Cited by 145Stress Responses and CortisolAdrenal Hormones and DisordersCytokine Signaling Pathways and Interactions

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Interleukin-6 stimulates the hypothalamus-pituitary-adrenocortical axis in man.

Späth-Schwalbe, E, Born, J, Schrezenmeier, H, Bornstein, S R, Stromeyer, P, Drechsler, S, Fehm, H L, Porzsolt, F·1994·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jcem.79.4.7962296

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Abstract

A recent study in humans, animal studies, and in vitro data have suggested that interleukin-6 (IL-6) stimulates the secretory activity of the hypothalamus-pituitary-adrenocortical (HPA) axis. In a phase II study, one female and six male patients with metastatic renal cell carcinoma received IL-6 to evaluate a possible antitumor effect of IL-6. This offered the possibility of investigating the influence of IL-6 on the HPA axis in man. The subjects were studied 1 day before, on day 1, and on day 21 of IL-6 therapy (150 micrograms administered sc every day at 0900 h). Blood samples were taken at 0900, 1100, 1300, 1600, and 2000 h the day before, on day 1 of IL-6 therapy, 24 h after the first IL-6 injection, and on day 21 of IL-6 treatment. Plasma ACTH and cortisol levels promptly followed the rise of IL-6, which peaked 4 h after administration. They were significantly (P < 0.05) higher at 1100 and 1300 h on day 1 of IL-6 therapy compared with the corresponding plasma levels the day before IL-6 treatment. Cortisol concentrations remained significantly increased at 1600 and 2000 h after IL-6 administration. Twenty-four hours after the first IL-6 administration, IL-6, ACTH, and cortisol levels had reached preinjection values. Although plasma cortisol levels were similar on days 1 and 21, ACTH levels were lower on day 21 (than on day 1), but significantly elevated at 1100 h compared with levels on the day before the first IL-6 injection. Results confirming the very recent data of another study demonstrate a stimulating effect of IL-6 on the HPA axis in man. They support the notion that IL-6 is one of the cytokines involved in the interaction between the immune system and the HPA axis.

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Background
Cytokines and HPA Axis Regulation
Silverman, M. N., Pearce, B. D., & Miller, A. H. (2003) · Neurobiological foundation of aberrant behaviors · doi:10.1007/978-1-4615-0323-1_5 · Cited by 29
Interleukin‐3 and Interleukin‐6 Stimulate Bovine Adrenal Cortisol Secretion Through Different Pathways
Michl, Beikler, Engelhardt, & Weber (2000) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.2000.00423.x · Cited by 24
Further evidence for insufficient hypothalamic-pituitary-glandular axes in polymyalgia rheumatica.
Straub, R. H., & Cutolo, M. (2006) · PubMed · Cited by 23
Functional resting state connectivity is differentially associated with IL-6 and TNF-α in depression and in healthy controls
Schmitz, C. N., Sammer, G., Neumann, E., Blecker, C. R., Gründer, G., Adolphi, H., Lamadé, E. K., & Petrozzi, B. P. (2025) · Scientific Reports · doi:10.1038/s41598-025-85514-0 · Cited by 24
“…previous studies have reported that resting state FC is associated with the activity of the HPA axis 73,74 and IL-6 as well as TNF-α show in some cases opposing biological effects on the HPA axis 25,75,76 , IL-6 and TNF-α might exert distinct effects on DMN and SAL FC potentially via the HPA axis.”
Immunomodulatory Mechanisms Mediated by Sex Hormones in Rheumatoid Arthritisa
Cutolo, M., & CASTAGNETTA, L. A. M. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb16239.x · Cited by 20
Regulation of Steroidogenesis in Reproductive, Adrenal and Neural Tissues by Cytokines
Guzmán, C., Hernández‐Bello, R., & Morales‐Montor, J. (2010) · The Open Neuroendocrinology Journal · Cited by 19
Early shifts of adrenal steroid synthesis before and after relief of short-term cholestasis
Zietz, B., Wengler, I., Messmann, H., Lock, G., Schölmerich, J., & Straub, R. H. (2001) · Journal of Hepatology · doi:10.1016/s0168-8278(01)00152-0 · Cited by 18
Corticosterone binding globulin regulation and thymus changes after thermal injury in mice
D’Elia, M., Patenaude, J., Hamelin, C., Garrel, D. R., & Bernier, J. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00407.2004 · Cited by 19
“Depending on the nature of the stimulus, the HPA axis can be triggered by various factors such as TNF- , interleukin (IL)-1, and IL-6 released mainly from immune cells (42, 49).”
Background
Inappropriately normal plasma ACTH and cortisol concentrations in the face of increased circulating interleukin-6 concentration in exercise in patients with sarcoidosis
Mastorakos, G. P., Paltoglou, G., Greene, M. T., Ilias, Ι., Papamichalopoulos, A., Dimopoulos, S. K., Pouliou, E., Fatouros, I. G., & Nanas, S. (2012) · Stress · doi:10.3109/10253890.2012.715221 · Cited by 17
“Thus, in sarcoidosis patients, a dysfunctional IL-6-induced response of the HPA axis or an adaptation of this axis in the face of the chronically elevated IL-6 concentrations might exist (Mastorakos et al. 1993; Späth-Schwalbe et al. 1994).”
Background
Pituitary-adrenal function in uncomplicated falciparum malaria.
Wilson, M., Davis, T. M. E., Bình, T. Q., Long, T. T. A., Danh, P. T., & Robertson, K. (2001) · UWA Profiles and Research Repository (UWA) · Cited by 17
Moxibustion at Mingmen Reduces Inflammation and Decreases IL-6 in a Collagen-Induced Arthritis Mouse Model
Kogure, M., Mimura, N., Ikemoto, H., et al. (2011) · Journal of Acupuncture and Meridian Studies · doi:10.1016/j.jams.2011.11.004 · Cited by 16
The effects of interleukin‐2 treatment on endothelin and the activation of the hypothalamic–pituitary–adrenal axis
Raab, C., Weidmann, E., Schmidt, A., Bergmann, L., Badenhoop, K. W. J., Usadel, K. H., & Haak, T. (1999) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1999.00592.x · Cited by 16
Systemic disease sequelae in chronic inflammatory diseases and chronic psychological stress: comparison and pathophysiological model
Straub, R. H. (2014) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12409 · Cited by 14
Impaired hypothalamo-pituitary-adrenal axis in patients with ankylosing spondylitis
Kebapçılar, L., Bilgir, O., Alacacıoğlu, A., Yıldız, Y., Taylan, A., Günaydın, R., Yüksel, A., Karaca, B., & Sarı, İ. (2009) · Journal of Endocrinological Investigation · doi:10.1007/bf03346548 · Cited by 13
The Application of Multiplex Biomarker Techniques for Improved Stratification and Treatment of Schizophrenia Patients
Steiner, J. H., Guest, P. C., Rahmoune, H., & Martins‐de‐Souza, D. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6730-8_2 · Cited by 11
Processing of Cytokine Signals at CNS Levels
Besedovsky, H. O., & del Rey, A. (2007) · Neuroimmune biology · doi:10.1016/s1567-7443(07)00212-8 · Cited by 12
Technological advances for deciphering the complexity of psychiatric disorders: merging proteomics with cell biology
Wesseling, H., Guest, P. C., Lago, S. G., & Bahn, S. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1017/s146114571400008x · Cited by 11
“Other well known processes mediated through the bloodstream which can affect both brain and peripheral function include the regulation of food intake (Mastorakos and Zapanti, 2004), immune system dysfunction (Spathschwalbe et al., 1994), metabolic disorders and insulin resistance (Pasquali et al.”
Background
Application of Proteomic Techniques for Improved Stratification and Treatment of Schizophrenia Patients
Steiner, J. H., Guest, P. C., & Martins‐de‐Souza, D. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-52479-5_1 · Cited by 10
Anti-tumour necrosis factor antibody treatment does not change serum levels of cortisol binding globulin in patients with rheumatoid arthritis but it increases androstenedione relative to cortisol
Straub, R. H., Sarzi‐Puttini, P., Atzeni, F., Buttgereit, F., Carrabba, M., & Cutolo, M. (2005) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2004.031997 · Cited by 10
MHC/class-II-positive cells inhibit corticosterone of adrenal gland cells in experimental arthritis: a role for IL-1β, IL-18, and the inflammasome
Stangl, H., Krammetsvogl, A., Lesiak, M., Wolff, C., & Straub, R. H. (2020) · Scientific Reports · doi:10.1038/s41598-020-74309-0 · Cited by 9
Activity of the neuroendocrine axes in patients with polymyalgia rheumatica before and after TNF-α blocking etanercept treatment
Kreiner, F. F., & Galbo, H. (2012) · Arthritis Research & Therapy · doi:10.1186/ar4017 · Cited by 9
“This is so, because plasma cortisol levels may be lower than expected, because concentrations of various cytokines (for example, IL-6) are increased [1,3,8-11], and because in non-PMR patients, injection with IL-6 has been shown to increase ACTH and cortisol levels in plasma [3,8,11-15].”
BackgroundInfluential
Hormone (ACTH, T3) content of immunophenotyped lymphocyte subpopulations
Pállinger, É., Kiss, G. A., & Csaba, G. (2016) · Acta Microbiologica et Immunologica Hungarica · doi:10.1556/030.63.2016.016 · Cited by 7
Induction of immune activation by a novel immunomodulatory oligonucleotide without thymocyte apoptosis
Jiang, W., Reich, C. F., You, D., Kandimalla, E., Agrawal, S., & Pisetsky, D. S. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.04.001 · Cited by 7
Macrophage regulation of hypothalamic-pituitary-adrenal and gonadal axis homeostasis and hormonal output
O’Brien, C. J. O. (2025) · Biomedical Journal · doi:10.1016/j.bj.2025.100866 · Cited by 7

Authors: Späth-Schwalbe, E., Born, J., Schrezenmeier, H., Bornstein, S. R., Stromeyer, P., Drechsler, S., Fehm, H. L., & Porzsolt, F.
Affiliations: Universität Ulm (DE)
ORCID: Born, J
Schrezenmeier, H
Bornstein, S R
Porzsolt, F
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 1994-10
Volume: 79
Issue: 4
Pages: 1212-1214
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jcem.79.4.7962296
OpenAlex: W2005611582
Cited by: 145
References: 0
Citations by year: 2026: 2 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 4 · 2016: 5 · 2015: 4 · 2014: 5 · 2013: 4 · 2012: 3
FWCI: 3.25
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
Site cant be reached (submittedVersion)
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Keywords: interleukin-6, ACTH, cortisol, metastatic renal cell carcinoma, cytokine therapy
MeSH terms: Adrenal Cortex, Adrenocorticotropic Hormone, Circadian Rhythm, Female, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Male, Middle Aged, Osmolar Concentration, Pituitary-Adrenal System, Recombinant Proteins, Interleukin-6

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Interleukin-6 stimulates the hypothalamus-pituitary-adrenocortical axis in man.

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