Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans.
Abstract
The inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 alpha and -beta (IL-1 alpha and -beta), and IL-6 can activate the hypothalamic-pituitary-adrenal (HPA) axis. Tumor necrosis factor-alpha and IL-1 have been tested in both experimental animals and humans, but their administration has been limited by significant toxicity, mainly severe hypotension. IL-6, on the other hand, has demonstrated modest toxicity in animals. We evaluated the ability of recombinant IL-6 to stimulate the human HPA axis in patients with cancer and a good performance status, who received daily morning sc injections of 30 micrograms/kg IL-6 for 7 consecutive days, during the course of a phase I trial. IL-6 caused impressively marked and prolonged elevations of plasma ACTH and cortisol on the first day and blunted ACTH responses on the seventh day of treatment, perhaps as a result of increased baseline cortisol levels. The overall cortisol response, however, on the seventh day was of similar magnitude, suggesting that a new equilibrium in the feedback regulation of the HPA axis occurs with chronic IL-6 administration. The toxic effects of IL-6 were modest, suggesting that it might be useful for clinical testing of the HPA axis, as an alternative to the insulin tolerance test.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Subcutaneous injection of IL-6 into human cancer patients elevates plasma ACTH and cortisol levels.
“Administration of exogenous IL-6 to rats stimulates ACTH and corticosterone production, and s.c. injection of IL-6 into human cancer patients has been shown to elevate plasma ACTH and cortisol levels (25–28).”
From Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation (2000) · cites this paper as [27]
Administration of exogenous IL-6 to rats stimulates ACTH and corticosterone production.
“Administration of exogenous IL-6 to rats stimulates ACTH and corticosterone production, and s.c. injection of IL-6 into human cancer patients has been shown to elevate plasma ACTH and cortisol levels (25–28).”
From Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation (2000) · cites this paper as [27]
Cites
BERNARDINI, R., KAMILARIS, T. C., CALOGERO, A. E., JOHNSON, E. O., GOMEZ, M. T., GOLD, P. W., & CHROUSOS, G. P. (1990) · Endocrinology · doi:10.1210/endo-126-6-2876 · Cited by 232 · see citing works
Self-citationSchulte, H. M., Chrousos, G. P., Gold, P. W., Booth, J. D., Oldfield, E. H., Cutler, G. B., & Loriaux, D. L. (1985) · Journal of Clinical Investigation · doi:10.1172/jci111890 · Cited by 103 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514 · see citing works
The Hypothalamic–Pituitary–Adrenal Axis and Immune-Mediated Inflammation
Chrousos, G. P. (1995) · New England Journal of Medicine · doi:10.1056/nejm199505183322008 · Cited by 2,579 · see citing works
Self-citationEndocrinology of the stress response
Charmandari, E., Tsigos, C., & Chrousos, G. (2005) · Annual Review of Physiology · doi:10.1146/annurev.physiol.67.040403.120816 · Cited by 1,799 · see citing works
Self-citationInflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?
Yudkin, J. S., Kumari, M., Humphries, S. E., & Mohamed-Ali, V. (2000) · Atherosclerosis · doi:10.1016/s0021-9150(99)00463-3 · Cited by 1,775 · see citing works
Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action
TURNBULL, A. V., & RIVIER, C. L. (1999) · Physiological Reviews · doi:10.1152/physrev.1999.79.1.1 · Cited by 1,297 · see citing works
The Pathophysiologic Roles of Interleukin-6 in Human Disease
Papanicolaou, D. A., Wilder, R. L., Manolagas, S. C., & Chrousos, G. P. (1998) · Annals of Internal Medicine · doi:10.7326/0003-4819-128-2-199801150-00009 · Cited by 1,146 · see citing works
Self-citationVgontzas, A. N., Papanicolaou, D. A., Bixler, E. O., Kales, A., Tyson, K., & Chrousos, G. P. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.5.3950 · Cited by 974 · see citing works
Self-citationCytokines and cognition–the case for a head-to-toe inflammatory paradigm.
Wilson, C. J., Finch, C. E., & Cohen, H. J. (2002) · Journal of the American Geriatrics Society · doi:10.1046/j.1532-5415.2002.50619.x · Cited by 637 · see citing works
Age-related inflammatory cytokines and disease
Brüünsgaard, H., & Pedersen, B. K. (2003) · Immunology and Allergy Clinics of North America · doi:10.1016/s0889-8561(02)00056-5 · Cited by 608 · see citing works
Intraadrenal interactions in the regulation of adrenocortical steroidogenesis.
Ehrhart-Bornstein, M., Hinson, J. P., Bornstein, S. R., Scherbaum, W. A., & Vinson, G. P. (1998) · Endocrine Reviews · doi:10.1210/edrv.19.2.0326 · Cited by 600 · see citing works
Neuroendocrinology and pathophysiology of the stress system
STRATAKIS, C. A., & CHROUSOS, G. P. (1995) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1995.tb44666.x · Cited by 533 · see citing works
Self-citationImmune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection
Silverman, M. N., Pearce, B. D., Biron, C. A., & Miller, A. H. (2005) · Viral Immunology · doi:10.1089/vim.2005.18.41 · Cited by 506 · see citing works
Vgontzas, A. N., & Chrousos, G. P. (2002) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(01)00005-6 · Cited by 414 · see citing works
Self-citationWikby, A., Ferguson, F., Forsey, R., Thompson, J., Strindhall, J., Löfgren, S., Nilsson, B.-O., Ernerudh, J., Pawelec, G., & Johansson, B. (2005) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/60.5.556 · Cited by 407 · see citing works
Agorastos, A., Pervanidou, P., Chrousos, G. P., & Baker, D. G. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00118 · Cited by 385 · see citing works
Self-citationBethin, K. E., Vogt, S. K., & Muglia, L. J. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.16.9317 · Cited by 382 · see citing works
Alesci, S., Martinez, P. E., Kelkar, S., Ilias, I., Ronsaville, D. S., Listwak, S. J., Ayala, A. R., Licinio, J., Gold, H. K., Kling, M. A., et al. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1667 · Cited by 372 · see citing works
Self-citationInflammation and Skeletal Muscle Wasting During Cachexia
Webster, J. M., Kempen, L. J. A. P., Hardy, R. S., & Langen, R. C. J. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.597675 · Cited by 372 · see citing works
Cytokine activation of the HPA axis
DUNN, A. J. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb05426.x · Cited by 352 · see citing works
Bornstein, S. R., & Chrousos, G. P. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.5.5631 · Cited by 354 · see citing works
Self-citationIL-6 and its circadian secretion in humans
Vgontzas, A. N., Bixler, E. O., Lin, H.-M., Prolo, P., Trakada, G., & Chrousos, G. P. (2005) · Neuroimmunomodulation · doi:10.1159/000084844 · Cited by 338 · see citing works
Self-citationDose-Dependent Effects of Recombinant Human Interleukin-6 on Glucose Regulation
Tsigos, C., Papanicolaou, D. A., Kyrou, I., Defensor, R., Mitsiadis, C. S., & Chrousos, G. P. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.12.4422 · Cited by 324 · see citing works
Self-citationPaul-Labrador, M., Polk, D., Dwyer, J. H., Velasquez, I., Nidich, S., Rainforth, M., Schneider, R., & Merz, C. N. B. (2006) · Archives of Internal Medicine · doi:10.1001/archinte.166.11.1218 · Cited by 284 · see citing works
Mastorakos, G., Weber, J. S., Magiakou, M. A., Gunn, H., & Chrousos, G. P. (1994) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.79.4.7962300 · Cited by 271 · see citing works
Self-citationCrofford, L. J. (1997) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.82.4.1279 · Cited by 242 · see citing works
Plasma and Cerebrospinal Fluid Interleukin-6 Concentrations in Posttraumatic Stress Disorder
Baker, D. G., Ekhator, N. N., Kasckow, J. W., Hill, K. K., Zoumakis, E., Dashevsky, B. A., Chrousos, G. P., & Geracioti Jr., T. D. (2001) · Neuroimmunomodulation · doi:10.1159/000049028 · Cited by 238 · see citing works
Self-citationThe hypothalamic-pituitary-adrenal axis and the female reproductive system
MAGIAKOU, M. A., MASTORAKOS, G., WEBSTER, E., & CHROUSOS, G. P. (1997) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1997.tb52128.x · Cited by 320 · see citing works
Self-citationHigher levels and blunted diurnal variation of cortisol in frail older women
Varadhan, R., Walston, J., Cappola, A. R., Carlson, M. C., Wand, G. S., & Fried, L. P. (2008) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/63.2.190 · Cited by 182 · see citing works
Nash, D., Hughes, M. G., Butcher, L., Aicheler, R., Smith, P., Cullen, T., & Webb, R. (2023) · Scandinavian Journal of Medicine & Science in Sports · doi:10.1111/sms.14241 · Cited by 182 · see citing works
Biomarkers of depression in cancer patients
Jehn, C. F., Kuehnhardt, D., Bartholomae, A., Pfeiffer, S., Krebs, M., Regierer, A. C., Schmid, P., Possinger, K., & Flath, B. C. (2006) · Cancer · doi:10.1002/cncr.22294 · Cited by 139 · see citing works
Straub, R. H., Herfarth, H., Falk, W., Andus, T., & Schölmerich, J. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00047-4 · Cited by 115 · see citing works
Härle, P., Straub, R. H., Wiest, R., Mayer, A., Schölmerich, J., Atzeni, F., Carrabba, M., Cutolo, M., & Sarzi-Puttini, P. (2006) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2005.038059 · Cited by 114 · see citing works
Straub, R. H., Vogl, D., Gross, V., Lang, B., Schölmerich, J., & Andus, T. (1998) · American Journal of Gastroenterology · doi:10.1111/j.1572-0241.1998.00535.x · Cited by 114 · see citing works
Dose-Dependent Effects of Recombinant Human Interleukin-6 on the Pituitary-Testicular Axis
Tsigos, C., Papanicolaou, D. A., Kyrou, I., Raptis, S. A., & Chrousos, G. P. (1999) · Journal of Interferon & Cytokine Research · doi:10.1089/107999099312948 · Cited by 111 · see citing works
Self-citationBiomarkers of post-covid depression
Lorkiewicz, P., & Waszkiewicz, N. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10184142 · Cited by 102 · see citing works
Peripheral Inflammatory Parameters in Late-Life Depression: A Systematic Review
Martínez-Cengotitabengoa, M., Carrascón, L., O’Brien, J., Díaz-Gutiérrez, M.-J., Bermúdez-Ampudia, C., Sanada, K., Arrasate, M., & González-Pinto, A. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17122022 · Cited by 85 · see citing works
Heuschkel, K., & Kuypers, K. P. C. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00224 · Cited by 86 · see citing works
Rudolf, S., Greggersen, W., Kahl, K. G., Hüppe, M., & Schweiger, U. (2014) · Psychiatry Research · doi:10.1016/j.psychres.2014.02.016 · Cited by 71 · see citing works
Interleukin-6 and use of social support in gynecologic cancer patients
Lutgendorf, S. K., Anderson, B., Sorosky, J. I., Buller, R. E., & Lubaroff, D. M. (2000) · International Journal of Behavioral Medicine · doi:10.1207/s15327558ijbm0702_3 · Cited by 56 · see citing works
Inhaled corticosteroids and secondary adrenal insufficiency
Sannarangappa, V., & Jalleh, R. (2014) · The Open Respiratory Medicine Journal · doi:10.2174/1874306401408010093 · Cited by 49 · see citing works
Chronic Systemic Inflammation Is Associated With Symptoms of Late-Life Depression: The ARIC Study
Sonsin-Diaz, N., Gottesman, R. F., Fracica, E., Walston, J., Windham, B. G., Knopman, D. S., & Walker, K. A. (2020) · The American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2019.05.011 · Cited by 44 · see citing works
Yavropoulou, M. P., Filippa, M. G., Mantzou, A., Ntziora, F., Mylona, M., Tektonidou, M. G., Vlachogiannis, N. I., Paraskevis, D., Kaltsas, G. A., Chrousos, G. P., et al. (2022) · Endocrine · doi:10.1007/s12020-021-02968-8 · Cited by 33 · see citing works
Self-citationMagnocellular vasopressin and the mechanism of “Glucocorticoid escape”
Antoni, F. A. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00422 · Cited by 26 · see citing works
The emerging role of peripheral corticotropin-releasing hormone (CRH)
Ilias, I., & Mastorakos, G. (2003) · Journal of Endocrinological Investigation · doi:10.1007/bf03345186 · Cited by 24 · see citing works
Self-citationLuthra, N. S., Clow, A., & Corcos, D. M. (2022) · Brain Sciences · doi:10.3390/brainsci12121695 · Cited by 20 · see citing works
- Authors
- Mastorakos, G., Chrousos, G. P., & Weber, J. S.
- Affiliations
- National Institutes of Health (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1993-12
- Volume
- 77
- Issue
- 6
- Pages
- 1690-1694
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2048958074
- Cited by
- 591
- References
- 2
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 6 · 2023: 11 · 2022: 17 · 2021: 21 · 2020: 13 · 2019: 18 · 2018: 15 · 2017: 16 · 2016: 13 · 2015: 17 · 2014: 21 · 2013: 15 · 2012: 16
- FWCI
- 10.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- interleukin-6, hypothalamic-pituitary-adrenal axis, ACTH, cortisol, inflammatory cytokines, TNF-α, interleukin-1, cancer patients, drug toxicity
- MeSH terms
- Adrenocorticotropic Hormone, Adult, Aged, Corticotropin-Releasing Hormone, Female, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Male, Middle Aged, Pituitary-Adrenal System, Recombinant Proteins, Interleukin-6
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review