Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols

Highlights

• TNF-α is one of the major mediators of inflammation.

• TNF activates inflammatory pathways through activation of nuclear factor (NF)-κB.

• Plant-based polyphenols suppress TNF-activated NF-κB pathway.

• Polyphenols have been shown to modulate inflammatory pathways.

• Polyphenols have a potential in prevention of chronic diseases.

Abstract

Human tumor necrosis factor (TNF), first isolated by our group as an anticancer agent, has been now shown to be a primary mediator of inflammation. Till today 19 different members of the TNF superfamily which interact with 29 different receptors, have been identified. Most members of this family exhibit pro-inflammatory activities, in part through the activation of the transcription factor, nuclear factor-kappaB (NF-κB). Thus TNF and the related pro-inflammatory cytokines have been shown to play a key role in most chronic diseases such as cancer, rheumatoid arthritis, cardiovascular diseases, psoriasis, neurologic diseases, Crohn’s disease, and metabolic diseases. Therefore, agents that can modulate the TNF-mediated inflammatory pathways may have potential against these pro-inflammatory diseases. Although blockers of TNF-α, such as infliximab (antibody against TNF-α), adalimumab (humanized antibody against TNF-α), and etanercept (soluble form of TNFR2) have been approved for human use, these blockers exhibit numerous side effects. In this review, we describe various plant-derived polyphenols that can suppress TNF-α activated inflammatory pathways both in vitro and in vivo. These polyphenols include curcumin, resveratrol, genistein, epigallocatechin gallate, flavopiridol, silymarin, emodin, morin isoliquiritigenin, naringenin, ellagic acid, apigenin, kaempferol, catechins, myricetin, xanthohumol, fisetin, vitexin, escin, mangostin and others. Thus these polyphenols are likely to have potential against various pro-inflammatory diseases.

Introduction

Extensive research over the past several years has shown that chronic inflammation causes numerous human chronic diseases, including cardiovascular, pulmonary, autoimmune, and degenerative diseases; cancer; diabetes; and Alzheimer disease [1]. While acute inflammation is therapeutic, chronic inflammation causes numerous chronic diseases. At the molecular level, inflammation is regulated by numerous molecules and factors, including cytokines [interleukin (IL)-1, IL-2, IL-6, IL-12, tumor necrosis factor (TNF)-α, TNF-β],¹ chemokines (monocyte chemoattractant protein 1, IL-8), proinflammatory transcription factors [nuclear factor-kappaB (NF-κB), signal transducer and activator of transcription (STAT)-3], proinflammatory enzymes [cyclooxygenase (COX)-2, 5-lipoxygenase (LOX), 12-LOX, matrix metalloproteinases (MMPs), prostate-specific antigen (PSA), C-reactive protein, adhesion molecules [intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM)-1, endothelial–leukocyte adhesion molecule (ELAM)-1), vascular endothelial growth factor (VEGF), and TWIST [1]. Among all these mediators, NF-κB is the central regulator of inflammation [1], [2]. It has been shown to activate more than 500 genes, most of which are implicated in inflammation [3], [4].

The association between inflammation and cancer is supported by epidemiological, pharmacological, and genetic studies [5]. That most cancers, especially solid tumors, are preceded by inflammation is evident from numerous studies. For instance, smokers are more susceptible to bronchitis. According to one report, 15–20% of smokers with bronchitis have a tendency to develop lung cancer [6]. Similarly, people who have colitis are at high risk of developing colon cancer [7]. Infection with Helicobacter pylori has been shown to induce gastritis, which in its chronic form can lead to gastric cancer [8]. Chronic inflammation is now known to induce various steps of tumorigenesis, including cellular transformation, survival, proliferation, invasion, angiogenesis, and metastasis [9], [10].

Most chronic diseases are caused by chronic inflammation and thus are potentially preventable by chronic treatment. In addition, most chronic diseases are caused by perturbations in multiple inflammatory molecules. Yet, most of the currently available treatments are based on the modulation of a single target and produce numerous side effects [11], [12], [13], [14]. The current paradigm for treatment of chronic diseases is either to combine several mono-targeted drugs or to design drugs that modulate multiple targets. Plant-derived polyphenols have gained considerable attention over the past decade because of their potential to target multiple inflammatory molecules. How these polyphenols target inflammatory pathways is the focus of this review.