Circadian Relationships between Interleukin (IL)-6 and Hypothalamic-Pituitary-Adrenal Axis Hormones: Failure of IL-6 to Cause Sustained Hypercortisolism in Patients with Early Untreated Rheumatoid Arthritis
Abstract
Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and this cytokine is also a potent stimulus of the hypothalamic-pituitary-adrenal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, cortisol, and IL-6 and their interactions in patients with early untreated RA, we recruited and studied five newly diagnosed, untreated RA patients early in the course of their disease and five age-, gender-, and race-matched control subjects. We collected serial blood samples over 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 every hour. The 24-h collection was followed by administration of ovine CRH (oCRH) and post-oCRH serial blood samples over 2 h. We analyzed the 24-h overall levels of these hormones and their circadian variations and performed time-lagged cross-correlation analyses among them. The untreated RA patients had 24 h time-integrated plasma ACTH, plasma cortisol levels, and urinary free cortisol excretion that were not significantly different from control subjects, in spite of their disease activity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCRH were similar in RA patients and controls. IL-6 levels were significantly increased in the RA patients compared with control subjects during the early morning hours (P < 0.05). There was pronounced circadian variation of plasma Il-6 levels. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with elevated levels of IL-6 before the elevations of ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. The data presented here suggest that although endogenous IL-6 may stimulate secretion of ACTH and cortisol, overall activity of the hypothalamic-pituitary-adrenal axis remains normal and apparently is insufficient to inhibit ongoing inflammation in early untreated RA patients.
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Adrenocortical dysfunction, also termed relative or functional adrenal insufficiency, has been described in patients with rheumatoid arthritis without any prior risk of, or evidence of, overt adrenal insufficiency.
“Adrenocortical dysfunction, termed also as ‘relative’ or ‘functional’ adrenal insufficiency, has been described in patients with rheumatoid arthritis (RA) without any prior risk of, or evidence of, overt adrenal insufficiency.1–8”
From Diurnal production of cortisol and prediction of treatment response in rheumatoid arthritis: a 6-month, real-life prospective cohort study (2024) · cites this paper as [3]
In chronic inflammatory diseases such as SLE or RA the HPA axis alters markedly, with inadequate ACTH secretion relative to circulating cytokines and inappropriately low spontaneous and stimulated cortisol secretion in relation to inflammation.
“In chronic inflammatory diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) the HPA axis alters markedly : (a) secretion of adrenocorticotropic hormone (ACTH) relative to circulating cytokines is inadequate 7 ; (b) patients have inappropriately low sponta- neous and stimulated cortisol secretion in relation to inflammation”
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Elenkov, I. J. (2008) · Neurochemistry International · doi:10.1016/j.neuint.2007.06.037 · Cited by 273 · see citing works
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Ruiz, F. S., Andersen, M. L., Martins, R. C., Zager, A., Lopes, J. D., & Tufik, S. (2012) · Innate Immunity · doi:10.1177/1753425910385962 · Cited by 132 · see citing works
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Cavalcante, L. O., Melo, M. R., Dinis, V. G., Castro, R. B., de Souza, B. D. B., & Longui, C. A. (2010) · Genetics and Molecular Research · doi:10.4238/vol9-4gmr970 · Cited by 14 · see citing works
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Yavropoulou, M. P., Filippa, M. G., Vlachogiannis, N. I., Fragoulis, G. E., Laskari, K., Mantzou, A., Panopoulos, S., Fanouriakis, A., Bournia, V.-K., Evangelatos, G., et al. (2024) · RMD Open · doi:10.1136/rmdopen-2023-003575 · Cited by 13 · see citing works
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Rastmanesh, R. (2009) · Medical Hypotheses · doi:10.1016/j.mehy.2009.05.035 · Cited by 6 · see citing works
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To, H. (2016) · ChronoPhysiology and Therapy · doi:10.2147/cpt.s87421 · Cited by 6 · see citing works
Catallani, B., Palma, B. D., Gil, F. Z., & Suchecki, D. (2007) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2007.08.010 · Cited by 5 · see citing works
Pongratz, G., Härle, P., Schnellinger, G., Janele, D., Schölmerich, J., & Straub, R. H. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.08.017 · Cited by 5 · see citing works
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Capellino, S., & Straub, R. H. (2008) · Technical report · doi:10.1016/s1571-5078(07)00201-2 · Cited by 1 · see citing works
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- Authors
- Crofford, L. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Crofford, L. J.
- ORCID
- Crofford, L. J.
- Venue
- Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1997-04-01
- Volume
- 82
- Issue
- 4
- Pages
- 1279-1283
- ISSN
- 0021-972X (ISSN-L)
- OpenAlex
- W2056763517
- Cited by
- 242
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 4 · 2019: 6 · 2018: 7 · 2017: 7 · 2016: 12 · 2015: 9 · 2014: 9 · 2013: 9 · 2012: 5
- FWCI
- 7.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- rheumatoid arthritis, interleukin-6, hypothalamic-pituitary-adrenal axis, ACTH, cortisol, circadian rhythm, hypercortisolism, urinary free cortisol
- MeSH terms
- Adrenocorticotropic Hormone, Adult, Arthritis, Rheumatoid, Circadian Rhythm, Corticotropin-Releasing Hormone, Humans, Hydrocortisone, Middle Aged, Reference Values, Sleep, Interleukin-6
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