• DOI:10.7326/0003-4819-128-2-199801150-00009
• Corpus ID: 37260638

The Pathophysiologic Roles of Interleukin-6 in Human Disease

@article{Papanicolaou1998ThePR,
  title={The Pathophysiologic Roles of Interleukin-6 in Human Disease},
  author={Dimitris A. Papanicolaou and Ronald L. Wilder and Stavros C. Manolagas and George P. Chrousos},
  journal={Annals of Internal Medicine},
  year={1998},
  volume={128},
  pages={127-137}
}

• D. Papanicolaou, R. Wilder, +1 author G. Chrousos
• Published 15 January 1998
• Medicine, Biology
• Annals of Internal Medicine

Dr. Dimitris A. Papanicolaou (Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health [NIH], Bethesda, Maryland): During inflammation, the inflammatory cytokines tumor necrosis factor-, interleukin-1, and interleukin-6 are secreted, in that order [1, 2]. Interleukin-6 then inhibits the secretion of tumor necrosis factor- and interleukin-1 [3], activates the production of acute-phase reactants from the liver [4], and stimulates the hypothalamic-pituitary-adrenal axis [5] to help control the inflammation. In this sense, interleukin-6 is both a proinflammatory and an anti-inflammatory cytokine. It is produced not only by immune and immune accessory cells (such as monocytes, macrophages, lymphocytes, endothelial cells, fibroblasts, mast cells, astrocytes, and microglia) but also by many nonimmune cells and organs (such as osteoblasts, bone marrow stromal cells, keratinocytes, synoviocytes, chondrocytes, intestinal epithelial cells, Leydig cells of the testis, folliculostellate cells of the pituitary, endometrial stromal cells, trophoblasts, and vascular smooth-muscle cells) [4, 6-12]. What makes interleukin-6 particularly interesting to physicians is its marked pleiotropy and its involvement not only in inflammation but in the regulation of endocrine and metabolic functions. Its diverse actions are summarized in the Table 1 [13]. Table 1. Actions of Interleukin-6 Molecular Biology of Interleukin-6 Located on the short arm of chromosome 7, the interleukin-6 gene consists of 5 exons and 4 introns and has a fairly complex transcriptional regulation [14]. The interleukin-6 promoter has recognition sites for transcription factors NF-IL6 (C/EBP ), which belongs to the C/EBP family, and NF-B, which is a major mediator of inflammatory stimuli [15, 16] (Figure 1). Figure 1. Transcriptional regulation of the interleukin-6 (IL-6) promoter. Interleukin-6 exerts its broad range of action through the interleukin-6 receptor, a single-pass transmembrane receptor not directly involved in signal transduction. Instead, activation of the receptor by interleukin-6 induces homodimerization of another transmembrane receptor, gp130, which initiates the transduction cascade [13]. The interleukin-6 receptor has a second soluble form that consists of the extracellular domain of the membrane receptor. Interleukin-6 also activates gp130 through this soluble form, even on cells that lack the interleukin-6 receptor on their membranes [17, 18]. For example, interleukin-6 can cause cardiac hypertrophy through gp130, even though cardiac myocytes lack the interleukin-6 receptor. The gp130 receptor is shared by many cytokines and growth factors for signal transduction, including interleukin-11, oncostatin-M, leukemia inhibitory factor, ciliary neurotrophic factor, cardiotropin-1, and leptin [13] (Figure 2). Figure 2. Pleiotropy of interleukin-6 (IL-6) action. Endocrine and Metabolic Actions of Interleukin-6 As Figure 3 shows, interleukin-6 has a broad array of actions on the endocrine and metabolic systems. Figure 3. Regulation of the secretion and endocrine actions of interleukin-6 (IL-6). Hypothalamic-Pituitary-Adrenal Axis Animal studies have shown that interleukin-6 acutely activates the hypothalamic-pituitary-adrenal axis by acting primarily on the corticotropin-releasing hormone neuron. Specifically, a blockade of corticotropin-releasing hormone inhibits the effects of exogenous interleukin-6 on the hypothalamic-pituitary-adrenal axis in rats [19]. Subcutaneous administration of interleukin-6 to normal human volunteers resulted in elevated plasma levels of adrenocorticotropin hormone (ACTH) and then an increase in plasma levels of cortisol [20]. The plasma level of cortisol peaked after the plasma level of ACTH peaked; this indicates that, at least in this acute setting, cortisol's response to interleukin-6 administration is mediated by release of ACTH [21]. Interleukin-6 seems to be one of the most potent stimuli of the hypothalamic-pituitary-adrenal axis in humans. Subcutaneous administration of interleukin-6 once a day for 7 days resulted in remarkable enlargement of the adrenal glands similar to that seen after prolonged activation of the adrenal glands by ACTH (as in Cushing disease or ectopic ACTH production) [22]. In animals and humans, glucocorticoids inhibit production of interleukin-6 in vitro and in vivo [23, 24]. In a recent study [25], administration of hydrocortisone or dexamethasone attenuated exercise-induced elevation of plasma levels of interleukin-6. Conversely, correction of hypercortisolism by surgical removal of a corticotroph adenoma when plasma levels of cortisol were undetectable increased plasma levels of interleukin-6 more than fourfold in patients with Cushing disease [26]. Therefore, interleukin-6 stimulates the hypothalamic-pituitary-adrenal axis and cortisol exerts negative feedback on secretion of interleukin-6. Interleukin-6 thus functions as a hormone in the traditional sense: It participates in a feedback loop of the hypothalamic-pituitary-adrenal axis. Thermogenesis and Basal Metabolic Rate Several cytokines, especially interleukin-1, are pyrogenic in humans and animals [27]. Administration of interleukin-6 causes elevations in body temperature and resting metabolic rate in humans [20]. In animals, the fact that nonsteroidal anti-inflammatory agents can inhibit the thermogenic effect of interleukin-6 suggests that this effect may be mediated by prostanoids [28]. The Steroid Withdrawal Syndrome The concept of the steroid withdrawal syndrome was introduced in 1965 by Amatruda and colleagues [29]. The syndrome is characterized by fever; headache; nausea; fatigue; malaise; somnolence; anorexia; and, less commonly, flu-like symptoms, such as arthralgias and myalgias. These symptoms occur during an abrupt reduction in levels of circulating cortisol and have been seen in patients who became severely hypocortisolemic when they underwent curative transsphenoidal surgery for Cushing disease. At that time, plasma levels of interleukin-6 were greatly elevated [26]. Normal volunteers and patients who received interleukin-6 had similar symptoms; this suggests that interleukin-6 participates in the pathogenesis of the steroid withdrawal syndrome [20, 21, 30]. Vasopressin and the Syndrome of Inappropriate Secretion of Antidiuretic Hormone The release of arginine vasopressin by the posterior pituitary is controlled by changes in intravascular volume and by osmotic stimuli. The syndrome of the inappropriate secretion of antidiuretic hormone occurs in the absence of serum hyperosmolarity or hypovolemia and can be caused by several conditions, including certain types of trauma, infections (meningitis and pneumonia), and inflammation [31]. During the syndrome, production of inflammatory cytokines (including interleukin-6) increases. Because high doses of interleukin-6 increase plasma levels of vasopressin in humans [32], endogenous interleukin-6 may also participate in the pathogenesis of this syndrome. Interleukin-6 as a Stress Hormone Because it innervates many immune organs, such as the spleen and the thymus, the autonomic nervous system interacts directly with the immune system [33, 34]. Stress or administration of adrenaline to animals elevates levels of endogenous interleukin-6, but pretreatment with a -adrenergic antagonist abolishes this effect. These effects suggest that interleukin-6 secretion is stimulated through -adrenergic receptors [35, 36]. In a recent study [37], administering adrenaline to humans increased plasma levels of interleukin-6. In normal volunteers, treadmill exercise also increased levels of plasma interleukin-6. In addition, peak plasma levels of catecholamines were positively correlated with plasma levels of interleukin-6 [25]. These data indicate that interleukin-6 is secreted during stress, probably through a -adrenergic receptor mechanism, and that it participates in the stress response. Lipid Metabolism Normal volunteers had precipitous reductions in serum total cholesterol levels, apolipoprotein B levels (this reflects low-density lipoprotein cholesterol), and triglyceride levels within 24 hours of interleukin-6 administration [38]. During sustained elevation of plasma catecholamine levels (such as that which occurs immediately after myocardial infarction), serum lipid levels are temporarily reduced, rendering serum cholesterol measurements misleading [39]. Whether catecholamine-stimulated endogenous interleukin-6 contributes to the transient decrease in serum lipid concentrations observed in conditions with increased sympathoneural discharge requires further study. Thyroid Axis and the Euthyroid Sick Syndrome Exogenous interleukin-6 decreased the secretion of thyroid-stimulating hormone in animals in vivo [5], and interleukin-6 was recently shown to be associated with a decrease in serum levels of thyroid-stimulating hormone and triiodothyronine in humans within 4 hours of administration. Interleukin-6 seemed to have a more lasting effect on triiodothyronine levels; the decrease persisted for at least 24 hours after a single injection of interleukin-6 [20, 21]. Thus, interleukin-6 was associated with changes in thyroid function test results similar to those seen in the euthyroid sick syndrome, a condition of physiologic hypothyroidism that occurs during nonthyroidal illness, apparently in an attempt by the organism to conserve energy. Depending on the severity and duration of the illness, it ranges from an isolated decrease in serum triiodothyronine levels in mild cases to a decrease in serum levels of free thyroxine and, finally, to subnormal thyroid-stimulating hormone levels in more severe cases [40]. Interleukin-6 levels are frequently elevated in conditions that are associated with the euthyroid sick syndrome (such as infection or inflammation, major trauma or surgery, and prolonged stays in the intensive care unit) and