Circadian dynamics of tumor necrosis factor alpha (cachectin) lethality.

Hrushesky, William J. M.; Langevin, Todd; Kim, Young Jin; Wood, Patricia A.

doi:10.1084/jem.180.3.1059

Cited by 73 publications

(47 citation statements)

References 37 publications

(44 reference statements)

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“…However, in both cases, the overall dynamics of the system (an acute response and recovery to baseline) are similar. These computational results match with clinical observations that sepsis patients are at elevated risk of mortality from 02:00 to 06:00, before the circadian peak in cortisol secretion (31). Considering this type of circadian dependence on responses to pathogens and also to therapies is important in optimizing treatment of inflammatory disease (32).…”

Section: Discussionsupporting

confidence: 77%

Modeling autonomic regulation of cardiac function and heart rate variability in human endotoxemia

Scheff¹,

Mavroudis

Calvano

et al. 2011

Physiological Genomics

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Scheff JD, Mavroudis PD, Calvano SE, Lowry SF, Androulakis IP. Modeling autonomic regulation of cardiac function and heart rate variability in human endotoxemia. Physiol Genomics 43: 951-964, 2011. First published June 14, 2011 doi:10.1152/physiolgenomics.00040.2011.-Heart rate variability (HRV), the quantification of beat-to-beat variability, has been studied as a potential prognostic marker in inflammatory diseases such as sepsis. HRV normally reflects significant levels of variability in homeostasis, which can be lost under stress. Much effort has been placed in interpreting HRV from the perspective of quantitatively understanding how stressors alter HRV dynamics, but the molecular and cellular mechanisms that give rise to both homeostatic HRV and changes in HRV have received less focus. Here, we develop a mathematical model of human endotoxemia that incorporates the oscillatory signals giving rise to HRV and their signal transduction to the heart. Connections between processes at the cellular, molecular, and neural levels are quantitatively linked to HRV. Rhythmic signals representing autonomic oscillations and circadian rhythms converge to modulate the pattern of heartbeats, and the effects of these oscillators are diminished in the acute endotoxemia response. Based on the semimechanistic model developed herein, homeostatic and acute stress responses of HRV are studied in terms of these oscillatory signals. Understanding the loss of HRV in endotoxemia serves as a step toward understanding changes in HRV observed clinically through translational applications of systems biology based on the relationship between biological processes and clinical outcomes. systems biology; inflammation; circadian HEART RATE VARIABILITY (HRV) is generally defined as the quantification of the distribution of time intervals between successive heartbeats. Reduction in HRV, a manifestation of altered autonomic function under stress, is potentially a useful predictor of outcome in myocardial infarction (42), congestive heart failure (63), diabetic neuropathy (58), and neonatal sepsis (46). Diminished HRV has also been observed in critically ill patients in intensive care units (ICU) (52), which motivates interest in HRV as a critical variable in the recovery from critical illness (50). Due to this clinical relevance, dynamic characteristics of HRV have been assessed by time domain, frequency domain (76), and nonlinear metrics (46, 60). The majority of HRV research has thus far focused on the interpretation of the patterns of HRV (45) rather than linking cellular-level mechanisms to patterns (11). The realization that health may be characterized by a certain degree of variability of human heart signals motivates the hypothesis that appropriate physiological variability is the manifestation of robust dynamics of control signals whose fluctuations equip the host with the ability to anticipate external and internal disturbances. We hypothesize that these variable dynamics are driven by the convergence of rhythmic physiological signals on...

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Section: Discussionsupporting

confidence: 77%

Modeling autonomic regulation of cardiac function and heart rate variability in human endotoxemia

Scheff¹,

Mavroudis

Calvano

et al. 2011

Physiological Genomics

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“…The dramatic diurnal variations in survival rate observed in an endotoxic shock mouse model first described by Halberg and colleagues (21,22,34) suggest a biological significance of the timing of immune functions. Although we cannot formally exclude other influences, we speculate that the high amplitude in mortality is due to circadian variation in proinflammatory cytokine secretion.…”

Section: Discussionmentioning

confidence: 99%

A circadian clock in macrophages controls inflammatory immune responses

Keller¹,

Mazùch²,

Abraham

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

672

675

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Time of day-dependent variations of immune system parameters are ubiquitous phenomena in immunology. The circadian clock has been attributed with coordinating these variations on multiple levels; however, their molecular basis is little understood. Here, we systematically investigated the link between the circadian clock and rhythmic immune functions. We show that spleen, lymph nodes, and peritoneal macrophages of mice contain intrinsic circadian clockworks that operate autonomously even ex vivo. These clocks regulate circadian rhythms in inflammatory innate immune functions: Isolated spleen cells stimulated with bacterial endotoxin at different circadian times display circadian rhythms in TNF-␣ and IL-6 secretion. Interestingly, we found that these rhythms are not driven by systemic glucocorticoid variations nor are they due to the detected circadian fluctuation in the cellular constitution of the spleen. Rather, a local circadian clock operative in splenic macrophages likely governs these oscillations as indicated by endotoxin stimulation experiments in rhythmic primary cell cultures. On the molecular level, we show that >8% of the macrophage transcriptome oscillates in a circadian fashion, including many important regulators for pathogen recognition and cytokine secretion. As such, understanding the cross-talk between the circadian clock and the immune system provides insights into the timing mechanism of physiological and pathophysiological immune functions.adrenalectomy ͉ LPS ͉ IL-6 ͉ microarray ͉ TNF-␣ A 24-h periodicity in the environment has led to the evolution of molecular circadian clocks in organisms ranging from cyanobacteria to humans. Circadian rhythms display a near 24-h period and persist even in the absence of external timing information. In mammals, a small hypothalamic region, the suprachiasmatic nucleus (SCN), has been identified as the master pacemaker regulating circadian rhythms in physiology, metabolism, and behavior (1). Recent evidence shows that also peripheral organs such as liver, heart, kidney, skin, and even cultured cell lines contain circadian oscillators. Although the SCN probably sets the phase of these peripheral clocks (by as yet unknown means), recent reports implicate peripheral clocks in the regulation of local physiology (2-4). The fundamental mechanism of rhythm generation is cell autonomous and highly conserved in SCN and peripheral cells: Interlocked transcriptional/translational feedback loops involving clock genes, such as Per1-3, Cry1-2, Clock, Bmal1, and Rev-Erb␣ create oscillations on the molecular level (reviewed in ref. 2).In the immune system, many functions and parameters have been described to be time-of-day dependent, e.g., lymphocyte proliferation (5), natural killer (NK) cell activity (6), humoral immune response (7), rhythms in absolute and relative numbers of circulating white blood cells and their subsets (8), cytokine levels (9), and serum cortisol (10) (reviewed in ref. 11). In addition, time-of-day variation in susceptibility to infection (12), cour...

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“…Circadian clock-controlled expression of CRY proteins regulate the production of cAMP, which in turn contributes to the observed circadian rhythms in cytosolic cAMP, which is a necessary component to core clock function in SCN neurons and in peripheral cell types (33). We presume that temporally gated oscillations of cAMP levels (33) and resultant PKA activity temporally modulates the basal activation state of the NF-κB pathway and may explain the well-described circadian rhythms in immune responses in mammals (34). Our data support the hypothesis that when CRY proteins are present they bind to adenylyl cyclase (Fig.…”

Section: Discussionmentioning

confidence: 99%

Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines

Narasimamurthy

Hatori

Nayak

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

336

264

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Chronic sleep deprivation perturbs the circadian clock and increases susceptibility to diseases such as diabetes, obesity, and cancer. Increased inflammation is one of the common underlying mechanisms of these diseases, thus raising a hypothesis that circadianoscillator components may regulate immune response. Here we show that absence of the core clock component protein cryptochrome (CRY) leads to constitutive elevation of proinflammatory cytokines in a cell-autonomous manner. We observed a constitutive NF-κB and protein kinase A (PKA) signaling activation in Cry1 −/− ; Cry2 −/− cells. We further demonstrate that increased phosphorylation of p65 at S276 residue in Cry1 −/− ;Cry2 −/− cells is due to increased PKA signaling activity, likely induced by a significantly high basal level of cAMP, which we detected in these cells. In addition, we report that CRY1 binds to adenylyl cyclase and limits cAMP production. Based on these data, we propose that absence of CRY protein(s) might release its (their) inhibition on cAMP production, resulting in elevated cAMP and increased PKA activation, subsequently leading to NF-κB activation through phosphorylation of p65 at S276. These results offer a mechanistic framework for understanding the link between circadian rhythm disruption and increased susceptibility to chronic inflammatory diseases.biological clock | immune system I n response to the rotation of the earth, many of the mammalian physiological processes such as sleep-wake cycle and feeding pattern undergo an ∼24-h oscillation referred as the circadian clock. Circadian oscillation helps organisms anticipate and adapt to predictable daily changes in the environment. The hypothalamic suprachiasmatic nucleus (SCN) functions as a master circadian oscillator, which controls behaviors. At molecular level, the circadian oscillator is based on a cell-autonomous transcription-translation feedback loop, in which transcriptional activators circadian locomotor output cycles kaput (CLOCK)/brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like (BMAL)1 activate the expression of Cryptochrome (Cry) and Period (Per), in turn their protein products repress BMAL1 and CLOCK activity, thus producing Cry and Per expression rhythms (1, 2). Reverse orientation c-erb (REV-ERB)s and RAR-related orphan receptor (ROR)s also participate in the rhythmic transcriptional activity of the molecular oscillator (3). Molecular components of the circadian clock network are conserved in the SCN and also in peripheral cells. The oscillator uses direct and indirect mechanisms to impose rhythms and regulate several physiological processes, such as rest-activity cycle, endocrine system, and metabolism (4).Sleep loss or chronic sleep deprivation disrupts the circadian rhythm. It has been reported that people exposed to constant circadian disruption, such as shift-workers, show increased incidence of chronic diseases such as diabetes, obesity, and also cancer (5-7). Chronic inflammation is one of the important pathogenic features of these di...

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Circadian dynamics of tumor necrosis factor alpha (cachectin) lethality.

Cited by 73 publications

References 37 publications

Modeling autonomic regulation of cardiac function and heart rate variability in human endotoxemia

Modeling autonomic regulation of cardiac function and heart rate variability in human endotoxemia

A circadian clock in macrophages controls inflammatory immune responses

Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines

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