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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
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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.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1998;128(2):127-137. doi:10.7326/0003-4819-128-2-199801150-00009
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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.




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Figure 1.
Transcriptional regulation of the interleukin-6 (IL-6) promoter.

Glucocorticoids inhibit transcription of interleukin-6 through interaction of the ligand-activated glucocorticoid receptor (GR) with the Re1A subunit of transcription factor NF-κB. Estrogens suppress transcription (slashed arrows) of interleukin-6 through formation of heteromeric estrogen receptor (ER)-C/EBPbeta and estrogen receptor-NF-κB complexes. AP-1 = AP-1 site; CREB = cyclic adenosine 5′-monophosphate-response element binding site; C/EBP = C/EBP binding site; NF-κB = NF-κB binding site. The triangle represents glucocorticoid; the rhombus represents estrogen.

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Figure 2.
Pleiotropy of interleukin-6 (IL-6) action.

Binding of circulating interleukin-6 to the soluble interleukin-6 receptor (sIL-6R) may activate gp130 subunits present on cells that lack the specific interleukin-6 receptor, probably those that are activated by the leptin receptor (OB-R), leukemia inhibitory factor receptor (LIF-R) (for leukemia inhibitory factor, oncostatin-M, ciliary neurotrophic factor, and cardiotropin-1), and oncostatin-M receptor (OMR) (for oncostatin-M).

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Figure 3.
Regulation of the secretion and endocrine actions of interleukin-6 (IL-6).

Interleukin-6 production is stimulated by tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). Interleukin-6, in turn, inhibits further production of tumor necrosis factor-α and interleukin-1. Catecholamines stimulate interleukin-6 production, whereas glucocorticoids, estrogens, and androgens suppress it. Interleukin-6 acutely stimulates the corticotropin-releasing hormone (CRH) neuron, which leads to increased secretion of adrenocorticotropin hormone (ACTH) and cortisol. It also stimulates the secretion of growth hormone (GH) and arginine vasopressin (AVP) (at high levels) but suppresses thyroid-stimulating hormone (TSH) secretion and levels of circulating lipids.

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