Diurnal and sleep–wake dependent variations of soluble TNF- and IL-2 receptors in healthy volunteers

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Abstract

There is very little published information on the diurnal variation of cytokines and their receptors, in healthy individuals during normal sleep–wake patterns or during sustained wakefulness. The aim of the current investigation was to characterize concentrations of soluble tumor necrosis factor receptors (sTNF-Rs) and interleukin-2 receptor (sIL-2R) during normal sleep and wakefulness, as well as during a 24 h vigil. Plasma levels of the sTNF-R p55, sTNF-R p75, and sIL-2R did not differ significantly between nocturnal sleep and nocturnal wakefulness. Rhythmic analysis (2-h intervals) revealed significant diurnal variations for both sTNF-R p55 and sTNF-R p75, but not levels of sIL-2R. Diurnal variations of both sTNF-Rs were characterized by a single cosine curve with an average peak near 06:00 h in the morning. This peak occurred well before that of cortisol, and fluctuated inversely with the diurnal rhythm of temperature. These diurnal variations in sTNF-Rs levels are consistent with the hypothesis that the TNF system plays a role in normal diurnal temperature regulation.

Introduction

Cytokines and their receptors play key roles in host defense and immune surveillance. The production of cytokines varies with health and disease states (Remick and Friedland, 1997), and tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-2, IL-6, and other cytokines have been reported to show diurnal variation (Petrovsky and Harrison, 2000). This diurnal variation is thought to be influenced by sleep and wakefulness, suggesting a role for sleep in the maintenance of host defense, and there are data linking sleep and wakefulness with the TNF-α and IL-2 systems (Irwin, 2002; Krueger et al., 2003). While there is little information about the diurnal rhythm of cytokines, there are no published reports on diurnal and sleep–wake dependent variations of their soluble receptors, although they are crucially involved in modulating and regulating the biological activity of their ligands.

Soluble TNF receptors (sTNF-Rs) act as natural occurring inhibitors and modulators of TNF activity (for review see Aderka, 1996). Two soluble receptors exists for TNF-α, the sTNF-R p55 and p75, also referred to as receptors 1 and 2, respectively. Both are shed by almost all cells types, such as activated T cells, B cells, neutrophils, epithelial cells, and tumor cells, into the circulation, where they bind free TNF with high affinity. Thus, they compete with cellular TNF receptors for TNF, and reduce and/or extend in time, its bioavailability and consequently their physiological actions.

Under conditions of an experimental immune challenge, soluble TNF receptors increase rapidly (Mullington et al., 2000; Haack et al., 2001). They are also increased in a variety of clinical conditions, such as sepsis, hepatitis, rheumatoid arthritis, and psoriasis, and may serve as markers of disease activity (reviewed in Aderka, 1996). These increases seen in disease states can be dramatically higher than those seen under normal, healthy conditions. In healthy humans, circulating TNF-α levels or the stimulated in vitro production of TNF by whole blood cells has been shown to vary across the nycthemeron (Young et al., 1995; Entzian et al., 1996; Petrovsky et al., 1998; Vgontzas et al., 2002, Vgontzas et al., 2003), with most studies showing peak values during the nighttime. Many factors may be involved in the regulation of diurnal fluctuations of cytokines, including melatonin, cortisol, and temperature. Physiological sleep is attenuated by i.c.v. administration of the soluble sTNF-R p55 (Takahashi et al., 1995, Takahashi et al., 1996), but not the sTNF-R p75 (Lancel et al., 1997), thus supporting that sTNF-R p55 is involved in inhibiting the somnogenic effects of TNF. Also, changes in peripheral, circulating levels of soluble TNF receptors, even in the picogram range, are likely to affect complex brain functions, such as sleep, and mood (reviewed in Pollmächer et al., 2002). In humans, only one study has investigated sleep–wake dependent variations of sTNF-R p55, and found an increase of sTNF-R p55 across 88 h of total sleep deprivation, but this effect was not seen for subjects who were permitted a 2 h nap every 12 h throughout the vigil (Shearer et al., 2001). Taken together, not much is known about the natural diurnal variation of soluble TNF receptors and their dependency on sleep and wakefulness, although they are important for furthering the understanding of the role of the TNF system in regulating sleep and wakefulness.

The soluble IL-2 receptor (sIL-2R) is sometimes used as a surrogate marker of T cell activation (Morris and Waldmann, 2000), because activated T cells, and to a considerably lesser extent, resting T cells, B cells, and monocytes, are believed to shed the soluble IL-2R into circulation. The function of soluble IL-2R is probably to bind circulating IL-2, thus it down regulates IL-2-induced T cell activation (Rubin et al., 1985; Waldner et al., 1994). In healthy subjects, sIL-2R circulates in low amounts in plasma/serum (Satoh et al., 1998), and concentrations can be markedly elevated in various pathological diseases, in particular autoimmune diseases and infections (reviewed in Morris and Waldmann, 2000). In healthy subjects, the stimulated in vitro production of IL-2 has been found to be increased in blood samples taken from sleeping subjects and suppressed in samples taken from sleep deprived individuals (Irwin et al., 1996; Born et al., 1997), thus suggesting that these changes are sleep-dependent. In contrast, in vivo, circulating levels of IL-2 seem to be not affected by sleep or sleep loss (Dinges et al., 1995; Irwin et al., 1999). Although measures of stimulated in vitro production and circulating levels of IL-2 in vivo are difficult to compare, it has been argued that one reason for discrepancies between in vitro and in vivo results may be rapid binding of circulating IL-2 on the longer lasting sIL-2R and consequently IL-2 changes in vivo are hard to detect. Here, we measured the sIL-2R in order to provide further information about the response of the in vivo IL-2 system to sleep loss.

The aims of this study were to explore: (a) the effects of one night of sleep deprivation on soluble TNF- and IL-2 receptors in healthy men, and (b) to investigate whether these soluble cytokine receptors vary in a rhythmic manner across the day.

Section snippets

Subjects

The data presented here are part of a larger study on the effect of endotoxin on human sleep. Twenty-two healthy males between the ages of 21 and 34 years (mean 27.6 years) participated in the study after written informed consent was obtained. Subjects were screened by medical history, including sleep disorders, evaluation of sleeping habits, physical examination, EEG and ECG in order to exclude acute or chronic diseases, a personal or family history of psychiatric disorders, alcohol or

Results

Cortisol was measured in all 22 subjects (12 vs. 10 in the sleep vs. sleep deprivation condition), and, depending on the availability of plasma, sIL-2R was analyzed in 19 subjects (9 vs. 10 in the sleep vs. sleep deprivation condition), sTNF-R p75 in 21 subjects (11 vs. 10 subjects in the sleep vs. sleep deprivation condition), and sTNF-R p55 in 11 subjects (6 vs. 5 subjects in the sleep vs. sleep deprivation condition).

Discussion

The present investigation shows clear-cut diurnal variations in plasma levels of both soluble TNF receptors p55 and p75 in healthy men, with peak values in the early morning hours, whereas the soluble IL-2R did not vary systematically across the 24-h day. These variations seem to be sleep–wake independent, i.e., neither sTNF-Rs nor sIL-2R levels were significantly affected by a single night of sleep deprivation.

Acknowledgments

We are grateful to Irene Gunst and Gabriele Kohl for technical assistance. This work was supported by Grant 1/71979 from the Volkswagen-Stiftung (Hannover, Germany) to T.P., by the National Institutes of Health to J.M.M. (MH60641), and the German Research Foundation to M.H.

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