factors that antagonize NFkB or AP-1 (see reference 41).…”

“…18 Pretreatment of human MFs with GPE, which is rich in QUE, attenuated inflammation in MFs and adipocytes, and MF-mediated insulin resistance in adipocytes. 18 Mechanisms by which polyphenols like QUE have been reported to reduce inflammation include: (1) serving as an antioxidant or inducing the expression of antioxidant genes, (2) interfering with inflammatory signaling pathways, (3) blocking inflammatory gene expression by preventing histone acetylation, or (4) increasing the activation of transcription factors that antagonize NFkB or AP-1 (see reference 41). Concerning this last mechanism, QUE may block inflammation by increasing PPARg expression or activation.…”

Mecanismos moleculares de ação anti-inflamatória e antioxidante de polifenóis de uvas e vinho tinto na aterosclerose

“…A modulação das enzimas antioxidantes por polifenóis parece ocorrer via ativação do fator de transcrição "Nuclear factor-E2-related factor" (Nrf2) (Chuang & Mcintosh, 2011;Palsamy & Subramanian, 2011). Este pode ser um mecanismo crucial pelo qual os polifenóis conferem cardioproteção.…”

“…Em macrófagos humanos com inflamação mediada pelo LPS, extratos de uva (Vitis labrusca) em pó (GPE) atenuaram a fosforilação da JNK e p38 e diminuíram a degradação do IkBá e a fosforilação da c-Jun, bem como bloquearam o NF-kB. Fato interessante observado é que o GPE não produziu os mesmos efeitos na ausência do LPS (Overman et al, 2010). Em adipócitos pré-diferenciados, o GPE atenuou a inflamação mediada por TNF-á por meio da inibição da expressão das IL-6, IL-1â, IL-8, MCP-1, COX-2 e do receptor toll-like 2 e da inibição do AP-1 e do NFkB, sendo o efeito dose-dependente (Chuang et al, 2011).…”