| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Department of Internal Medicine, Humboldt University (E.S.-S.), Charité, 10117 Berlin; Departments of Clinical Neuroendocrinology and Internal Medicine, University of Luebeck (K.H., F.S., L.M., H.L.F., J.B.), 23538 Luebeck; Department of Internal Medicine, University of Ulm (H.S.), 89081 Ulm; Sandoz Pharma Ltd. (K.B.), 90429 Nuernberg; and Department of Physiological Psychology, University of Bamberg (J.B.), 96045 Bamberg, Germany
Address all correspondence and requests for reprints to: Ernst Späth-Schwalbe, Universitätsklinikum Charité, Medizinische Klinik und Poliklinik II, Schumann-Straße 20/21, 10117 Berlin, Germany.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
, and
interferon-
. The results underscore the importance of IL-6 in the
cascade of cytokines for the neuroendocrine response during the acute
phase reaction. In addition, IL-6 appears to be involved in changes of
sleep and behavior accompanying infection and inflammatory disorders. |
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
and IL-1 (7).
Because of the cascade-like release of TNF-, IL-1, and IL-6 during
the early inflammatory reaction, it is difficult to disentangle the
contribution of each of these cytokines to the sequence of events
representing the APR. However, a promising way of separating the
biological activities of these cytokines in vivo appears to
be the administration of any one of these substances or of an antibody,
selectively blocking the action of a certain cytokine. The availability
of large quantities of recombinant IL-6 and other cytokines has enabled
the specification of multifunctional effects of individual
cytokines.
This study was performed to determine the role of the IL-6 component of the cytokine cascade on neuroendocrine, central nervous, and immunological features of the APR. Recent studies have provided some suggestive evidence for a specific regulatory function of IL-6 on immune and endocrine activity in humans. However, respective results are to be interpreted cautiously, because they were exclusively obtained in patients treated with IL-6 at rather high doses (up to 30 µg/kg per day) and for longer periods (i.e. over 6–42 days) (8, 9, 10, 11). Considering the severe illness of the patients, results obtained in those studies may not provide an adequate reflection of the regulatory role of IL-6 during the APR. In this study, we investigated the acute effects of a low dose of IL-6 (0.5 µg/kg body weight) on secretory profiles of ACTH, cortisol, GH, and TSH; on mood; on nocturnal sleep; and also on concentrations of C-reactive protein (CRP) and serum cytokine levels in healthy men. The low dose administered was expected to mimic systemic increases in IL-6 typically observed under (patho-) physiological conditions on infectious challenge (12, 13).
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The experimental protocol was approved by the ethics committee of the University of Luebeck. Sixteen healthy men, aged 22–30 yr, participated in the study after written informed consent was obtained. All men were within 10% of ideal body weight (mean weight 74.3 kg, range 65.0–85.0 kg). The subjects were acclimatized to the experimental setting by an adaptation night.
Each volunteer participated in two experimental 14-h sessions (placebo vs. IL-6), separated by an interval of at least 7 days. A session started at 1800 h and ended at 0800 h the next morning. At 1900 h, IL-6 (0.5 µg/kg body weight) or placebo was administered sc according to a double-blind cross-over design. The order of treatment conditions was balanced across subjects.
On arrival at the sleep laboratory at 1800 h, subjects were prepared for blood sampling and polysomnographic recordings. Following insertion of an iv polyvinyl catheter, blood (4 mL) was sampled half hourly to determine ACTH, cortisol, GH, and TSH. In addition, at 1830 h, 2230 h, 0130 h, and 0730 h, blood (8 mL) was collected for determination of cytokines and CRP. Blood was sampled via a long thin tube from an adjacent room, without disturbing the subject’s sleep. To prevent clotting, 300 mL saline solution was infused throughout the night.
Continuous polysomnographic recordings were obtained between 2300 h, the time when lights were turned off and subjects were allowed to sleep, and 0700 h the next morning, when subjects were awakened. During the wake periods from 1800–2300 h and after 0700 h, the subject sat in bed and was allowed to read, watch television, or talk to the experimenter. During these time intervals, blood pressure, heart rate, and body temperature (sublingual) were measured hourly.
At 2200 h and 0700 h, subjects were asked to complete an extensive checklist of adjectives (EWL) to assess their activation level, degree of tiredness, and mood (14). For each adjective, the subject had to indicate whether or not it applied to his current feelings. In this list, a total of 161 adjectives are employed to obtain an estimate of the subject’s mood on 15 dimensions.
IL-6 preparation
The IL-6 used in this study (provided by Novartis, Basel, Switzerland; formerly Sandoz), was a purified nonglycosylated protein product (purity >99%). It was produced in Escherichia coli using recombinant DNA techniques and provided in lyophilized form.
Hormone assays
For determination of ACTH, cortisol, GH, and TSH, blood samples were centrifuged immediately after collection, and plasma was aliquoted and stored at -20 C until assay. Hormonal plasma levels were measured with commercial assays (ACTH LUMItest, Henning, Berlin, Germany; Enzymun-test Cortisol, Boehringer, Mannheim, Germany; BeriLux hTSH-ELISA, Behring, Marburg, Germany; and human GH-RIA, Hermann Biermann GmbH, Bad Nauheim, Germany, respectively). Intra- and interassay coefficients of variation were under 10% for all assays. All measurements were performed in duplicate.
Sleep analysis
Sleep stages were determined from the electroencephalographic, electrooculographic, and electromyographic recordings that were scored off-line according to standard criteria (15). The sleep recordings were scored visually at 30-s intervals as wake, stages I, II, III, IV, or as rapid eye movement (REM) sleep. The amount of slow-wave sleep (SWS) was defined as the total amount of stages III plus IV. For each night, sleep onset (with reference to lights off at 2300 h), total sleep time, and percentage of total sleep time (as well as of the first and second half of sleep time) spent in the different sleep stages were determined. Latencies of sleep stage II, SWS, and REM were determined with reference to sleep onset.
Cytokine and CRP assessment
Concentrations of IL-6, IL-2, IL-8, interferon (IFN)-, and
IFN- were determined directly in serum. Blood samples were
centrifuged immediately and the serum was stored at -70 C until assay.
All cytokines were measured by ELISA kits (R&D Systems, Minneapolis, MN
for determination of IL-6, IL-2, and IL-8; Hoffmann-La Roche, Basel,
Switzerland, for determination of IFN-; Hbt, Uden, The Netherlands,
for determination of IFN-). The sensitivities of the assays were
0.094 pg/mL for IL-6, 20 pg/mL for IL-2, 36.5 pg/mL for IL-8, 2.5 for
IFN-, and 6.0 pg/mL for IFN-. The intra- and interassay
coefficients of variation were less than 8% and 9%, respectively, for
all assays.
CRP was measured with a commercial assay (N Latex CRP mono; Behring Werke AG, Marburg, Germany).
Statistical analyses
Data are presented as means ± SEM. Statistical analysis of differences between the effects of IL-6 and placebo on endocrine and immune parameters, body temperature, heart rate, and blood pressure relied on analysis of covariance (ANCOVA), including the values before substance administration obtained at 1830 h as a covariate (16). The analyses included two repeated measures factors representing the treatments (IL-6 vs. placebo) and the time course, i.e. the multiple measurements following treatment administration. Only when the effects obtained for the treatment factor and for the treatment x time interaction reached significance were pairwise comparisons calculated to evaluate the differences for each time point after substance administration. Analysis of sleep parameters relied on multiple analysis of variance. Wilcoxon’s tests were used to examine differences in self-reported activation, tiredness, and mood. Degrees of freedom were corrected after Greenhouse-Geisser (17), which provides a more conservative test of the repeated measures factors and is more appropriate for relatively small sample sizes. A P < 0.05 (two-tailed) was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
As expected from a previous study (18), in the samples taken 210
min after sc administration of IL-6, the highest serum concentrations
of the cytokine were measured, although because of the infrequent
sampling, an earlier or later peak cannot be excluded for the present
study. IL-6 levels were still markedly elevated at 0130 h.
Baseline IL-6 serum levels were reached at 0730 h (Fig. 1
).
|
Baseline levels of ACTH before administration of IL-6 at 1900
h did not differ significantly between the placebo and IL-6 conditions
(Fig. 2). Thirty minutes after sc
injection of IL-6, plasma ACTH levels began to rise. They remained
significantly elevated for 5.5 h. During this time following
placebo, ACTH levels first declined and then remained at a minimum
until 0130 h, which represents the typical time course of ACTH
concentrations during the early night. Thus, although displaying an
undulating pattern, the increase in ACTH concentrations following IL-6
continued to be significant until 0130 h, which was about the time
when ACTH plasma concentrations during the placebo nights began to rise
to reach maximum levels at 0730 h. Accordingly, during the first
half of sleep time, ACTH release was significantly higher following
IL-6 than placebo (17.3 ± 2.3 pg/mL vs. 10.2 ±
0.9 pg/mL; P < 0.003). In contrast, during the second
half of the night, average ACTH concentrations were significantly lower
following IL-6 than following placebo (18.1 ± 1.5 pg/mL
vs. 26.2 ± 1.9 pg/mL; P < 0.002).
|
Before IL-6 administration, plasma cortisol levels did not differ
between both treatment conditions (Fig. 2
). Effects of IL-6 on plasma cortisol
concentrations were, between the time of cytokine administration and
0330 h, parallel to those observed for ACTH. Compared with the
placebo condition, IL-6 increased cortisol concentration from 2000
h until 0230 h. Accordingly, average cortisol concentrations
during the first half of sleep time were significantly higher following
IL-6 than placebo (9.8 ± 0.9 µg/dL vs. 2.9 ±
0.6 µg/dL; P < 0.001). However, in contrast with the
reduced ACTH levels observed during the late part of the night after
IL-6, plasma cortisol levels during the second half of sleep time
remained virtually identical in the IL-6 and placebo conditions
(9.3 ± 0.4 µg/dL vs. 10.0 ± 0.8 µg/dL,
respectively).
TSH
Plasma TSH levels were similar on both nights before drug
administration (1900 h; Fig. 3). On the
placebo nights, the typical nocturnal TSH surge, beginning before sleep
onset, was observed. Administration of IL-6 almost completely blunted
the TSH surge before sleep, and kept TSH levels significantly lower
between 2300 until 0600 h in the morning.
|
Plasma GH levels (data not shown) before and after IL-6 administration did not differ between the two treatment conditions. Average GH concentrations during the first and second half of the night were nearly identical in both conditions (IL-6 vs. placebo; first half: 3.1 ± 0.3 ng/mL vs. 3.2 ± 0.4 ng/mL; second half: 1.4 ± 0.1 ng/mL vs. 1.2 ± 0.1 ng/mL).
Sleep
Table 1 summarizes the effects of
IL-6 on sleep parameters (latencies and time spent in the different
sleep stages) for the entire night, and separately for the first and
second half of sleep time. Total sleep time and time till sleep onset
were comparable in both conditions. IL-6 injection significantly
reduced the time as well as the percentage of time spent in REM sleep,
and increased the latency of REM sleep. The reduction of REM sleep was
more consistent during the first (P < 0.001) than
second half of the night (P = 0.06). IL-6 decreased
time in SWS during the first half of the night (P <
0.05), but the amount of SWS was increased 2-fold in the second half of
sleep time (P < 0.005). Thus, for the entire night,
differences in time in SWS following IL-6 and placebo remained
nonsignificant (Fig. 4).
|
|
IL-6 distinctly affected self-reported mood as determined by the
adjective checklist. At 2200 h, after IL-6 subjects felt more
tired, inactive, and less capable of concentrating. Also, self-reliance
and high spirits were altered at 2200 h following IL-6 (Fig. 5). Example adjectives were for the
dimension of fatigue: sleepy and weary; for the dimension of
inactivation: indifferent, weak, and lazy; for the dimension of
concentration: attentive and vigilant; for the dimension of
self-reliance: carefree and self-satisfied; and for the dimension of
high spirits: cheerful and effusive. In contrast to the evaluation at
2200 h, at 0700 h after sleep, self-reported measures did not
differ any more between both conditions.
|
IL-6 did not consistently affect any of the other cytokine
concentrations assessed in serum. Concentrations averaged across
samples collected at 2230 and 0130 h following IL-6 and placebo,
respectively, were for IL-2 3390 ± 926 vs. 3036
± 759 pg/mL and for IFN- 193.6 ± 31.3 vs.
179.1 ± 23.1 pg/mL. Serum concentrations of IL-8 and IFN- were
below the assay sensitivity on most occasions.
CRP concentration markedly increased after IL-6, with a delay of more than 6.5 h following substance injection (Fig. 6).
Temperature, heart rate, blood pressure
After IL-6 injection, body temperature gradually increased and at
2300 h was on average 0.8 C higher than following placebo
(P < 0.001). Body temperature following IL-6 was still
slightly but significantly increased at the time of awakening (Fig. 7).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
, and IFN-), and according to a
previous study, also TNF- and IL-1, which are the first cytokines
being released during the APR, are not stimulated by IL-6 (9).
Therefore, our data provide an idea about to what extent the changes
observed during the APR could directly result from the IL-6 component
of the cytokine cascade. The principal endocrine action of IL-6 was its stimulating influence on the secretory activity of the hypothalamic-pituitary-adrenal (HPA) axis. This finding agrees with results from recent studies in humans (18, 19). However, those studies were performed in patients who were treated with higher doses of IL-6, and who displayed advanced malignancies. These circumstances so far have prevented clear-cut conclusions regarding the role of IL-6 under normal physiological conditions in humans. Therefore, the present results are not merely confirmative but strengthen the notion that IL-6 is one (of possibly several) physiological factors stimulating HPA secretory activity during the APR. Our findings support the concept that IL-6 modulates secretory activity of the HPA axis at different levels including an acute effect at the hypothalamic level and/or on the pituitary, and an additional delayed effect on the adrenals. Also, IL-6 may sensitize the adrenals to ACTH (20, 21), which could explain our observation that in the late part of the night, ACTH levels were lower following IL-6 in the face of similar cortisol levels like in the placebo condition. IL-6 and ACTH appear to have synergistic stimulating effects on glucocorticoid release according to a recent study with adrenal gland cells (22). Data from other in vitro studies suggest that, alternatively, IL-6 may directly stimulate cortisol secretion from the adrenals (23, 24).
TSH secretion, which normally peaks in the late evening (25), was inhibited by IL-6, resulting in a blunted TSH surge. This finding agrees with two foregoing studies on the effects of IL-6 in cancer patients (26, 27). The exact mechanism of the inhibitory effect of IL-6 on TSH secretion is unclear. Studies of Kakucska et al. (28) using IL-1 or endotoxin in rats suggested that proinflammatory cytokines directly inhibit TRH messenger RNA expression in hypophysiotropic neurons (28). But reduced TSH secretion after IL-6 could be also a consequence of the cytokine-induced increase in cortisol levels. Experiments in rats indicated that glucocorticoids profoundly reduce the concentration of pro-TRH messenger RNA, and thereby could change the biosynthesis and release of TRH in hypophysiotropic neurons (29). However, another study in rats suggested that the suppression of TSH release following IL-6 does not involve the hypothalamus but rather represents a direct effect on the thyrotrophs (30). Irrespective of the exact mechanism, the alterations of the hypothalamic-hypophysial-thyroid axis induced by IL-6 support the view that IL-6 is one of the factors involved in the pathogenesis of the sick euthyroid syndrome, which can be observed in patients with inflammation, infection, or trauma (26, 27, 30, 31, 32).
Changes in sleep and mood following IL-6 suggested a regulatory
influence of the cytokine on central nervous function during infection.
IL-6 reduced REM sleep and shifted SWS, typically dominant during the
first part of the night, into the second part of the night. These
actions argue against a sleep-promoting effect of IL-6, which has been
suspected on the basis of observations in patients with excessive
daytime sleepiness and with sleeping sickness (African trypanosomiasis)
who displayed enhanced plasma concentrations of IL-6 (33, 34). Also,
the effects of IL-6 observed in this study in humans contrast with
those observed in a recent study in rabbits in which human recombinant
IL-6 failed to affect sleep although, as in the present study,
administration of the cytokine induced fever (35). However, in light of
well-known species-specific characteristics of sleep and immune
functions, the discrepancy between both studies may not be surprising.
Considering previous reports of marked REM sleep suppression after
administration of glucocorticoids (36), this effect of IL-6 on REM
sleep can probably be explained by its stimulating effect on cortisol
release. A reduction in REM sleep along with an increase in plasma
concentrations of proinflammatory cytokines (TNF-, IL-6) likewise
has been observed following injection of endotoxin in humans (37).
Unlike the effects on REM sleep, the acute suppression of SWS and its
recovery in the second half of the night after IL-6 cannot be explained
by a stimulation of pituitary-adrenal secretory activity (36).
Considering that available data also do not support a mediation of this
effect by the decrease in TSH concentrations (38, 39) nor by the
increased body temperature after IL-6 (40, 41, 42), a more direct action of
the cytokine on central nervous sleep mechanisms remains to be
considered. There is convincing evidence for direct effects of
cytokines on neural function (43). Different pathways of
cytokine-to-brain communication have been described. Cytokines may act
locally in the brain or, in quite a different manner, cytokines may
signal the brain by stimulating afferent terminals of peripheral nerves
(43, 44).
The changes of mood, including increased tiredness and feelings of being inactive and less capable to concentrate, after IL-6 closely mirrored the symptoms often reported during infections. Related behavioral changes have been collectively termed sickness behavior (45). Our findings, hence, appear consistent with the notion that cytokines released in the course of an infection cause such changes in mood. Interestingly, after sleep, mood was very similar in the IL-6 and placebo conditions, although the architecture of preceding sleep was altered substantially, and other influences of IL-6 such as the increase in CRP were still prominent. Whether sleep contributed to the normalization of mood, or whether this normalization only reflected the return of IL-6 levels to baseline cannot be answered by the present data. In any case, a contribution of pituitary-adrenal secretion to the effects of IL-6 on mood can be excluded considering the completely different changes in mood found in previous studies after administration of ACTH and cortisol (46, 47).
In summary, our findings underline the pleiotropic actions of IL-6 in humans. The discrepancies between the effects of IL-6 observed in the present study and those observed in previous studies in animals and in vitro emphasizes the necessity to examine cytokine effects under normal physiological conditions in humans. A variety of these effects (including the decrease in TSH concentrations, REM sleep suppression, and a facilitated synthesis of CRP) appear to involve stimulation of the pituitary-adrenal axis, suggesting that the action of IL-6 on this axis represents one mechanism by which the cytokine exerts its coordinating influence during the APR. In the light of foregoing studies, however, direct effects of this cytokine on neural function have to be considered as well. The effects of IL-6 on central nervous processes such as the changes in sleep architecture and mood, may be part of a concert of actions with functions supplementary to the formation of APR, although their exact contribution to the organism combating an infectious challenge remains to be elucidated. Irrespective of these questions, the present data demonstrate that in the course of the APR, the IL-6 component is important for neuroendocrine, immune, and central nervous responses.
|
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received October 10, 1997.
Revised January 23, 1997.
Accepted January 29, 1998.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
and interleukin-1 in the
induction of sickness behaviour in mice. Psychoneuroendocrinology. 19:197–207.[CrossRef][Medline]
This article has been cited by other articles:
 |
|
 |
|
  A. H. Miller, S. Ancoli-Israel, J. E. Bower, L. Capuron, and M. R. Irwin Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer J. Clin. Oncol., February 20, 2008; 26(6): 971 - 982. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Liukkonen, P. Rasanen, A. Ruokonen, J. Laitinen, J. Jokelainen, M. Leinonen, V. B. Meyer-Rochow, and M. Timonen C-reactive protein Levels and Sleep Disturbances: Observations Based on The Northern Finland 1966 Birth Cohort Study Psychosom Med, October 1, 2007; 69(8): 756 - 761. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. N VGONTZAS, E. O BIXLER, and G. P CHROUSOS Obesity-Related Sleepiness and Fatigue: The Role of the Stress System and Cytokines Ann. N.Y. Acad. Sci., November 1, 2006; 1083(1): 329 - 344. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dimitrov, T. Lange, C. Benedict, M. A. Nowell, S. A. Jones, J. Scheller, S. Rose-John, and J. Born Sleep enhances IL-6 trans-signaling in humans FASEB J, October 1, 2006; 20(12): 2174 - 2176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Collado-Hidalgo, J. E. Bower, P. A. Ganz, S. W. Cole, and M. R. Irwin Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer Survivors. Clin. Cancer Res., May 1, 2006; 12(9): 2759 - 2766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hiscock, C. P. Fischer, M. Sacchetti, G. van Hall, M. A. Febbraio, and B. K. Pedersen Recombinant human interleukin-6 infusion during low-intensity exercise does not enhance whole body lipolysis or fat oxidation in humans Am J Physiol Endocrinol Metab, July 1, 2005; 289(1): E2 - E7. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Alesci, P. E. Martinez, S. Kelkar, I. Ilias, D. S. Ronsaville, S. J. Listwak, A. R. Ayala, J. Licinio, H. K. Gold, M. A. Kling, et al. Major Depression Is Associated with Significant Diurnal Elevations in Plasma Interleukin-6 Levels, a Shift of Its Circadian Rhythm, and Loss of Physiological Complexity in Its Secretion: Clinical Implications J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2522 - 2530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Rich, P. F. Innominato, J. Boerner, M. C. Mormont, S. Iacobelli, B. Baron, C. Jasmin, and F. Levi Elevated Serum Cytokines Correlated with Altered Behavior, Serum Cortisol Rhythm, and Dampened 24-Hour Rest-Activity Patterns in Patients with Metastatic Colorectal Cancer Clin. Cancer Res., March 1, 2005; 11(5): 1757 - 1764. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Hartkamp, R Geenen, M Bijl, A A Kruize, G L R Godaert, and R H W M Derksen Serum cytokine levels related to multiple dimensions of fatigue in patients with primary Sjogren's syndrome Ann Rheum Dis, October 1, 2004; 63(10): 1335 - 1337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Meier-Ewert, P. M. Ridker, N. Rifai, M. M. Regan, N. J. Price, D. F. Dinges, and J. M. Mullington Effect of sleep loss on C-Reactive protein, an inflammatory marker of cardiovascular risk J. Am. Coll. Cardiol., February 18, 2004; 43(4): 678 - 683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Jensen Cytokine Regulation of Lipolysis in Humans? J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3003 - 3004. [Full Text] [PDF]
|
|
|
|
|
|
A. N. Vgontzas, M. Zoumakis, E. O. Bixler, H.-M. Lin, P. Prolo, A. Vela-Bueno, A. Kales, and G. P. Chrousos Impaired Nighttime Sleep in Healthy Old Versus Young Adults Is Associated with Elevated Plasma Interleukin-6 and Cortisol Levels: Physiologic and Therapeutic Implications J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2087 - 2095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Redwine, J. Dang, M. Hall, and M. Irwin Disordered Sleep, Nocturnal Cytokines, and Immunity in Alcoholics Psychosom Med, January 1, 2003; 65(1): 75 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z A Erkut, E Endert, I Huitinga, and D F Swaab Cortisol is increased in postmortem cerebrospinal fluid of multiple sclerosis patients: relationship with cytokines and sepsis Multiple Sclerosis, June 1, 2002; 8(3): 229 - 236. [Abstract] [PDF]
|
|
|
|
|
|
J. M. Mullington, D. Hinze-Selch, and T. Pollmacher Mediators of Inflammation and Their Interaction with Sleep: Relevance for Chronic Fatigue Syndrome and Related Conditions Ann. N.Y. Acad. Sci., March 1, 2001; 933(1): 201 - 210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Meier-Ewert, P. M. Ridker, N. Rifai, N. Price, D. F. Dinges, and J. M. Mullington Absence of Diurnal Variation of C-Reactive Protein Concentrations in Healthy Human Subjects Clin. Chem., March 1, 2001; 47(3): 426 - 430. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W Wilmore and H. Kehlet Recent advances: Management of patients in fast track surgery BMJ, February 24, 2001; 322(7284): 473 - 476. [Full Text]
|
|
|
|
|
|
A. Schuld, J. Mullington, E. Friess, D. M. Hermann, C. Galanos, F. Holsboer, and T. Pollmächer Changes in Dehydroepiandrosterone (DHEA) and DHEA-Sulfate Plasma Levels during Experimental Endotoxinemia in Healthy Volunteers J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4624 - 4629. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. Kumpfel, F. T. Bergh, T. Pollmacher, F. Holsboer, and C. Trenkwalder Acute effects of interferon beta-1a on plasma cytokine levels in patients with MS Neurology, October 24, 2000; 55(8): 1231 - 1233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Redwine, R. L. Hauger, J. C. Gillin, and M. Irwin Effects of Sleep and Sleep Deprivation on Interleukin-6, Growth Hormone, Cortisol, and Melatonin Levels in Humans J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3597 - 3603. [Abstract] [Full Text]
|
|
|
|
 |
|
 T.M. O'CONNOR, D.J. O'HALLORAN, and F. SHANAHAN The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia QJM, June 1, 2000; 93(6): 323 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Mullington, C. Korth, D. M. Hermann, A. Orth, C. Galanos, F. Holsboer, and T. Pollmacher Dose-dependent effects of endotoxin on human sleep Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2000; 278(4): R947 - R955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
and solid
lines) administration at 1900 h (arrow).
Horizontal hatched bar indicates sleep period. *,
P < 0.05; **, P < 0.01; ***,
P < 0.001 for pairwise comparisons after
significance of treatment x time interaction was confirmed.
