the pathophysiologic roles of interleukin-6 in human disease

The Pathophysiologic Roles of Interleukin-6 in Human DiseaseModerator: Dimitris A. Papanicolaou, MD; Discussants: Ronald L. Wilder, MD, PhD;Stavros C. Manolagas, MD, PhD; and George P. Chrousos, MD

lnterleukin-6f an inflammatory cytokine, is characterizedby pleiotropy and redundancy of action. Apart from itshematologic, immune, and hepatic effects, it has manyendocrine and metabolic actions. Specifically, it is a potentstimulator of the hypothalamic-pituitary-adrenal axis andis under the tonic negative control of glucocorticoids. Itacutely stimulates the secretion of growth hormone, in-hibits thyroid-stimulating hormone secretion, and de-creases serum lipid concentrations. Furthermore, it is se-creted during stress and is positively controlled bycatecholamines. Administration of interleukin-6 results infever, anorexia, and fatigue. Elevated levels of circulatinginterleukin-6 have been seen in the steroid withdrawalsyndrome and in the severe inflammatory, infectious, andtraumatic states potentially associated with the inappro-priate secretion of vasopressin. Levels of circulating inter-leukin-6 are also elevated in several inflammatory dis-eases, such as rheumatoid arthritis. Interleukin-6 isnegatively controlled by estrogens and androgens, and itplays a central role in the pathogenesis of the osteoporosisseen in conditions characterized by increased bone resorp-tion, such as sex-steroid deficiency and hyperparathyroid-ism. Overproduction of interleukin-6 may contribute toillness during aging and chronic stress. Finally, administra-tion of recombinant human interleukin-6 may serve as a stimulation test for the integrity of the hypothalamic-pituitary-adrenal axis.

Ann Intern Med. 1998;128:127-137.

Dr. Dimitris A. Papanicolaou (DevelopmentalEndocrinology Branch, National Institute of

Child Health and Human Development, NationalInstitutes of Health [NIH], Bethesda, Maryland):During inflammation, the inflammatory cytokinestumor necrosis factor-a, interleukin-1, and interleu-kin-6 are secreted, in that order (1, 2). Interleukin-6then inhibits the secretion of tumor necrosis fac-

tor-a and interleukin-1 (3), activates the productionof acute-phase reactants from the liver (4), andstimulates 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 byimmune and immune accessory cells (such as mono-cytes, macrophages, lymphocytes, endothelial cells,fibroblasts, mast cells, astrocytes, and microglia) butalso by many nonimmune cells and organs (such asosteoblasts, bone marrow stromal cells, keratino-cytes, synoviocytes, chondrocytes, intestinal epithe-lial cells, Leydig cells of the testis, folliculostellatecells of the pituitary, endometrial stromal cells, tro-phoblasts, and vascular smooth-muscle cells) (4, 6-12). What makes interleukin-6 particularly interest-ing to physicians is its marked pleiotropy and itsinvolvement not only in inflammation but in theregulation of endocrine and metabolic functions. Itsdiverse actions are summarized in the Table (13).

Molecular Biology of Interleukin-6

Located on the short arm of chromosome 7, theinterleukin-6 gene consists of 5 exons and 4 intronsand has a fairly complex transcriptional regulation(14). The interleukin-6 promoter has recognitionsites for transcription factors NF-IL6 (C/EBP/3),which belongs to the C/EBP family, and NF-KB,

which is a major mediator of inflammatory stimuli(15, 16) (Figure 1).

Interleukin-6 exerts its broad range of actionthrough the interleukin-6 receptor, a single-passtransmembrane receptor not directly involved in sig-nal transduction. Instead, activation of the receptorby interleukin-6 induces homodimerization of an-other transmembrane receptor, gpl30, which ini-tiates the transduction cascade (13).

The interleukin-6 receptor has a second solubleform that consists of the extracellular domain of themembrane receptor. Interleukin-6 also activatesgpl30 through this soluble form, even on cells thatlack the interleukin-6 receptor on their membranes(17, 18). For example, interleukin-6 can cause car-diac hypertrophy through gpl30, even though car-diac myocytes lack the interleukin-6 receptor. The

An edited summary of a Clinical Staff Conference held on 13March 1996 at the National Institutes of Health, Bethesda, Mary-land.

Authors who wish to cite a section of the conference andspecifically indicate its author may use this example for the formof the reference:

Wilder RL. Interleukin-6 in autoimmune and inflammatorydiseases, pp 130-132. In: Papanicolaou DA, moderator. Thepathophysiologic 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 oftext.

© 1998 American College of Physicians 127

Table. Actions of lnterleukin-6

Hematologic

Proliferation of multipotential hematopoietic progenitorsMyeloma and plasmacytoma cell growth

ImmunologicDifferentiation and maturation of B cells (B-cell stimulating factor-2)Production of immunoglobulin by B cellsProliferation and differentiation of T cells

Hepatic

Hepatocyte stimulationInduction of various genes of the acute-phase response (C-reactive

protein, haptoglobin, fibrinogen)Neurologic

Nerve cell differentiationGliosis (in transgenic mice)

CardiacMyocardial hypertrophy

EndocrineInduction of thermogenesis (endogenous pyrogen)

Stimulation of the hypothalamic-pituitary-adrenal axisStimulation of vasopressin secretionStimulation of growth hormone secretion

Suppression of the thyroid axisSuppression of serum lipid levelsOsteoporosis (postmenopausal or due to hypogonadism)

gpl30 receptor is shared by many cytokines andgrowth factors for signal transduction, including in-terleukin-11, oncostatin-M, leukemia inhibitory fac-tor, ciliary neurotrophic factor, cardiotropic 1, andleptin (13) (Figure 2).

Endocrine and Metabolic Actions ofInterleukin-6

As Figure 3 shows, interleukin-6 has a broad arrayof actions on the endocrine and metabolic systems.

Hypothalamic-Pituitary-Adrenal Axis

Animal studies have shown that interleukin-6acutely activates the hypothalamic-pituitary-adrenalaxis by acting primarily on the corticotropin-releasinghormone neuron. Specifically, a blockade of corti-cotropin-releasing hormone inhibits the effects of ex-ogenous interleukin-6 on the hypothalamic-pituitary-adrenal axis in rats (19). Subcutaneous administrationof interleukin-6 to normal human volunteers re-sulted in elevated plasma levels of adrenocortico-tropin hormone (ACTH) and then an increase inplasma levels of Cortisol (20). The plasma level of

Cortisol peaked after the plasma level of ACTHpeaked; this indicates that, at least in this acutesetting, Cortisol's response to interleukin-6 adminis-tration is mediated by release of ACTH (21).

Interleukin-6 seems to be one of the most potentstimuli of the hypothalamic-pituitary-adrenal axis inhumans. Subcutaneous administration of interleu-kin-6 once a day for 7 days resulted in remarkableenlargement of the adrenal glands similar to thatseen after prolonged activation of the adrenal glandsby ACTH (as in Cushing disease or ectopic ACTHproduction) (22).

In animals and humans, glucocorticoids inhibitproduction of interleukin-6 in vitro and in vivo (23,24). In a recent study (25), administration of hy-drocortisone or dexamethasone attenuated exercise-induced elevation of plasma levels of interleukin-6.Conversely, correction of hypercortisolism by surgi-cal removal of a corticotroph adenoma when plasmalevels of Cortisol were undetectable increased plasmalevels of interleukin-6 more than fourfold in pa-tients with Cushing disease (26). Therefore, inter-leukin-6 stimulates the hypothalamic-pituitary-adre-nal axis and Cortisol exerts negative feedback onsecretion of interleukin-6. Interleukin-6 thus func-tions as a hormone in the traditional sense: It par-ticipates in a feedback loop of the hypothalamic-pituitary-adrenal axis.

Thermogenesis and Basal Metabolic Rate

Several cytokines, especially interleukin-1, are py-rogenic in humans and animals (27). Administrationof interleukin-6 causes elevations in body tempera-ture and resting metabolic rate in humans (20). Inanimals, the fact that nonsteroidal anti-inflamma-tory agents can inhibit the thermogenic effect ofinterleukin-6 suggests that this effect may be medi-ated by prostanoids (28).

The Steroid Withdrawal Syndrome

The concept of the steroid withdrawal syndromewas introduced in 1965 by Amatruda and colleagues(29). The syndrome is characterized by fever; head-ache; nausea; fatigue; malaise; somnolence; anorex-

Figure 1. Transcriptional regulation of the interleukin-6 {IL-6) promoter. Glucocorticoids inhibit transcription of interleukin-6 through interaction ofthe ligand-activated glucocorticoid receptor (GR) with the Re1A subunit of transcription factor NF-KB. Estrogens suppress transcription (slashed arrows) ofinterleukin-6 through formation of heteromeric estrogen receptor (£/?)-C/EBPj3 and estrogen receptor-NF-KB complexes. AP-1 = AP-1 site; CREB = cyclicadenosine 5'-monophosphate-response element binding site; C/EBP = C/EBP binding site; NF-KB = NF-KB binding site. The triangle represents glucocorticoid;the rhombus represents estrogen.

128 15 January 1998 • Annals of Internal Medicine • Volume 128 • Number 2

Figure 2. Pleiotropy of interleukin-6 {IL-6) action. Binding of circulating interleukin-6 to the soluble interleukin-6 receptor (slL-6R) may activate gp130subunits present on cells that lack the specific interleukin-6 receptor, probably those that are activated by the leptin receptor (OB-R), leukemia inhibitory factorreceptor (LIF-R) (for leukemia inhibitory factor, oncostatin-M, ciliary neurotrophic factor, and cardiotropic 1), and oncostatin-M receptor (OMR) (for oncostatin-M).

ia; and, less commonly, flu-like symptoms, such asarthralgias and myalgias. These symptoms occurduring an abrupt reduction in levels of circulatingCortisol and have been seen in patients who becameseverely hypocortisolemic when they underwent cur-ative transsphenoidal surgery for Cushing disease.At that time, plasma levels of interleukin-6 weregreatly elevated (26). Normal volunteers and pa-tients who received interleukin-6 had similar symp-toms; this suggests that interleukin-6 participates inthe pathogenesis of the steroid withdrawal syn-drome (20, 21, 30).

Vasopressin and the Syndrome of InappropriateSecretion of Antidiuretic Hormone

The release of arginine vasopressin by the poste-rior pituitary is controlled by changes in intravascu-lar volume and by osmotic stimuli. The syndrome ofthe inappropriate secretion of antidiuretic hormoneoccurs in the absence of serum hyperosmolarity orhypovolemia and can be caused by several condi-tions, including certain types of trauma, infections(meningitis and pneumonia), and inflammation (31).During the syndrome, production of inflammatorycytokines (including interleukin-6) increases. Be-cause high doses of interleukin-6 increase plasmalevels of vasopressin in humans (32), endogenousinterleukin-6 may also participate in the pathogen-esis of this syndrome.

Interleukin-6 as a Stress HormoneBecause it innervates many immune organs, such

as the spleen and the thymus, the autonomic ner-vous system interacts directly with the immune sys-tem (33, 34). Stress or administration of adrenalineto animals elevates levels of endogenous interleu-kin-6, but pretreatment with a j8-adrenergic antag-onist abolishes this effect. These effects suggest that

interleukin-6 secretion is stimulated through j3-ad-renergic receptors (35, 36). In a recent study (37),administering adrenaline to humans increased plasmalevels of interleukin-6. In normal volunteers, tread-mill exercise also increased levels of plasma inter-leukin-6. In addition, peak plasma levels of cate-cholamines were positively correlated with plasmalevels of interleukin-6 (25). These data indicate thatinterleukin-6 is secreted during stress, probablythrough a j8-adrenergic receptor mechanism, andthat it participates in the stress response.

Figure 3. Regulation of the secretion and endocrine actions ofinterleukin-6 (IL-6). Interleukin-6 production is stimulated by tumor necro-sis factor-a (TNF-a) and interleukin-1 (IL-1). Interleukin-6, in turn, inhibitsfurther production of tumor necrosis factor-a and interleukin-1. Cate-cholamines stimulate interleukin-6 production, whereas glucocorticoids, es-trogens, and androgens suppress it. Interleukin-6 acutely stimulates the cor-ticotropin-releasing hormone (CRH) neuron, which leads to increasedsecretion of adrenocorticotropin hormone (ACThl) and Cortisol. It also stim-ulates the secretion of growth hormone (GH) and arginine vasopressin (AVF) (at high levels) but suppresses thyroid-stimulating hormone (TSH) secretionand levels of circulating lipids.

15 January 1998 • Annals of Internal Medicine • Volume 128 • Number 2 129

Lipid Metabolism

Normal volunteers had precipitous reductions inserum total cholesterol levels, apolipoprotein B levels (this reflects low-density lipoprotein cholester-ol), and triglyceride levels within 24 hours of inter-leukin-6 administration (38). During sustained ele-vation of plasma catecholamine levels (such as thatwhich occurs immediately after myocardial infarc-tion), serum lipid levels are temporarily reduced, ren-dering serum cholesterol measurements misleading(39). Whether catecholamine-stimulated endoge-nous interleukin-6 contributes to the transient de-crease in serum lipid concentrations observed inconditions with increased sympathoneural dischargerequires further study.

Thyroid Axis and the Euthyroid Sick Syndrome

Exogenous interleukin-6 decreased the secretionof thyroid-stimulating hormone in animals in vivo(5), and interleukin-6 was recently shown to be as-sociated with a decrease in serum levels of thyroid-stimulating hormone and triiodothyronine in hu-mans within 4 hours of administration. Interleukin-6seemed to have a more lasting effect on triiodothy-ronine levels; the decrease persisted for at least 24hours after a single injection of interleukin-6 (20,21). Thus, interleukin-6 was associated with changesin thyroid function test results similar to those seenin the euthyroid sick syndrome, a condition of phys-iologic hypothyroidism that occurs during nonthyroi-dal illness, apparently in an attempt by the organismto conserve energy. Depending on the severity andduration of the illness, it ranges from an isolateddecrease in serum triiodothyronine levels in mildcases to a decrease in serum levels of free thyroxineand, finally, to subnormal thyroid-stimulating hor-mone levels in more severe cases (40). Interleukin-6levels are frequently elevated in conditions that areassociated with the euthyroid sick syndrome (suchas infection or inflammation, major trauma or sur-gery, and prolonged stays in the intensive care unit)and are negatively correlated with serum triiodothy-ronine levels in nonthyroidal illness (41).

In summary, interleukin-6 seems to activate thehypothalamic-pituitary-adrenal axis, to be nega-tively controlled by glucocorticoids, to stimulatethermogenesis and the basal metabolic rate, and toparticipate in the pathogenesis of the steroid with-drawal syndrome. It also stimulates vasopressin se-cretion and is probably involved in the syndrome ofinappropriate secretion of antidiuretic hormone.Furthermore, it participates in the stress response,probably downstream from the catecholamines, andacutely decreases serum lipid levels. Finally, it isassociated with the suppression of thyroid function

and is probably associated with the euthyroid sicksyndrome.

Interleukin-6 in Autoimmune andInflammatory Diseases

Dr. Ronald L. Wilder (Arthritis and RheumatismBranch, National Institute of Arthritis and Muscu-loskeletal and Skin Diseases, NIH): Production ofinterleukin-6 is increased in many clinical situationscharacterized by tissue injury, such as trauma (in-cluding major surgery), ischemia, burns, malignantconditions, exposure to toxins and aseptic irritants,infections, immune hypersensitivity reactions, andautoimmune diseases. Interleukin-6 is one of theprincipal mediators of the clinical manifestations oftissue injury, including fever, cachexia, leukocytosis,thrombocytosis, increased plasma levels of acute-phase proteins, and decreased plasma levels of al-bumin. Interleukin-6 also stimulates plasmacytosisand hypergammaglobulinemia and activates the hy-pothalamic-pituitary-adrenal axis.

Interleukin-6 in Transgenic and Gene

Knockout Mice

One of the most incisive approaches to elucidat-ing the role of interleukin-6 in inflammation andimmunity uses genetically engineered transgenic(42-45) and gene knockout mice (46-52). Overex-pression of interleukin-6 in transgenic mice resultsin massive plasmacytosis in the spleen, lymph nodes,thymus, lung, liver, and kidney that is associatedwith pronounced hypergammaglobulinemia, particu-larly of the IgG-1 subclass. In the context of theserelatively specific B-lymphocyte growth and differ-entiation effects, it should be noted that interleu-kin-6 receptors are expressed on activated but notresting B cells.

In addition to showing plasma cell expansion,interleukin-6 transgenic mice exhibit thrombocytosisand marked increases in the number of maturemegakaryocytes in the bone marrow. These micealso have kidney abnormalities, particularly mesan-gial proliferative glomerulonephritis. The murinesyndrome that results from persistent overexpres-sion of interleukin-6 resembles a human conditionknown as the Castleman syndrome (53), which isassociated with lymph node enlargement, massivehypergammaglobulinemia, and increased synthesisof acute-phase protein. In some cases, the conditionprogresses to myeloma.

The converse of overexpression of murine trans-genic interleukin-6 is represented by murine inter-leukin-6 gene knockout mice. In response to diversestimuli, mice with no interleukin-6 gene manifest a major impairment in acute-phase protein synthesis.


They also have reduced antimicrobial resistance, im-paired T-cell growth and function, impaired B-cellmaturation, and deficient mucosal IgA production.The numbers of uncommitted progenitor cells in thebone marrow are reduced, and the capacity to gen-erate leukocytosis is impaired.

Corticosteroid production in response to inflam-matory stimuli in knockout mice has been reportedas normal and subnormal (46, 47). Production oftumor necrosis factor-a is markedly increased inthese mice compared with normal mice, and corti-costeroids provide feedback suppression on produc-tion of tumor necrosis factor-a. These observationssuggest that restraints on the production of proin-flammatory mediators by the hypothalamic-pituitary-adrenal axis are blunted in interleukin-6 knockoutmice.

The acute-phase response consists of enhancedproduction of more than 40 proteins (54) that haveeither proinflammatory or anti-inflammatory prop-erties, depending on the nature of the stimulus. Theacute-phase proteins include several components ofthe complement system, which are involved in theaccumulation of phagocytes at an inflammatory siteand the killing of microbial pathogens. C-reactiveprotein, a prominent acute-phase protein, binds var-ious pathogens and materials from damaged cells,promotes opsonization of these materials, and acti-vates the complement system. In this context, inter-leukin-6-induced production of acute-phase pro-teins can be viewed as a protective host defensemechanism that limits tissue injury (55, 56).

The concept of increased production of acute-phase protein as a host defense mechanism becomesmore complicated when discussed in terms of theresponse of interleukin-6 gene-deficient mice tovarious defined stimuli (47, 49, 50). Synthesis ofacute-phase protein in interleukin-6 knockout miceis greatly impaired in response to nonspecific irri-tants. Thus, interleukin-6-deficient mice injectedintraperitoneally with a sterile irritant, such as tur-pentine, show only mild anorexia, do not loseweight, and have markedly blunted synthesis ofacute-phase protein. In contrast, wild-type mice stopeating, lose weight, and have markedly elevated lev-els of acute-phase protein. Moreover, normal miceshow increases in plasma levels of tumor necrosisfactor-a and interleukin-6, whereas the plasma lev-els of either cytokine do not increase in interleukin-6-deficient mice. No increase in mortality rate isassociated with the response to turpentine in eitherthe knockout or the wild-type mice. Therefore, inthe context of the response to a sterile irritant, theinterleukin-6-dependent acute-phase response is as-sociated with greater illness and tissue injury com-pared with the absence of interleukin-6 production(46, 47).

However, interleukin-6-deficient mice do not de-velop leukocytosis in response to an infectiousagent, such as Listeria monocytogenes, whereas pro-duction of interferon-?, which is critical in manyhost defense mechanisms, is similar to that found inwild-type mice. The mortality rate among interleu-kin-6 knockout mice infected with L. monocytogenes is markedly increased compared with that amongnormal mice, indicating that interleukin-6 is criticalto host defense and survival in response to thisinfectious agent (49, 50, 52).

Rheumatoid ArthritisMany clinical symptoms and signs associated with

rheumatoid arthritis have been linked to interleu-kin-6 (57-64). For example, severe disease is typi-cally characterized by thrombocytosis, hypergamma-globulinemia, an elevated erythrocyte sedimentationrate, and elevated levels of C-reactive protein; theseabnormalities are highly correlated with plasma andsynovial levels of interleukin-6. In fact, persistentlyelevated levels of C-reactive protein predict a verypoor outcome for patients with rheumatoid arthritis(59). In addition, systemic and periarticular boneloss, which is common in severe disease, is highlycorrelated with interleukin-6 levels in bone marrow(57, 62). Consistent with these data, small-scaletherapeutic studies with humanized anti-interleu-kin-6 antibodies have noted improvement in clinicaland laboratory variables (61).

An interesting association between interleukin-6and rheumatoid arthritis relates to age at onset andsex-steroid hormone deficiency. Rheumatoid arthritisis much more common in women than in men, andthe peak incidence of disease occurs in the peri-menopausal, postmenopausal, or postpartum period:that is, when levels of gonadal steroid hormones arelow. All available data indicate that interleukin-6production is inversely correlated with gonadal ste-roid levels (48, 51, 65) and that interleukin-6 pro-duction increases with age. Rheumatoid arthritis isuncommon in men younger than 45 years of age,but the incidence increases markedly in older menand approaches the incidence in women. Becauseandrogen levels decrease with aging, androgens maybe involved in regulating increased susceptibility todisease expression (65, 66).

Links between the hypothalamic-pituitary-adre-nal axis and interleukin-6 in rheumatoid arthritis areof great interest. Interleukin-6 is produced at highlevels and in a circadian fashion in patients withrheumatoid arthritis, with peak levels occurring be-tween 4 a.m. and 6 a.m. Patients with rheumatoidarthritis have "inappropriately normal" or, less com-monly, subnormal (albeit circadian) daily Cortisolproduction. This suggests a mismatch in sensitivity


between interleukin-6 and the hypothalamic-pitu-itary-adrenal axis in rheumatoid arthritis (67, 68).

Systemic Lupus Erythematosus

The role of interleukin-6 in systemic lupus ery-thematosus is still unclear (69-72). Whereas ele-vated plasma levels of interleukin-6 are a commonfeature of active disease, levels of circulating inter-leukin-6 are normal in the inactive form. It is inter-esting that levels of C-reactive protein (a surrogatefor interleukin-6 action) but not erythrocyte sedi-mentation rates are usually normal in patients withlupus. This raises the question of whether patientswith lupus may have a defect in selected componentsof the acute-phase response to interleukin-6 (64).

In summary, interleukin-6 seems to be a majormediator of the host response to tissue injury inmany autoimmune and inflammatory diseases andplays an important role in regulating the immune,hepatic, hematopoietic, skeletal, and neuroendo-crine systems. Abnormalities that lead to persistentoversecretion or undersecretion of interleukin-6 orexcessive or blunted effects of interleukin-6 may beinvolved in various disease states, including autoim-mune and inflammatory diseases.

Pathophysiologic Role of Interleukin-6 inOsteoporosis and Other Bone Diseases

Dr. Stavros C. Manolagas (Division of Endocri-nology Metabolism and Center for Osteoporosisand Metabolic Bone Diseases, Department of Inter-nal Medicine, University of Arkansas for MedicalSciences, Little Rock, Arkansas): The adult skeletonundergoes a continuous turnover, termed bone re-modeling, during which old bone is resorbed by os-teoclasts and new bone is formed by osteoblasts onsurfaces on which resorption has recently been com-pleted. Osteoclasts are derived from hematopoieticprecursors of bone marrow, probably the colony-forming units for granulocytes and macrophages,which also give rise to monocytes and tissue mac-rophages. Osteoblasts, however, originate from mul-tipotent mesenchymal progenitors that also give riseto fibroblastic cells of the bone marrow stroma,chondrocytes, adipocytes, and muscle cells. To en-sure the renewal of the skeleton while maintainingits anatomic and structural integrity, the processesof bone resorption and formation are tightly cou-pled. About 25% of trabecular bone is resorbed andreplaced every year in adults, whereas only 3% ofcortical bone undergoes remodeling. This indicatesthat the rate of remodeling is primarily controlledby local factors.

Extensive evidence produced in the past fewyears indicates that the cellular activity of bone

marrow and bone remodeling are tightly linked. In-deed, it is now thought that bone homeostasis, likehomeostasis of other regenerating tissues, dependson the orderly replenishment of cellular constituentsand that the fundamental problem in osteoporosis isaberrant cell production relative to demand. Thus,an oversupply of osteoclasts relative to the need forremodeling (probably associated with a decreasedrate of apoptosis) and an undersupply of osteoblastsrelative to the need for cavity repair are the criticalpathophysiologic changes in postmenopausal andage-related osteopenia, respectively (73).

Cytokines and Bone Remodeling

By stimulating the development of osteoclasts,interleukin-6 type cytokines play a profound role inskeletal homeostasis, and increasing evidence sug-gests that interleukin-6 type cytokines also promotethe development of osteoblasts (74). Moreover, it isnow established that bone-active systemic hor-mones, such as sex steroids, parathyroid hormone,parathyroid hormone-related peptide, 1,25-dihy-droxyvitamin D3, and thyroxine, exert their potentinfluences on bone remodeling and skeletal ho-meostasis by regulating the production and action ofinterleukin-6 and interleukin-11. Hormones affectthe actions of these interleukins by regulating theexpression 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 thestromal-osteoblastic lineage is inhibited in vitro byestrogen and androgen (51, 75) through receptor-mediated actions on the transcriptional activity ofthe interleukin-6 gene promoter (51, 76-78). Con-versely, estrogen loss results in increased productionof interleukin-6 by ex vivo bone marrow cell cul-tures, and increased production of interleukin-6 fol-lows the withdrawal of estradiol from primary cul-tures of calvarial cells (79). In agreement with invitro evidence, circulating levels of interleukin-6 areelevated in estrogen-deficient mice, rats, and hu-mans (74). Direct support for the contention thatinterleukin-6 is responsible for increased bone re-sorption after loss of sex steroids is derived fromstudies showing that injections of an interleukin-6-neutralizing antibody in female or male mice thathave had gonadectomy prevents the increase in os-teoclastogenesis in bone marrow and the increase inthe number of osteoclasts in sections of trabecularbone (51, 80). Furthermore, unlike wild-type con-trols, interleukin-6 knockout mice do not show cel-lular changes in the marrow and trabecular bonesections and are protected from the loss of trabec-ular bone after the loss of sex steroids (48, 51).

Even though interleukin-6 is implicated as a


pathogenetic factor in osteoporosis, it does notseem to be important for osteoclastogenesis undernormal conditions (51, 80, 81). Thus, administeringan interleukin-6-neutralizing antibody to estrogen-sufficient mice or ex vivo cultures of bone marrowcells from sex-steroid-sufficient mice has no effecton osteoclastogenesis. Furthermore, osteoclastogen-esis is unaffected in interleukin-6-deficient mice(48, 51, 80), indicating that the osteoclastogenicprocess in the estrogen-sufficient state is insensitiveto interleukin-6.

An explanation of the importance of interleu-kin-6 for bone remodeling in the sex-steroid-defi-cient state has been provided from evidence that sexsteroids suppress not only the expression of inter-leukin-6 but also its receptor. Indeed, in vitro stud-ies have determined that 17/3-estradiol or dihydro-testosterone decreased the amount of messengerRNA of the interleukin-6 receptor and messengerRNA of gpl30 in cells of the bone marrow stromal-osteoblastic lineage. These agents also decreasedlevels of gpl30 protein. Consistent with these find-ings, ovariectomy in mice increased the expressionof interleukin-6 receptor and gpl30 and the amountof interleukin-6 messenger RNA in ex vivo bonemarrow cell cultures. These results were determinedby quantitative reverse transcriptase polymerasechain reaction and confirmed on an individual cellbasis by using in situ reverse transcriptase polymer-ase chain reaction (82).

Results of clinical studies indicate that the inter-leukin-6 receptor is upregulated after the loss ofestrogen in humans. Girasole and coworkers (83)studied women who had hysterectomy alone, ovari-ectomy, or ovariectomy with transdermal estrogenreplacement. In the course of 12 months, the ex-pected increases in markers of bone formation andbone resorption were accompanied at the same timepoints by a 35% increase in levels of soluble inter-leukin-6 receptor and a 20% increase in serum lev-els of interleukin-6. Estrogen replacement reversedthe increased levels of serum and soluble interleu-kin-6 receptor induced by ovariectomy. Similarly,Chen and colleagues (84) investigated 151 healthywomen whose menstruation status differed andfound that levels of soluble interleukin-6 receptorwere substantially increased in postmenopausalwomen compared with premenopausal and peri-menopausal women.

Role of Interleukin-6 in Other Disease States

Characterized by Increased Bone Resorption

Evidence accumulated in the past 5 years to sup-port the contention that interleukin-6 is a pathoge-netic factor in osteoporosis that results from theloss of either male or female sex steroids has im-plicated interleukin-6 in the pathophysiology of

several other diseases caused by increased osteo-clastic bone resorption. These diseases include hy-perparathyroidism (85, 86), Paget disease (87), mul-tiple myeloma (88), rheumatoid arthritis (57, 89),Gorham-Stout disease (90), hyperthyroidism (91,92), the McCune-Albright syndrome (93), and renalosteodystrophy (94). An increase in the expressionof the soluble interleukin-6 receptor has beenshown in these diseases and in sex-steroid defi-ciency. The mechanism of increased production ofinterleukin-6 in these diseases is still unclear, withthe exceptions of hyperparathyroidism (in whichparathyroid hormone stimulates production of inter-leukin-6) and the McCune-Albright syndrome (inwhich the constitutive activation of the Gsa-subunitof the G protein and the eventual increase in levelsof intracellular cyclic adenosine 5'-monophosphatelead to elevated levels of interleukin-6 levels in theaffected bone).

In conclusion, the increased rate of remodelingand bone loss that characterizes several diseasestates may be explained by increased osteoclast de-velopment caused by increased production or actionof such cytokines as interleukin-6.

Integration of the Immune and EndocrineSystems by Interleukin-6

Dr. George P. Chrousos (Developmental Endo-crinology Branch, National Institute of Child Healthand Human Development, NIH): The stress systemhas a central nervous system component and a pe-ripheral component (95). The central componentconsists of the hypothalamus, which includes corti-cotropin-releasing hormone and vasopressin neu-rons of the paraventricular nucleus, and the brainstem, which includes the noradrenergic neurons ofthe locus ceruleus and other autonomic centers. Theperipheral component consists of the hypothalamic-pituitary-adrenal axis and the peripheral autonomicnervous system, which also includes the adrenal me-dullae. Activation of the stress system leads to sup-pression of the growth and reproductive axes (96),alterations in thyroid function recognized in the eu-thyroid sick syndrome (40), and suppression of theimmune-inflammatory reaction associated with a shift from the Thl to the Th2 profile (97).

Interleukin-6 has a profound stimulatory effecton the stress system (20-22) and is secreted whenthe system is activated during inflammatory (98, 99)and (to a lesser extent) noninflammatory stress (25,35, 36, 100). Interleukin-6 may play a pathogeneticrole in conditions related to chronic stress and phys-iologic aging. Aging is characterized by progressivelyincreasing concentrations of glucocorticoids and cat-echolamines and decreasing production of growth


Figure 4. Changes in circulating hormones and interleukin-6 withaging in men and women.

and sex hormones, a pattern reminiscent of that

seen in chronic stress (Figure 4). Recent studies

(101, 102) have shown that plasma levels of inter-

leukin-6 increase with age, probably as the result of

catecholamine hypersecretion and sex-steroid hypo-

secretion, 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 arthri-

tis (59, 63), and disorders of excessive daytime

sleepiness (104); the marked correlation of interleu-

kin-6 with exercise-induced exhaustion (Papanico-

laou DA, Singh A, Gold PW, Deuster PA, Chrousos

GP. Exercise-induced fatigue correlates with plasma

interleukin-6 [IL-6] levels in normal women. Pre-

sented at the Third International Congress of the

International Society for Neuroimmunomodulation,

15 November 1996, Washington, DC); and the abil-

ity 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 neu-

tralizing anti-interleukin-6 antibodies or interleu-

kin-6 receptor antagonists may be particularly help-

ful 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 pathogen-

esis 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 neurodegenera-

tion and gliosis seen in such conditions as AIDS

encephalopathy (107, 108) and Alzheimer disease

(109, 110). Thus, potential suppressants of interleu-

kin-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-depen-

dent manner suggests that this cytokine could be used

for the differential diagnosis of disorders associated

with abnormalities of the corticotropin-releasing hor-

mone 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 mel-

ancholic depression or chronic active alcoholism

and the alcohol withdrawal syndrome) and between

atypical and melancholic depression. Such a differ-

entiation would be based on the fact that the cor-

ticotropin-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 de-

pression are on opposite sides of the spectrum in

terms of activity of the corticotropin-releasing hor-

mone neuron (112-115).

Glossary

AP-l site: A specific DNA sequence that binds thec-jun and c-fos heterodimers.

C/EBP: A transcription factor that regulates severaladipocyte-specific and hepatocyte-specific genes.

CIEBP& (NF-IL6): A transcription factor that is min-imally expressed in normal tissues but is drastically in-duced by stimulation of lipopolysaccharides, interleukin-1,tumor necrosis factor-a, or interleukin-6.

c-fos: A transcription factor that regulates growth as a heterodimer with c-jun; the heterodimers bind to theAP-l sites.

c-jun: A transcription factor that regulates growth as a heterodimer with c-fos; the heterodimers bind to theAP-l sites.

Exon: A coding section of a gene retained at its mes-senger RNA before translation.

Intron: A noncoding section of a gene that is removedfrom RNA transcripts before they are translated.

NF-KB: A transcription factor activated during inflam-

mation.Stress: Disturbance of homeostasis.Thl: CD4+ cells that produce interleukin-2 and inter-

feron-y, which promote cellular immunity.Th2: CD4+ cells that produce interleukin-4, which pro-


motes humoral immunity. The term has been expanded to

include cytokines that promote humoral immunity, such

as interleukin-5, interleukin-9, interleukin-11, and inter-

leukin-13.

Transcription: The making of an RNA molecule by

using the information encoded in the DNA.

Transcription factor: A protein that binds to the regu-

latory regions of genes and influences their rates of tran-

scription.

Requests for Reprints: Dimitris A. Papanicolaou, MD, Develop-mental Endocrinology Branch, National Institute of Child Healthand Human Development, Building 10, Room 10N262, 10 CenterDrive MSC 1862, Bethesda, MD 20892-1862

Current Author Addresses: Dr. Papanicolaou: Developmental En-docrinology Branch, National Institute of Child Health and Hu-man Development, National Institutes of Health, Building 10,Room 10N262, 10 Center Drive MSC 1862, Bethesda, MD20892-1862.Dr. Wilder: Arthritis and Rheumatism Branch, National Instituteof Arthritis and Musculoskeletal and Skin Diseases, NationalInstitutes of Health, Building 10, Room 9N240, 10 Center DriveMSC 1862, Bethesda, MD 20892.Dr. Manolagas: Division of Endocrinology Metabolism and Cen-ter for Osteoporosis and Metabolic Bone Diseases, Departmentof Internal Medicine, University of Arkansas for Medical Sci-ences, 4301 West Markham Street, Slot 587, Little Rock, AR72205-7199.Dr. Chrousos: Developmental Endocrinology Branch, NationalInstitute of Child Health and Human Development, NationalInstitutes of Health, Building 10, Room 10N244, 10 Center DriveMSC 1862, Bethesda, MD 20892-1862.

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I was unwell, you hurried round, surroundedBy ninety students, Doctor. Ninety chillNorth-wind-chapped hands that pawed and probed and pounded.I was unwell; now I'm extremely ill.

MartialThe Epigrams Harmondsworth, UK: Penguin; 1978

Submitted by:Jan V. Hirschmann, MDUniversity of Washington School of MedicineSeattle, WA 98108

Submissions from readers are welcomed. If the quotation is published, the sender's name will be acknowl-edged. Please include a complete citation, as done for any reference.—The Editor


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