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The Pathophysiologic Roles of Interleukin-6 in Human Disease
- Dimitris A. Papanicolaou, MD;
- Ronald L. Wilder, MD, PhD;
- Stavros C. Manolagas, MD, PhD; and
- George P. Chrousos, MD
- An edited summary of a Clinical Staff Conference held on 13 March 1996 at the National Institutes of Health, Bethesda, Maryland. Authors who wish to cite a section of the conference and specifically indicate its author may use this example for the form of the reference: Wilder RL. Interleukin-6 in autoimmune and inflammatory diseases, pp 130-132. In: Papanicolaou DA, moderator. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med. 1998; 128:127-137. For definitions of terms used in the text, see Glossary at end of text. Requests for Reprints: Dimitris A. Papanicolaou, MD, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Building 10, Room 10N262, 10 Center Drive MSC 1862, Bethesda, MD 20892-1862 Current Author Addresses: Dr. Papanicolaou: Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive MSC 1862, Bethesda, MD 20892-1862.
Abstract
Interleukin-6, an inflammatory cytokine, is characterized by pleiotropy and redundancy of action. Apart from its hematologic, immune, and hepatic effects, it has many endocrine and metabolic actions. Specifically, it is a potent stimulator of the hypothalamic-pituitary-adrenal axis and is under the tonic negative control of glucocorticoids. It acutely stimulates the secretion of growth hormone, inhibits thyroid-stimulating hormone secretion, and decreases serum lipid concentrations. Furthermore, it is secreted during stress and is positively controlled by catecholamines. Administration of interleukin-6 results in fever, anorexia, and fatigue. Elevated levels of circulating interleukin-6 have been seen in the steroid withdrawal syndrome and in the severe inflammatory, infectious, and traumatic states potentially associated with the inappropriate secretion of vasopressin. Levels of circulating interleukin-6 are also elevated in several inflammatory diseases, such as rheumatoid arthritis. Interleukin-6 is negatively controlled by estrogens and androgens, and it plays a central role in the pathogenesis of the osteoporosis seen in conditions characterized by increased bone resorption, such as sex-steroid deficiency and hyperparathyroidism. Overproduction of interleukin-6 may contribute to illness during aging and chronic stress. Finally, administration of recombinant human interleukin-6 may serve as a stimulation test for the integrity of the hypothalamic-pituitary-adrenal axis.
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-α, interleukin-1, and interleukin-6 are secreted, in that order [1, 2]. Interleukin-6 then inhibits the secretion of tumor necrosis factor-α 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].
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 β), which belongs to the C/EBP family, and NF-κB, which is a major mediator of inflammatory stimuli [15, 16] (Figure 1).
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).
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.
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 β-adrenergic antagonist abolishes this effect. These effects suggest that interleukin-6 secretion is stimulated through β-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 β-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 are negatively correlated with serum triiodothyronine levels in nonthyroidal illness [41].
In summary, interleukin-6 seems to activate the hypothalamic-pituitary-adrenal axis, to be negatively controlled by glucocorticoids, to stimulate thermogenesis and the basal metabolic rate, and to participate in the pathogenesis of the steroid withdrawal syndrome. It also stimulates vasopressin secretion and is probably involved in the syndrome of inappropriate secretion of antidiuretic hormone. Furthermore, it participates in the stress response, probably downstream from the catecholamines, and acutely decreases serum lipid levels. Finally, it is associated with the suppression of thyroid function and is probably associated with the euthyroid sick syndrome.
Interleukin-6 in Autoimmune and Inflammatory Diseases
Dr. Ronald L. Wilder (Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH): Production of interleukin-6 is increased in many clinical situations characterized by tissue injury, such as trauma (including major surgery), ischemia, burns, malignant conditions, exposure to toxins and aseptic irritants, infections, immune hypersensitivity reactions, and autoimmune diseases. Interleukin-6 is one of the principal mediators of the clinical manifestations of tissue injury, including fever, cachexia, leukocytosis, thrombocytosis, increased plasma levels of acutephase proteins, and decreased plasma levels of albumin. Interleukin-6 also stimulates plasmacytosis and hypergammaglobulinemia and activates the hypothalamic-pituitary-adrenal axis.
Interleukin-6 in Transgenic and Gene Knockout Mice
One of the most incisive approaches to elucidating the role of interleukin-6 in inflammation and immunity uses genetically engineered transgenic [42-45] and gene knockout mice [46-52]. Overexpression of interleukin-6 in transgenic mice results in massive plasmacytosis in the spleen, lymph nodes, thymus, lung, liver, and kidney that is associated with pronounced hypergammaglobulinemia, particularly of the IgG-1 subclass. In the context of these relatively specific B-lymphocyte growth and differentiation effects, it should be noted that interleukin-6 receptors are expressed on activated but not resting B cells.
In addition to showing plasma cell expansion, interleukin-6 transgenic mice exhibit thrombocytosis and marked increases in the number of mature megakaryocytes in the bone marrow. These mice also have kidney abnormalities, particularly mesangial proliferative glomerulonephritis. The murine syndrome that results from persistent overexpression of interleukin-6 resembles a human condition known as the Castleman syndrome [53], which is associated with lymph node enlargement, massive hypergammaglobulinemia, and increased synthesis of acute-phase protein. In some cases, the condition progresses to myeloma.
The converse of overexpression of murine transgenic interleukin-6 is represented by murine interleukin-6 gene knockout mice. In response to diverse stimuli, mice with no interleukin-6 gene manifest a major impairment in acute-phase protein synthesis. They also have reduced antimicrobial resistance, impaired T-cell growth and function, impaired B-cell maturation, and deficient mucosal IgA production. The numbers of uncommitted progenitor cells in the bone marrow are reduced, and the capacity to generate leukocytosis is impaired.
Corticosteroid production in response to inflammatory stimuli in knockout mice has been reported as normal and subnormal [46, 47]. Production of tumor necrosis factor-α is markedly increased in these mice compared with normal mice, and corticosteroids provide feedback suppression on production of tumor necrosis factor-α. These observations suggest that restraints on the production of proinflammatory mediators by the hypothalamic-pituitary-adrenal axis are blunted in interleukin-6 knockout mice.
The acute-phase response consists of enhanced production of more than 40 proteins [54] that have either proinflammatory or anti-inflammatory properties, depending on the nature of the stimulus. The acute-phase proteins include several components of the complement system, which are involved in the accumulation of phagocytes at an inflammatory site and the killing of microbial pathogens. C-reactive protein, a prominent acute-phase protein, binds various pathogens and materials from damaged cells, promotes opsonization of these materials, and activates the complement system. In this context, interleukin-6-induced production of acute-phase proteins can be viewed as a protective host defense mechanism that limits tissue injury [55, 56].
The concept of increased production of acute-phase protein as a host defense mechanism becomes more complicated when discussed in terms of the response of interleukin-6 gene-deficient mice to various defined stimuli [47, 49, 50]. Synthesis of acute-phase protein in interleukin-6 knockout mice is greatly impaired in response to nonspecific irritants. Thus, interleukin-6-deficient mice injected intraperitoneally with a sterile irritant, such as turpentine, show only mild anorexia, do not lose weight, and have markedly blunted synthesis of acute-phase protein. In contrast, wild-type mice stop eating, lose weight, and have markedly elevated levels of acute-phase protein. Moreover, normal mice show increases in plasma levels of tumor necrosis factor-α and interleukin-6, whereas the plasma levels of either cytokine do not increase in interleukin-6-deficient mice. No increase in mortality rate is associated with the response to turpentine in either the knockout or the wild-type mice. Therefore, in the context of the response to a sterile irritant, the interleukin-6-dependent acute-phase response is associated with greater illness and tissue injury compared with the absence of interleukin-6 production [46, 47].
However, interleukin-6-deficient mice do not develop leukocytosis in response to an infectious agent, such as Listeria monocytogenes, whereas production of interferon-γ, which is critical in many host defense mechanisms, is similar to that found in wild-type mice. The mortality rate among interleukin-6 knockout mice infected with L. monocytogenes is markedly increased compared with that among normal mice, indicating that interleukin-6 is critical to host defense and survival in response to this infectious agent [49, 50, 52].
Rheumatoid Arthritis
Many clinical symptoms and signs associated with rheumatoid arthritis have been linked to interleukin-6 [57-64]. For example, severe disease is typically characterized by thrombocytosis, hypergammaglobulinemia, an elevated erythrocyte sedimentation rate, and elevated levels of C-reactive protein; these abnormalities are highly correlated with plasma and synovial levels of interleukin-6. In fact, persistently elevated levels of C-reactive protein predict a very poor outcome for patients with rheumatoid arthritis [59]. In addition, systemic and periarticular bone loss, which is common in severe disease, is highly correlated with interleukin-6 levels in bone marrow [57, 62]. Consistent with these data, small-scale therapeutic studies with humanized anti-interleukin-6 antibodies have noted improvement in clinical and laboratory variables [61].
An interesting association between interleukin-6 and rheumatoid arthritis relates to age at onset and sex-steroid hormone deficiency. Rheumatoid arthritis is much more common in women than in men, and the peak incidence of disease occurs in the perimenopausal, postmenopausal, or postpartum period: that is, when levels of gonadal steroid hormones are low. All available data indicate that interleukin-6 production is inversely correlated with gonadal steroid levels [48, 51, 65] and that interleukin-6 production increases with age. Rheumatoid arthritis is uncommon in men younger than 45 years of age, but the incidence increases markedly in older men and approaches the incidence in women. Because androgen levels decrease with aging, androgens may be involved in regulating increased susceptibility to disease expression [65, 66].
Links between the hypothalamic-pituitary-adrenal axis and interleukin-6 in rheumatoid arthritis are of great interest. Interleukin-6 is produced at high levels and in a circadian fashion in patients with rheumatoid arthritis, with peak levels occurring between 4 a.m. and 6 a.m. Patients with rheumatoid arthritis have “inappropriately normal” or, less commonly, subnormal (albeit circadian) daily cortisol production. This suggests a mismatch in sensitivity between interleukin-6 and the hypothalamic-pituitary-adrenal axis in rheumatoid arthritis [67, 68].
Systemic Lupus Erythematosus
The role of interleukin-6 in systemic lupus erythematosus is still unclear [69-72]. Whereas elevated plasma levels of interleukin-6 are a common feature of active disease, levels of circulating interleukin-6 are normal in the inactive form. It is interesting that levels of C-reactive protein (a surrogate for interleukin-6 action) but not erythrocyte sedimentation rates are usually normal in patients with lupus. This raises the question of whether patients with lupus may have a defect in selected components of the acute-phase response to interleukin-6 [64].
In summary, interleukin-6 seems to be a major mediator of the host response to tissue injury in many autoimmune and inflammatory diseases and plays an important role in regulating the immune, hepatic, hematopoietic, skeletal, and neuroendocrine systems. Abnormalities that lead to persistent oversecretion or undersecretion of interleukin-6 or excessive or blunted effects of interleukin-6 may be involved in various disease states, including autoimmune and inflammatory diseases.
Pathophysiologic Role of Interleukin-6 in Osteoporosis and Other Bone Diseases
Dr. Stavros C. Manolagas (Division of Endocrinology Metabolism and Center for Osteoporosis and Metabolic Bone Diseases, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas): The adult skeleton undergoes a continuous turnover, termed bone remodeling, during which old bone is resorbed by osteoclasts and new bone is formed by osteoblasts on surfaces on which resorption has recently been completed. Osteoclasts are derived from hematopoietic precursors of bone marrow, probably the colonyforming units for granulocytes and macrophages, which also give rise to monocytes and tissue macrophages. Osteoblasts, however, originate from multipotent mesenchymal progenitors that also give rise to fibroblastic cells of the bone marrow stroma, chondrocytes, adipocytes, and muscle cells. To ensure the renewal of the skeleton while maintaining its anatomic and structural integrity, the processes of bone resorption and formation are tightly coupled. About 25% of trabecular bone is resorbed and replaced every year in adults, whereas only 3% of cortical bone undergoes remodeling. This indicates that the rate of remodeling is primarily controlled by local factors.
Extensive evidence produced in the past few years indicates that the cellular activity of bone marrow and bone remodeling are tightly linked. Indeed, it is now thought that bone homeostasis, like homeostasis of other regenerating tissues, depends on the orderly replenishment of cellular constituents and that the fundamental problem in osteoporosis is aberrant cell production relative to demand. Thus, an oversupply of osteoclasts relative to the need for remodeling (probably associated with a decreased rate of apoptosis) and an undersupply of osteoblasts relative to the need for cavity repair are the critical pathophysiologic changes in postmenopausal and age-related osteopenia, respectively [73].
Cytokines and Bone Remodeling
By stimulating the development of osteoclasts, interleukin-6 type cytokines play a profound role in skeletal homeostasis, and increasing evidence suggests that interleukin-6 type cytokines also promote the development of osteoblasts [74]. Moreover, it is now established that bone-active systemic hormones, such as sex steroids, parathyroid hormone, parathyroid hormone-related peptide, 1,25-dihydroxyvitamin D3, and thyroxine, exert their potent influences on bone remodeling and skeletal homeostasis by regulating the production and action of interleukin-6 and interleukin-11. Hormones affect the actions of these interleukins by regulating the expression of the receptors for these cytokines.
Role of Interleukin-6 and Its Receptors in the Osteoporosis of Sex-Steroid Deficiency
The production of interleukin-6 by cells of the stromal-osteoblastic lineage is inhibited in vitro by estrogen and androgen [51, 75] through receptor-mediated actions on the transcriptional activity of the interleukin-6 gene promoter [51, 76-78]. Conversely, estrogen loss results in increased production of interleukin-6 by ex vivo bone marrow cell cultures, and increased production of interleukin-6 follows the withdrawal of estradiol from primary cultures of calvarial cells [79]. In agreement with in vitro evidence, circulating levels of interleukin-6 are elevated in estrogen-deficient mice, rats, and humans [74]. Direct support for the contention that interleukin-6 is responsible for increased bone resorption after loss of sex steroids is derived from studies showing that injections of an interleukin-6-neutralizing antibody in female or male mice that have had gonadectomy prevents the increase in osteoclastogenesis in bone marrow and the increase in the number of osteoclasts in sections of trabecular bone [51, 80]. Furthermore, unlike wild-type controls, interleukin-6 knockout mice do not show cellular changes in the marrow and trabecular bone sections and are protected from the loss of trabecular bone after the loss of sex steroids [48, 51].
Even though interleukin-6 is implicated as a pathogenetic factor in osteoporosis, it does not seem to be important for osteoclastogenesis under normal conditions [51, 80, 81]. Thus, administering an interleukin-6-neutralizing antibody to estrogen-sufficient mice or ex vivo cultures of bone marrow cells from sex-steroid-sufficient mice has no effect on osteoclastogenesis. Furthermore, osteoclastogenesis is unaffected in interleukin-6-deficient mice [48, 51, 80], indicating that the osteoclastogenic process in the estrogen-sufficient state is insensitive to interleukin-6.
An explanation of the importance of interleukin-6 for bone remodeling in the sex-steroid-deficient state has been provided from evidence that sex steroids suppress not only the expression of interleukin-6 but also its receptor. Indeed, in vitro studies have determined that 17β-estradiol or dihydrotestosterone decreased the amount of messenger RNA of the interleukin-6 receptor and messenger RNA of gp130 in cells of the bone marrow stromal-osteoblastic lineage. These agents also decreased levels of gp130 protein. Consistent with these findings, ovariectomy in mice increased the expression of interleukin-6 receptor and gp130 and the amount of interleukin-6 messenger RNA in ex vivo bone marrow cell cultures. These results were determined by quantitative reverse transcriptase polymerase chain reaction and confirmed on an individual cell basis by using in situ reverse transcriptase polymerase chain reaction [82].
Results of clinical studies indicate that the interleukin-6 receptor is upregulated after the loss of estrogen in humans. Girasole and coworkers [83] studied women who had hysterectomy alone, ovariectomy, or ovariectomy with transdermal estrogen replacement. In the course of 12 months, the expected increases in markers of bone formation and bone resorption were accompanied at the same time points by a 35% increase in levels of soluble interleukin-6 receptor and a 20% increase in serum levels of interleukin-6. Estrogen replacement reversed the increased levels of serum and soluble interleukin-6 receptor induced by ovariectomy. Similarly, Chen and colleagues [84] investigated 151 healthy women whose menstruation status differed and found that levels of soluble interleukin-6 receptor were substantially increased in postmenopausal women compared with premenopausal and perimenopausal women.
Role of Interleukin-6 in Other Disease States Characterized by Increased Bone Resorption
Evidence accumulated in the past 5 years to support the contention that interleukin-6 is a pathogenetic factor in osteoporosis that results from the loss of either male or female sex steroids has implicated interleukin-6 in the pathophysiology of several other diseases caused by increased osteoclastic bone resorption. These diseases include hyperparathyroidism [85, 86], Paget disease [87], multiple myeloma [88], rheumatoid arthritis [57, 89], Gorham-Stout disease [90], hyperthyroidism [91, 92], the McCune-Albright syndrome [93], and renal osteodystrophy [94]. An increase in the expression of the soluble interleukin-6 receptor has been shown in these diseases and in sex-steroid deficiency. The mechanism of increased production of interleukin-6 in these diseases is still unclear, with the exceptions of hyperparathyroidism (in which parathyroid hormone stimulates production of interleukin-6) and the McCune-Albright syndrome (in which the constitutive activation of the Gsα-subunit of the G protein and the eventual increase in levels of intracellular cyclic adenosine 5′-monophosphate lead to elevated levels of interleukin-6 levels in the affected bone).
In conclusion, the increased rate of remodeling and bone loss that characterizes several disease states may be explained by increased osteoclast development caused by increased production or action of such cytokines as interleukin-6.
Integration of the Immune and Endocrine Systems by Interleukin-6
Dr. George P. Chrousos (Developmental Endocrinology Branch, National Institute of Child Health and Human Development, NIH): The stress system has a central nervous system component and a peripheral component [95]. The central component consists of the hypothalamus, which includes corticotropin-releasing hormone and vasopressin neurons of the paraventricular nucleus, and the brain stem, which includes the noradrenergic neurons of the locus ceruleus and other autonomic centers. The peripheral component consists of the hypothalamicpituitary-adrenal axis and the peripheral autonomic nervous system, which also includes the adrenal medullae. Activation of the stress system leads to suppression of the growth and reproductive axes [96], alterations in thyroid function recognized in the euthyroid sick syndrome [40], and suppression of the immune-inflammatory reaction associated with a shift from the Th1 to the Th2 profile [97].
Interleukin-6 has a profound stimulatory effect on the stress system [20-22] and is secreted when the system is activated during inflammatory [98, 99] and (to a lesser extent) noninflammatory stress [25, 35, 36, 100]. Interleukin-6 may play a pathogenetic role in conditions related to chronic stress and physiologic aging. Aging is characterized by progressively increasing concentrations of glucocorticoids and catecholamines and decreasing production of growth and sex hormones, a pattern reminiscent of that seen in chronic stress (Figure 4). Recent studies [101, 102] have shown that plasma levels of interleukin-6 increase with age, probably as the result of catecholamine hypersecretion and sex-steroid hyposecretion, and that interleukin-6 levels correlate with the functional disability of elderly persons [103]. Therefore, interleukin-6 may contribute to the increased morbidity and mortality seen in chronically stressed or physiologically aging persons. The potential involvement of interleukin-6 in the pathophysiology of aging and chronic stress calls for research on ways to suppress its secretion or effects.
The presence of high levels of interleukin-6 in states characterized by fatigue or somnolence, such as glucocorticoid deficiency [26], rheumatoid arthritis [59, 63], and disorders of excessive daytime sleepiness [104]; the marked correlation of interleukin-6 with exercise-induced exhaustion (Papanicolaou DA, Singh A, Gold PW, Deuster PA, Chrousos GP. Exercise-induced fatigue correlates with plasma interleukin-6 [IL-6] levels in normal women. Presented at the Third International Congress of the International Society for Neuroimmunomodulation, 15 November 1996, Washington, DC); and the ability of interleukin-6 to cause fatigue [20, 21] suggest that it may be a fatigue-mediating factor whose suppression or neutralization may help alleviate these symptoms when necessary. Humanized neutralizing anti-interleukin-6 antibodies or interleukin-6 receptor antagonists may be particularly helpful in rehabilitating patients with rheumatic diseases and debilitating fatigue [61].
A recent study [105] provided indirect evidence that interleukin-6 may be involved in the pathogenesis of myocardial infarction. Specifically, men who had elevated baseline levels of C-reactive protein, a surrogate for interleukin-6 action [106], were at greater risk for myocardial infarction than men who had normal levels of C-reactive protein. In addition, marked gliosis occurs in the brains of transgenic animals in which interleukin-6 is overexpressed in the central nervous system [45]; this indicates that this cytokine may participate in the neurodegeneration and gliosis seen in such conditions as AIDS encephalopathy [107, 108] and Alzheimer disease [109, 110]. Thus, potential suppressants of interleukin-6 secretion or interleukin-6 antagonists might be a promising adjuvant therapy for such states.
The ability of interleukin-6 to stimulate secretion of corticotropin-releasing hormone in a dose-dependent manner suggests that this cytokine could be used for the differential diagnosis of disorders associated with abnormalities of the corticotropin-releasing hormone neuron. Thus, an interleukin-6 stimulation test could be useful in differentiating between the Cushing syndrome and pseudo-Cushing syndrome states (such as the combination of obesity and melancholic depression or chronic active alcoholism and the alcohol withdrawal syndrome) and between atypical and melancholic depression. Such a differentiation would be based on the fact that the corticotropin-releasing hormone neuron is chronically suppressed in the Cushing syndrome and chronically activated in pseudo-Cushing syndrome states [111]. In addition, melancholic depression and atypical depression are on opposite sides of the spectrum in terms of activity of the corticotropin-releasing hormone neuron [112-115].
Glossary
AP-1 site: A specific DNA sequence that binds the c-jun and c-fos heterodimers.
C/EBP: A transcription factor that regulates several adipocyte-specific and hepatocyte-specific genes.
C/EBPbeta (NF-IL6): A transcription factor that is minimally expressed in normal tissues but is drastically induced by stimulation of lipopolysaccharides, interleukin-1, tumor necrosis factor-α, or interleukin-6.
c-fos: A transcription factor that regulates growth as a heterodimer with c-jun; the heterodimers bind to the AP-1 sites.
c-jun: A transcription factor that regulates growth as a heterodimer with c-fos; the heterodimers bind to the AP-1 sites.
Exon: A coding section of a gene retained at its messenger RNA before translation.
Intron: A noncoding section of a gene that is removed from RNA transcripts before they are translated.
NF-κB: A transcription factor activated during inflammation.
Stress: Disturbance of homeostasis.
Th1: CD4+ cells that produce interleukin-2 and interferon-γ, which promote cellular immunity.
Th2: CD4+ cells that produce interleukin-4, which promotes humoral immunity. The term has been expanded to include cytokines that promote humoral immunity, such as interleukin-5, interleukin-9, interleukin-11, and interleukin-13.
Transcription: The making of an RNA molecule by using the information encoded in the DNA.
Transcription factor: A protein that binds to the regulatory regions of genes and influences their rates of transcription.
Dr. Wilder: Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Room 9N240, 10 Center Drive MSC 1862, Bethesda, MD 20892.
Dr. Manolagas: Division of Endocrinology Metabolism and Center for Osteoporosis and Metabolic Bone Diseases, Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 587, Little Rock, AR 72205-7199.
Dr. Chrousos: Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N244, 10 Center Drive MSC 1862, Bethesda, MD 20892-1862.
- Copyright ©2004 by the American College of Physicians
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