ABSTRACT
The inflammatory response is a highly regulated physiological process that is critically important to homeostasis. The pleiotropic cytokine interleukin-6 (IL6) affects inflammatory reactions, hematopoiesis, bone metabolism, reproduction (spermatogenesis, menstrual cycle), and ageing. Aberrant IL6 gene expression has been associated with multiple
myeloma, neoplasia, rheumatoid arthritis, bowel disease, psoriasis, obesity, coronary heart disease, Alzheimer’s disease, reduced longevity, and postmenopausal osteoporosis (1,2). Serum IL6 levels are currently considered a diagnostic marker for tumor progression and prognosis in various types of cancer (renal cell carcinoma, breast, lung, ovarian, and gut cancer) (3,4). Briefly, the IL6 promoter behaves as a sophisticated biosensor for environmental stress, thus controlling immunological homeostasis (5). Interleukin-6 is normally tightly regulated and expressed at low levels, except during infection, trauma, ageing, or other stress conditions (5). Among several factors that can downregulate IL6 gene expression are estrogen and testosterone hormones. After menopause or andropause, IL6 levels are elevated, even in the absence of infection, trauma, or stress (6-8). Natural menopause is associated with a rapid decline in circulating sex hormones and, apart from the loss of reproductive function, this can lead to unpleasant symptoms such as hot flushes and vaginal dryness, with a long-term increased risk of bone loss, cardiovascular disease, and neurological disorders (dementia). There is no unifying mechanism that would be able to explain all consequences of menopause on the metabolism of organs as diverse as bone, blood vessels, or adipose tissue. However, menopause triggered changes in the activity of proinflammatory cytokines are beginning to emerge as a common theme that may have a significant impact on the function of all of these tissues (2,8). It has been proposed that the age-associated increase in IL6 accounts for certain of the phenotypic changes of advanced age including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, lymphoproliferative disorders, multiple myeloma, periodontal disease, frailty, and chronic inflammatory disease (2). The functional interaction, or ‘‘crosstalk,’’ between the estrogen receptor (ER) and the proinflammatory transcription factor, nuclear factor (NF)-kB, as demonstrated in vitro, has been suggested to play a key role in estrogen prevention of those age-related conditions in vivo, besides modulation of nitric oxide antioxidative effects, plasma membrane actions, and changes in immune cell functions (2,6-11). In this
respect, restoring hormonal imbalance by hormone replacement therapy (HRT) (either by synthetic or plant derived hormone preparations) in the ageing population is an attractive therapeutic option, although the risks=benefits of HRT are still an area of hot debate (12-18). Because the average life expectancy for women in Western countries exceeds 80 year and women thus spend more than a third of their lifetime in postmenopause, the possible implications of estrogen deficiency on the rates of cardiovascular disease and osteoporosis are of enormous public health importance. Currently, there is a renewed interest in naturally occurring phytoestrogens as potential alternatives to synthetic ‘‘selective estrogen receptor modulators’’ (SERMs), currently applied in HRT. Traditionally, plant extracts have been used to treat various diseases and such therapies are still continuing (19). Various phytotherapeuticals with a claimed hormonal activity are recommended for prevention of discomforts related to a disturbed hormonal balance (8,12,14,15,20-22). Many hope that phytoestrogens can exert the cardioprotective, antiosteoporotic, and other beneficial effects of the estrogens used in HRT in postmenopausal women without adversely affecting the risk of thrombosis and the incidence of breast and uterine cancers. Despite their putative health benefits, it is clear that we need to know much more about the molecular mechanisms, safety, and efficacy of phytochemicals before they can be generally applied to postmenopausal women as an alternative treatment to estrogens for HRT (17,23-26).
