Soup Kettle Topics: Chronobiology

Title: Chronobiology and Chronotherapy in Medicine
Author: Kraft, M.; Martin, R. J.; (Date: Aug, 1995)
Journal: Dis Mon; V. 41; Issue: 8; Pages: 501-75

Abstract: There is a fascinating and exceedingly important area of medicine that most of us have not been exposed to at any level of our medical training. This relatively new area is termed chronobiology; that is, how time-related events shape our daily biologic responses and apply to any aspect of medicine with regard to altering pathophysiology and treatment response. For example, normally occurring circadian (daily cycles, approximately 24 hours) events, such as nadirs in epinephrine and cortisol levels that occur in the body around 10 PM to 4 AM and elevated histamine and other mediator levels that occur between midnight and 4 AM, play a major role in the worsening of asthma during the night. In fact, this nocturnal exacerbation occurs in the majority of asthmatic patients. Because all biologic functions, including those of cells, organs, and the entire body, have circadian, ultradian (less than 22 hours), or infradian (greater than 26 hours) rhythms, understanding the pathophysiology and treatment of disease needs to be viewed with these changes in mind. Biologic rhythms are ingrained, and although they can be changed over time by changing the wake-sleep cycle, these alterations occur over days. However, sleep itself can adversely affect the pathophysiology of disease. The non-light/dark influence of biologic rhythms was first described in 1729 by the French astronomer Jean-Jacques de Mairan. Previously, it was presumed that the small red flowers of the plant Kalanchoe bloss feldiuna opened in the day because of the sunlight and closed at night because of the darkness. When de Mairan placed the plant in total darkness, the opening and closing of the flowers still occurred on its intrinsic circadian basis. It is intriguing to think about how the time of day governs the pathophysiology of disease. On awakening in the morning, heart rate and blood pressure briskly increase, as do platelet aggregability and other clotting factors. This can be linked to the acrophase (peak event) of heart attacks. During the afternoon we hit our best mental and physical performance, which explains why most of us state that “I am not a morning person.” Even the tolerance for alcohol varies over the 24-hour cycle, with best tolerance around 5 pm (i.e. “Doctor, I only have a couple of highballs before dinner”). Thus, all biologic functions, from those of the cell, the tissue, the organs, and the entire body, run on a cycle of altering activity and function.(ABSTRACT TRUNCATED AT 400 WORDS)
Notes: Journal Article
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Author Address: Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, University of Colorado Health Sciences Center, Denver, USA.

Title: Diurnal Rhythmicity of Human Cytokine Production: A Dynamic Disequilibrium in T Helper Cell Type 1/T Helper Cell Type 2 Balance?
Author: Petrovsky, N.; Harrison, L. C.; (Date: Jun 1, 1997)
Journal: J Immunol; V. 158; Issue: 11; Pages: 5163-8

Abstract: Diurnal rhythmicity is a characteristic of neuroendocrine pathways but is less understood in relation to immune function. We asked whether cellular (type 1) or humoral (type 2) immune responses or type 1/type 2 balance exhibit diurnal rhythmicity in healthy humans, and, if so, whether this is related to plasma levels of cortisol or melatonin, two hormones with immunomodulatory actions. LPS- or tetanus-stimulated human whole blood IFN-gamma and IL-10 production, and the IFN-gamma/IL10 ratio exhibited significant diurnal rhythmicity. The IFN-gamma/IL-10 ratio peaked during the early morning and correlated negatively with plasma cortisol and positively with plasma melatonin. IFN-gamma and, to a lesser extent, IL-10 production was sensitive to inhibition by exogenous cortisone; the IFN-gamma/IL-10 ratio decreased by >70% after the administration of oral cortisone acetate (25 mg). Our findings support the concept that plasma cortisol and possibly melatonin regulate diurnal variation in the IFN-gamma/IL-10 ratio. As IFN-gamma and IL-10 have opposing effects on cellular immunity, changes in their balance would be anticipated to impose diurnal rhythmicity on cellular immunity. This implies that the nature of an immune response, e.g., to vaccination, may be modified by the time of day of Ag presentation and could be therapeutically manipulated by the administration of cortisol or melatonin.
Notes: Journal Article
Author Address: Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Australia.

Title: The Chronobiology of Human Cytokine Production
Author: Petrovsky, N.; Harrison, L. C.; 1998)
Journal: Int Rev Immunol; V. 16; Issue: 5-6; Pages: 635-49

Abstract: Cytokine production in human whole blood exhibits diurnal rhythmicity. Peak production of the pro-inflammatory cytokines IFN-gamma, TNF-alpha, IL-1 and IL-12 occurs during the night and early morning at a time when plasma cortisol is lowest. The existence of a causal relationship between plasma cortisol and production is suggested by the finding that elevation of plasma cortisol within the physiological range by the administration of cortisone acetate results in a corresponding fall in pro-inflammatory cytokine production. Cortisol may not be the only neuroendocrine hormone that entrains cytokine rhythms; other candidates include 17-hydroxy progesterone, melatonin and dihydroepiandrostene dione (DHEAS). The finding of diurnal cytokine rhythms may be relevant to understanding why immuno-inflammatory disorders such as rheumatoid arthritis or asthma exhibit night-time or early morning exacerbations and to the optimisation of treatment for these disorders. Diurnal rhythmicity of cytokine production also has implications for the timing of blood samples drawn for diagnostic T-cell assays. Finally, diurnal rhythmicity of immune function suggests that the nature of an immune response, for example in response to vaccination, may be modified by the time of day of antigen administration and raises the possibility that immune responses could be therapeutically manipulated by co-administration of immuno-regulatory hormones such as glucocorticoids.
Notes: Journal Article
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Author Address: Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Australia.

Title: Diurnal Rhythms of Pro-Inflammatory Cytokines: Regulation by Plasma Cortisol and Therapeutic Implications
Author: Petrovsky, N.; McNair, P.; Harrison, L. C.; (Date: Apr, 1998)
Journal: Cytokine; V. 10; Issue: 4; Pages: 307-12

Abstract: Clinical features of certain immuno-inflammatory disorders such as rheumatoid arthritis and asthma exhibit diurnal fluctuation, which could be related to diurnal rhythmicity of pro-inflammatory cytokine production. To investigate the latter, the authors performed measurements of lipopolysaccharide (LPS)-stimulated whole blood, interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1) and IL-12 production in 13 healthy volunteers over 24 h. These cytokines exhibited distinct diurnal rhythms that peaked in the early morning and were inversely related to the rhythm of plasma cortisol. Elevation of plasma cortisol within the physiological range by administration of cortisone acetate, 25 mg at 21.00, markedly suppressed IFN-gamma, TNF-alpha, IL-1 and IL-12 production, but not the later early morning rise of endogenous plasma cortisol. Suppression of cytokine production was temporally dissociated from changes in numbers of circulating mononuclear cells. Regulation of pro-inflammatory cytokine production by plasma cortisol has potential therapeutic implications. In contrast to standard schedules, a small, late evening, dose of glucocorticoid to suppress the diurnal increase in pro-inflammatory cytokine production could alleviate early morning inflammatory symptoms and minimize side-effects.
Notes: Journal Article
Author Address: Walter and Eliza Hall Institute, Royal Melbourne Hospital, Parkville, Victoria, Australia.

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