Interleukin-6: The Endocrine Cytokine

The field of cytokines has expanded tremendously over the last 2 decades. Initially, they were thought to be products of the immune system alone that had immune and hematological functions only. Yet, it has become increasingly apparent that cytokines participate in a neuroendocrine and immune system network, in which both the nervous and endocrine systems participate. Interleukin-6 (IL-6) and, to a lesser extent, tumor necrosis factor α have been shown to have endocrine as well as autocrine and paracrine roles. IL-6, in particular, has drawn much attention in the endocrine field for it is the most “endocrine” of all cytokines. The current issue hosts two articles that further expand our knowledge in the endocrine significance of IL-6. IL-6 is a pleiotropic cytokine with many pathophysiologic roles in humans (1). It is being produced by numerous types of immune or immune accessory cells, such as monocytes, fibroblasts, lymphocytes, and glial cells. It is also produced by nonimmune cells, some typically endocrine. Recently, it has been shown that IL-6 and tumor necrosis factor-α are produced by the adipose tissue (2, 3), suggesting that they may be playing significant roles in lipid metabolism. IL-6 is a hormonally regulated cytokine. Its production is suppressed by glucocorticoids (4) and estrogens (5) and stimulated by catecholamines (6, 7). In turn, it has many endocrine effects. It is one of the major cytokines that stimulate the hypothalamic-pituitary-adrenal axis during inflammatory stress (8); it promotes osteoclastogenesis and participates in the development of osteoporosis associated with estrogen withdrawal (9); it plays a central role in the pathogenesis of the euthyroid sick syndrome (10), most likely by inhibiting 5′-deiodinase that converts T4 to T3 and reverse T3 to diiodothyronine (11). IL-6 was also shown to influence intermediary metabolism (12), to be secreted in a circadian fashion correlating with sleepiness, and to be stimulated by acute sleep deprivation (13). The study by Fernandez-Real et al. (14) in this issue shows that a certain polymorphism in the promoter region of the IL-6 gene results in constitutively higher circulating IL-6 levels, as well as higher circulating triglyceride but not total cholesterol levels, suggesting that changes in the IL-6 gene expression can affect lipid levels through changes in IL-6 production. It has been suggested that IL-6 may cause an increase in circulating lipid levels probably through a decrease in peripheral lipoprotein lipase activity (15). However, the effects of IL-6 on lipid metabolism are far more complex. For example, administration of recombinant human IL-6 was followed by reduction in circulating triglyceride levels in normal volunteers (16). In the same study, total cholesterol as well as apoprotein B levels were decreased after administration of IL-6. Reduction of total cholesterol levels after administration of IL-6 has been observed in nonhuman primates (17) and cancer patients (18), as well. Furthermore, IL-6 levels correlate negatively with cholesterol levels after major surgery (19, 20), in patients undergoing hemodialysis (21), or after myocardial infarction (22). These apparently contradictory data may, indeed, reflect different processes. In the study by Fernandez-Real et al. (14), circulating IL-6 levels correlated positively with circulating triglyceride levels in subjects otherwise normal and in no acute distress. None of these subjects was acutely ill, and the levels of circulating IL-6 were within the normal range. On the other hand, in situations of severe stress—such as major surgery, sepsis, and severe illness—much higher concentrations of circulating IL-6 have been reported that reach 10–1000 times the normal levels. During such situations, activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system is invariably present, besides stimulation of IL-6 production. In addition, the acute phase response is being activated, and this includes suppression of the hepatic production of certain lipoproteins, as well. Thus, it seems that the effects of IL-6 on lipid metabolism depend on the extent of IL-6 induction. It is possible that in the basal, healthy state IL-6 may be influencing triglyceride levels by decreasing lipoprotein lipase activity, without effect on cholesterol concentration. On the other hand, in situations of severe stress, when the acute phase response is activated, along with the nervous and the endocrine systems, the effects on lipid metabolism are far more complex. The decrease in cholesterol acutely after major surgery or a myocardial infarction may actually reflect the negative effect of IL-6 on circulating lipoproteins. Further work is needed to clarify the actions of IL-6 on lipid metabolism in different states of health and disease. The data regarding the correlation between the polymorphism and the free fatty acid (FFA) levels are interesting, but should be considered preliminary at this stage. Specifically, in the present study there is a significant overlap in FFA levels among the different genotypes (C/C, C/G, and G/G). One would expect a “gene dose effect” on the FFA levels, being expressed as a descending trend from the homozygote to the heterozygote to the normal genotype, regarding the polymorphism. Such a trend is not evident from the data. The multiple regression model may not be the most appropriate for such a small group of subjects. Future studies, including a larger number of subjects, would be needed to clarify the potential role of the described IL-6 gene polymorphism in lipid metabolism. The second study by Straub et al. (23) demonstrates that IL-6 levels are affected by estrogen replacement therapy in postmenopausal women. This study further extends the findings of previous studies that IL-6 production is negatively affected by estrogens (5). The study by Straub et al. (23) supports the notion that the tonic production of IL-6 is inhibited by estrogen replacement in postmenopausal women. We have shown that circulating IL-6 levels correlate with body mass index (BMI) in men (24), and Straub et al. (23) confirmed this observation in postmenopausal women. The fact that the correlation between IL-6 and BMI is lost with hormonal replacement may reflect the dampening of IL-6 production in general, affecting this particular correlation as well. This study provides a potential mechanism for the beneficial effects of estrogen replacement therapy on long-term cardiovascular mortality in women (25, 26). It has been postulated that a chronic low-grade inflammatory state is involved in the pathogenesis of atherosclerosis and coronary artery disease. Specifically, patients with unstable angina have elevated circulating IL-6 and C-reactive protein (CRP) levels (27). Elevated circulating CRP (an acute phase reactant considered a surrogate marker of IL-6 action) has also been shown to be an independent marker of morbidity and mortality in patients with unstable angina (28). Therefore, it is plausible that estrogens exert their beneficial action on long-term cardiovascular mortality—at least partially—by decreasing the chronic production of IL-6, and, hence, the acute phase reactants. Additional studies are needed to evaluate this theory of estrogen effects, focusing on measurement of CRP, as well as of fibrinogen, both of which are stimulated by IL-6. The suggestion by Straub et al. (23) that the correlation of IL-6 with BMI is not affected by antihypertensive treatment, including treatment with β-blockers, should be taken with caution, considering the fact that the stimulatory effects of the sympathetic nervous system on IL-6 production through the β-adrenergic receptor has been well established (6, 7). The results of both studies provide further insight to the results of our study published in the same issue (29). In this study, we found that IL-6 elevation in sleep apnea correlated with both obesity and sleep disturbance. From these data we suggested that IL-6 might play a role in the increased frequency of cardiovascular complications associated with obesity and sleep apnea. Interestingly, it has been shown that sleep apnea is much less prevalent in postmenopausal women receiving estrogen replacement therapy than in those who do not (30). Therefore, it is possible that the reduction in sleep apnea in the estrogen-treated group is, at least partially, through suppression of IL-6. In conclusion, the current studies support and extend the major role that IL-6 plays in metabolism, obesity, and sleep. The strong association of IL-6 with obesity and sleep apnea (with the potential consequences on the cardiovascular system) need to be approached in multidisciplinary studies involving investigators from endocrinology, immunology, cardiology, and the field of sleep disorders. The data from the past decade are very promising and support such initiatives. We thank Dr. G. P. Chrousos for his insightful comments and suggestions.