Immunomodulatory properties of cacao extracts - potential consequences for medical applications

Abstract

Anti-inflammatory properties of cacao, fruits of Theobroma cacao L. (Sterculiaceae), are well documented, and therapeutic applications are described for gastrointestinal, nervous, and cardiovascular abnormalities. Most, if not all of these disease conditions involve inflammation or immune activation processes. The pro-inflammatory cytokine interferon-γ (IFN-γ) and related biochemical pathways like tryptophan breakdown by indoleamine 2,3-dioxygenase (IDO) and neopterin formation are deeply involved in their pathogenesis. Neopterin concentrations and the kynurenine to tryptophan ratio (Kyn/Trp, an estimate of IDO activity) are elevated in a significant proportion of patients with virus infections, cancer, autoimmune syndrome, neurodegeneration, and coronary artery disease. Moreover, higher neopterin and Kyn/Trp concentrations are indicative for poor prognosis. When investigating the effect of aqueous or ethanolic extracts of cacao on IFN-γ, neopterin and Kyn/Trp concentrations in mitogen-stimulated human peripheral blood mononuclear cells, breakdown of tryptophan by IDO, and formation of neopterin and IFN-γ were dose-dependently suppressed. The effects observed in the cell-based assays are associated with the antioxidant activity of the cacao extracts as determined by the cell-free oxygen radical absorption capacity assay. The influence of cacao extracts on IDO activity could be of particular relevance for some of the beneficial health effects ascribed to cacao: tryptophan breakdown by IDO is strongly involved in immunoregulation, and the diminished availability of tryptophan limits the biosynthesis of neurotransmitter serotonin. The inhibition of tryptophan breakdown by cacao constituents could thus be relevant not only for immune system restoration in patients, but also contribute to mood elevation and thereby improve quality of life. However, the available data thus far are merely in vitro only and future studies need to investigate the influence of cacao on tryptophan metabolism in vivo.

Keywords: anti-inflammatory; cacao; cocoa; immunology; neurobiochemistry; tryptophan metabolism.

FIGURE 1

The essential amino acid tryptophan is required for protein biosynthesis or is metabolized via two biochemical routes: (i) via tryptophan 5-hydroxylase (T5H) and subsequent decarboxylation to 5-hydroxytrytophan and serotonin, and (ii) via tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) to kynurenine, which is fur-ther converted to several metabolites (adapted from Widner et al., 2002).

FIGURE 2

In various cells the Th1-type cytokine interferon-γ (IFN-γ) induces the GTP-cyclohydrolase I (GCH I) to produce 7,8-dihydroneopterintriphosphate. Due to a deficiency in pyruvoyltetrahydropterin synthase (PTPS) in human monocyte-derived macrophages and dendritic cells, the production of 5,6,7,8-tetrahydrobiopterin is almost zero and neopterin is produced in high concentrations.

FIGURE 3

Mean neopterin and tryptophan concentrations in mitogen (PHA)-stimulated freshly isolated peripheral blood mononuclear cells (PBMCs), either treated with 10 μg/ml aqueous cacao extracts or left untreated, compared to unstimulated controls. The results are shown in % of the baseline in the supernatants of unstimulated PBMC. Experiments were run in duplicates and in four independent approaches [**p < 0.05 compared to unstimulated cells; #p < 0.05 compared to stimulated cells; adapted from Jenny et al. (2009)].

FIGURE 4

During Th1-type immune response, activated T-cells and natural killer (NK) cells release large amounts of the inflammatory cytokine interferon-γ (IFN-γ), which triggers various immunoregulatory and anti-proliferative activities in target cells like macrophages (MΦ) and dendritic cells (DC). Indoleamine 2,3-dioxygenase (IDO) converts tryptophan into kynurenine. In parallel GTP-cyclohydrolase I (GCH) is induced to produce neopterin out of GTP. Neopterin plays a major role in the release of reactive oxygen species (ROS) in human macrophages. When oxidative stress is rising to higher levels, transcription factor nuclear factor-κB (NF-κB) becomes activated and induces the pro-inflammatory signaling pathways. Cacao, acting as an antioxidant, can influence and counteract against these cascades.