Elsevier

Biochemical Pharmacology

Volume 68, Issue 6, 15 September 2004, Pages 1171-1185
Biochemical Pharmacology

Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections: Multi-purpose nutraceuticals at the crossroad of hormone replacement, anti-cancer and anti-inflammatory therapy

https://doi.org/10.1016/j.bcp.2004.05.036Get rights and content

Abstract

Interleukin-6 is a pleiotropic cytokine which plays a crucial role in immune physiology and is tightly controlled by hormonal feedback mechanisms. After menopause or andropause, loss of the normally inhibiting sex steroids (estrogen, testosterone) results in elevated IL6 levels that are further progressively increasing with age. Interestingly, excessive IL6 production promotes tumorigenesis (breast, prostate, lung, colon, ovarian), and accounts for several disease-associated pathologies and phenotypical changes of advanced age, such as osteoporosis, rheumatoid arthritis, multiple myeloma, neurodegenerative diseases and frailty. In this respect, pharmacological modulation of IL6 gene expression levels may have therapeutical benefit in preventing cancer progression, ageing discomforts and restoring immune homeostasis. Although “plant extracts” are used in folk medicine within living memory, it is only since the 20th century that numerous scientific investigations have been performed to discover potential health-protective food compounds or “nutraceuticals” which might prevent cancer and ageing diseases. About 2000 years ago, Hippocrates already highlighted “Let food be your medicine and medicine be your food”. Various nutrients in the diet play a crucial role in maintaining an “optimal” immune response, such that deficient or excessive intakes can have negative consequences on the organism’s immune status and susceptibility to a variety of pathologies. Over the last few decades, various immune-modulating nutrients have been identified, which interfere with IL6 gene expression. Currently, a broad range of phyto-pharmaceuticals with a claimed hormonal activity, called “phyto-estrogens”, is recommended for prevention of various diseases related to a disturbed hormonal balance (i.e. menopausal ailments and/or prostate/breast cancer). In this respect, there is a renewed interest in soy isoflavones (genistein, daidzein, biochanin) as potential superior alternatives to the synthetic selective estrogen receptor modulators (SERMs), which are currently applied in hormone replacement therapy (HRT). As phyto-chemicals integrate hormonal ligand activities and interference with signaling cascades, therapeutic use may not be restricted to hormonal ailments only, but may have applications in cancer chemoprevention and/or NF-κB-related inflammatory disorders as well.

Section snippets

Soy isoflavone phyto-pharmaceuticals

Numerous botanical species and plant parts contain a diverse array of polyphenolic non-steroidal phyto-chemicals that are synthesized as floral pigments for the attraction of insect pollinators and as signal molecules for beneficial micro-organisms in the rhizosphere. Besides these functions, they also have a role as anti-microbial/fungal defense compounds, and furthermore afford photoprotection [1].

Based on their chemical structure, phenolic phyto-estrogens can be classified into four main

Health-beneficial effects of isoflavones

Impetus to the scientific inquiry into phyto-pharmaceutical effects is given by the epidemiological observation of striking historical and/or ethnic differences in hormone-related cancer rates and menopausal ailments [47], [50], [51]. The highest incidences of these cancers, menopausal symptoms as well as cardiovascular diseases are typically found in populations with western lifestyle, which include relatively high fat, meat-based and low-fiber diets [52]. Asian populations, however, with

IL6 physiology and pathology

The process of an inflammatory response to invading pathogens or damaging insults is of critical importance to the homeostasis of the human body. As this physiological inflammatory reaction, based on innate or adaptive immunity, determines health or illness, it needs to be precisely controlled by various feedback mechanisms [93], [94], [95], [96]. As such, balanced inflammation consequently allows acute timely effects but no accelerated overreaction or chronic responses. Furthermore,

NF-κB at the interface of inflammation and tumorigenesis: a paradigm for phyto-pharmaceuticals

A key player in IL6 gene expression is the transcription factor NF-κB, of which the transcriptional activity is regulated at multiple levels [99], [132], [133], [134], [135]. The NF-κB/IκB family of transcriptional regulators modulate the expression of a few hundred target genes, the majority of which participate in host immune responses [136], [137], [138], [139]. Gene knock-out and other studies not only establish roles for NF-κB in the ontogeny of the immune system, but also demonstrate that

IL6 gene regulation, HRT and “inflamm-ageing”

Transcription and expression of the multifunctional IL6 cytokine gene is tightly regulated at the level of its promoter, which acts as a sophisticated biosensor for environmental stress, thus controlling the above-described immunological homeostasis [99]. IL6 is normally expressed at low levels, except during infection, trauma, ageing or other stress conditions, upon which it can be secreted by various cell types, including endothelial cells, B-cells, T-cells, macrophages, dendritic cells, and

Nutrigenomics: the next frontier in nutraceutical therapy?

Progress in the battle against ageing disease and suffering is being accelerated by the availability of genomic information for humans, mice and other organisms. The interface between the nutritional environment and cellular/genetic processes is being referred to as “nutrigenomics”. Nutrigenomics seeks to provide a molecular genetic understanding of how common dietary chemicals (i.e. nutrition) affect health by altering the expression and/or structure of an individual’s genetic make-up. This in

Acknowledgements

This research was supported by the Interuniversitaire Attractiepolen (IUAP) and the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO). Nathalie Dijsselbloem is a fellow with the Vlaams Instituut voor de Bevordering van het Wetenschappelijk-Technologisch Onderzoek in de Industrie (IWT). Wim Vanden Berghe is a postdoctoral fellow with the FWO.

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