Tumor
necrosis factor-p LEVENTE
KAPAS
Department
of Physiology
AND JAMES
induces M. KRUEGER
and Biophysics,
University
Kapbs, Levente, and James M. Krueger. Tumor necrosis factor-p induces sleep, fever, and anorexia. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R703-R707, 1992.-The enhanced sleep, fever, and anorexia experienced during general infections are attributed to the increased production of cytokines. Cytokines such as interleukin-1 and tumor necrosis factor-a (TNF-cu) have characteristic somnogenic, pyrogenic, and anorectic effects. TNF-P is closely related to TNF-cu, and they share common receptors. The effects of TNF-P on sleep-wake activity, brain temperature (Tbr), and food intake were, however, heretofore unknown. We injected 0.5-200 ng TNF-P into rabbits intracerebroventricularly (icv) in the light period, and the electroencephalogram, movement, and Tbr were recorded for 6 h from rabbits. The highest dose, 200 ng TNF-P, induced increases in non-rapid-eye-movement sleep and decreases in rapid-eye-movement sleep accompanied with biphasic febrile responses. Icv injection of 100 ng TNF-P at dark onset suppressed 12-h and 24-h food intake in rats. These data suggest to us that TNF-P may belong to the group of endogenous pyrogens/sleep factors. lymphotoxin; rat; rabbit; thermoregulation; food intake; rapideye-movement sleep; non-rapid-eye-movement sleep GENERALIZED INFECTIONS Central nervous system symptoms often observed include excess sleep, fever, and anorexia. These symptoms seem to result from the actions of a complex array of cytokines (17). Cytokines are best known as immunocyte products mediating inflammatory responses and immune functions, though they are also produced by neurons and glia cells (4). Regulatory relationships between cytokines are very complex and incompletely understood. Nevertheless, systemic or central injections of certain cytokines, such as tumor necrosis factor-a (TNF-(u), induce sleep (34), fever (7, 23, 24, 34), and anorexia (6, 26, 31). The objective of the present study was to investigate whether a related cytokine, TNF-P, has similar effects on sleep, thermoregulation, and food intake. TNF-/3 has about a 30% homology with TNF-a at the amino acid level (30). Although TNF-cu and -6 share the same receptors (1,9), their bioactivities are not identical (see Ref. 40 for a review). For example, there are differences between TNF-a and -0 in their cytotoxic effects (3,5), effects on sympathetic nervous system (IO), and on interleukin-1 (IL-l) secretion (21). We report herein that TNF-P promotes non-rapid-eye-movement sleep (NREMS), induces fever, and suppresses food intake. DURING
MATERIALS
AND
METHODS
Sleep experiments. Male New Zealand rabbits (3-4 kg) were provided with a lateral cerebral ventricular guide cannula and stainless steel electroencephalographic (EEG) electrodes using ketamine-xylazine (35 and 5 mg/kg) anesthesia. A calibrated thermistor was implanted over the parietal cortex to measure brain temperature (Tbr). EEG electrodes were placed over the frontal and parietal cortices. The leads from EEG electrodes and the thermistor were routed to a Teflon plug; the wires, electrodes, and guide tube were held in place with dental acrylic. Animals were allowed to recover from the surgery for at least 0363-6119/92
$2.00
sleep, fever, and anorexia
Copyright
of Tennessee, Memphis,
Tennessee 38163
2 wk. A 12:12-h light-dark cycle was maintained (light onset at 0600 h) at an ambient temperature of 21 & l°C in the recording chambers and the housing facility. Food and water were provided ad libitum. The rabbits were placed in the recording chambers (Hotpack 352600, Philadelphia, PA) for at least two 24-h habituation sessions before recordings were taken from the animals for the first time. Before use in an experiment, the rabbits were placed in the recording chambers the preceding evening. A flexible tether connected the electrode and thermistor leads mounted on the rabbit head to an electronic swivel. The rabbits were relatively free to move within the experimental cages; body movements were detected by ultrasonic motion sensors. The EEG, Tbr, and body movements were recorded on Grass 7D polygraphs placed in an adjacent room. In addition, the EEG signal was led through two band-pass filters (0.5-3.5 Hz, 6, and 4.0-7.5 Hz, 0), the signals were rectified, and the ratio of 8 to 8 activity was continuously computed and recorded on the polygraphs. The Tbr values taken every 10 min were also recorded on computer. Rapid-eye-movement sleep (REMS), NREMS, and wakefulness (W) were visually identified in 12-s epochs by an experimenter who was not aware of the treatment the rabbits had received. In brief, W was characterized by fast, low-amplitude EEG waves, relative high o-to-6 ratio, slowly increasing Tbr, and high incidence of gross body movements. NREMS was characterized by slow, high-amplitude EEG waves, low o-to-6 ratio, decreasing Tbr, and lack of body movements. REMS was characterized by fast, low-amplitude EEG waves, high e-to-6 ratio, sharply increasing Tbr at REMS onset, and lack of motor activity interrupted by occasional twitches. The percentages (duration) of NREMS and REMS (&SE) were calculated for l-h and 6-h periods. TNF-P was injected intracerebroventricularly (icv) in a volume of 25 ~1 into the cerebral ventricle (0.5 ng, n = 7; 5 ng, n = 6; 50 ng, n = 7; 200 ng, n = 6) between 0845 and 0915 h; each injection took ~2 min. After injections, animals were returned to the recording chambers and were recorded for 6 h. For control experiments, equal amounts of artificial cerebrospinal fluid (aCSF) containing dimethyl sulfoxide (DMSO) was used as injectant. These recordings were obtained from the same animal; thus matched-pairs design was used. A total number of 12 rabbits was used. Some of the rabbits were used for testing two or three different doses of TNF-P. In these cases, the TNF-P treatments were separated by at least 1 wk. Food intake measurements. The method previously used to determine the anorectic effects of TNF-cu in rats was used (31). Seven male Sprague-Dawley rats (260-310 g) were provided with lateral icv cannula using ketamine-xylazine (87 and 13 mg/kg, respectively) anesthesia. The animals were kept on 12:12-h dark-light cycle (light on at 0730 h) at 23 t l°C. Food and water were provided ad libitum. After the stabilization of daily food intake, two experimental days, separated by a recovery day, followed. Each rat was injected icv (5 ~1) in a random order with vehicle on one day (baseline food intake) and with 100 ng TNF-P on the other day at dark onset. After the injection, premeasured solid rat food pellets (Purina Rat Chow) were placed in the cages. The food intake [g/kg body wt (&SE)] was determined 12, 24, and 48 h after the treatments. Sleep-wake activity and Tbr were not recorded in these rats. Statistics. In case of the sleep experiments, differences between the experimental and control days were evaluated by analysis of variance (ANOVA) across the 6-h recording period,
0 1992 the American
Physiological
Society
R703
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R704
TNF-P, SLEEP, FEVER, AND ANOREXIA
basedon the hourly values. This was followed by paired Student’s t test. Temperature data, collected at IO-min intervals, were comparedbetweenvehicle- and TNF-treated groupsacross the 6-h recording period by ANOVA. To detect dose-dependent effects, hourly differences in sleep, and IO-min differences in Tbr between the control and TNF treatments, were computed for each dose.Thesevalues were comparedby ANOVA. In case of the food intake experiments, the differences between the effects of vehicle and TNF-P 12, 24, and 48 h after the treatments were evaluated by paired Student’s t test. Materials. Human recombinant TNF-P (R & D Systems, Minneapolis, MN) was dissolved in a mixture of DMSO and aCSF such that the specimenany rabbit or rat received contained 20% DMSO. Separate,supplementary experimentsindicated that icv injection of aCSF containing 20% DMSO does not affect sleepand Tbr in rabbits (25 ~1)or food intake in rats (5 ~1)per secomparedwith the effects of pure aCSF [percent of NREMS t SE (n = 5) during 6-h period after aCSF, 46.6 t 2.6; after DMSO, 49.0 t 1.8; percent of REMS after aCSF, 13.1 t 1.3; after DMSO, 10.0 t 0.6; maximum Tbr (n = 6) after aCSF, 38.2 & 0.2”C; after DMSO, 38.3 t 0.2”C; 24-h food intake (g/kg, = 7) after aCSF, 86.5 t 10.6; after DMSO, 97.7 t 8.9, NS, Jlaired t test]. RESULTS
TNF-@ elicited dose-dependent increases in Tbr and NREMS (Fig. 1). The three lowest doses induced slight increases in NREMS, although only the increase in NREMS after the lowest dose (0.5 ng) was significant (significant TNF effect across 6-h by ANOVA, signifi-
DISCUSSION
cant effect in postinjection hour 4 and 6 by paired t test). The highest dose of TNF-P (200 ng) elicited a robust increase in NREMS and induced a slight but statistically significant decrease in REMS (percent of REMS, 6.3 t 0.7 after vehicle vs. 3.5 t 0.6 after TNF-fl) across the 6-h 80
0.5
experimental period (Fig. 1). The effects of TNF-fi on sleep were first evident during the second postinjection hour, then persisted for the remainder of the experimental period. Increases in Tbr paralleled the somnogenic actions of TNF-p; 50 ng TNF-P slightly increased Tbr, whereas 200 ng elicited a strong biphasic fever (Fig. 1). The first peak in Tbr was during the first postinjection hour. During the second postinjection hour, Tbr increased again, and thereafter Tbr did not return to baseline levels during the 6-h experimental period. Tbr changes, associated with vigilance state transitions (i.e., transitions from W to NREMS, NREMS to REMS or W, and from REMS to NREMS or W), persisted during the fever. Icv injection of 100 ng TNF-P at dark onset significantly suppressed food intake in rats for 24 h (control, 67.6 t 5.97 vs. TNF-& 45.6 t 1.37 g/kg, P < 0.05). The suppression occurred during the dark period, the period that immediately followed the injection of TNF-/3; during the light period no significant effects were detected (dark control, 44.6 t 4.16 vs. TNF-P, 27.1 t 2.73 g/kg, P < 0.05; light control, 23.1 t 3.22 vs. TNF-P, 18.4 t 1.72 g/kg, NS). On the recovery day, the food intake returned to the baseline level (dark, 75.3 t 5.3; light, 15.3 t 2.1 g/kg). TNF-P did not induce gross behavioral abnormalities in rats or rabbits, although behavioral responses were not systematically evaluated. Two forms of TNF have been identified; TNF-cu primarily of monocyte/macrophage origin and its lymphocyte-derived homologue, TNF-P (see Ref. 40 for a review). The role of TNFs in inflammatory and immunological 50 ng
ng
200
ng
70 W I F
cl z 0 g 0 k k x
60
50 40
30 20 10
t
I
I
I
I
1
1
I
I
I
I
I
0
60
120
180
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360
0
60
120
180
240
POSTINJECTION
MINUTES
POSTINJECTION
I1
300
MINUTES
360
I
I
I
I
1
I
1
r
I
I
I
I
l
I
0
60
120
180
240
300
360
0
60
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POSTINJECTION
MINUTES
POSTINJECTION
MINUTES
Fig. 1. Effects of intracerebroventricular injection of various doses of TNF-P (solid symbols) and vehicle (open symbols) on sleep and brain temperature in rabbits. Injections were done at time 0. Error bars indicate SE. Squares, brain temperature; circles, non-rapid-eye-movement sleep (NREMS); triangles, rapid-eye-movement sleep (REMS). Highest dose of TNF-P elicited a biphasic fever, promoted NREMS, and suppressed REMS. Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (018.218.056.169) on September 30, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
TNF-fi,
SLEEP,
FEVER,
processes are under extensive investigation, although their effects on brain functions are much less understood. The capacity of astrocytes to produce TNF-cu and -p (20) and direct modulatory effects of TNF-cx (31, 33) and TNF-P (25) on hypothalamic neurons indicate that TNFs may be involved in central regulatory mechanisms. Despite the sharing of common receptors by TNF-cx and -p (1, 9) there are differences in the effects of these two related cytokines. TNF-a and -p have disparate effects on sympathetic efferents in rats (10). They have different cytotoxic potencies in several tumor lines (3,5). TNF-a! is more active in inducing IL-l secretion (21) and granulocyte colony-stimulating factor secretion (15) than TNF-P, whereas TNF-P, but not TNF-a, causes inflammatory reaction in normal skin (2). Although it is known that TNF-cu promotes NREMS (34), fever (7,23,24,34), and suppresses food intake (6,26,31), these effects of the related cytokine TNF-P were previously not studied. In the present experiments, TNF-P elicited dose-dependent fevers that were biphasic after the highest dose. Similar biphasic fevers were reported after the administration of TNF-a (7, 23, 24, 34). It has been postulated that the first peak of the febrile response after TNF-cr injection can be attributed to a central effect of TNF-cx on prostaglandin synthesis (7, 24), whereas the second peak is due to TNF-a-induced IL-l secretion (7). TNF-P also induces IL-l secretion (21, 32) and, acting on central sites, increases the sympathic output to the brown adipose tissue, resulting in elevated body temperature in anesthetized rats (10). Thus two physiological mechanisms might also be involved in the pyrogenic actions of TNF-& During infections, TNF-P levels are elevated (19) as are other pyrogenic cytokines (see Ref. 14 for a review). It is very likely that TNF-P also contributes to the development of naturally occurring fever; i.e., TNF-P is possibly an endogenous pyrogen. TNF-P induced increases in NREMS and decreases in REMS. Similar sleep patterns were observed during the initial phase of generalized bacterial or fungal (37) infections. NREMS increase and REMS suppression were reported after the injection of other immunoactive sleep factors such as TNF-CY (34), IL-l (18), and interferon-a2 (16). It is assumed that a cascade-activation of the cytokine system brings about the characteristic autonomic and behavioral responses, such as excess sleep during infections. The relative long latency to the somnogenic response to TNF-P indicates that the increased sleep might be a secondary effect mediated via the release of other somnogenic substance(s). We hypothesize that TNF-P, as one of the cytokines released during infections, in concert with the other immunoactive sleep factors may contribute to the excess sleep during infections. It is unlikely that TNF-P-enhanced NREMS is a result of TNF-P-enhanced body temperature; there is much evidence showing a separation of the effects of a variety of substances on sleep and body temperature. For example, the febrile effects of IL-lp can be blocked by a protein synthesis inhibitor (18) or a cyclooxygenase inhibitor (12) without affecting sleep responses. In rats, low doses of IL-l promote sleep without having effects on Tbr (13). In rabbits, muramyl dipeptide induces both sleep and
AND
R705
ANOREXIA
febrile responses during the day, whereas at night certain doses induce enhanced NREMS without affecting Tbr (35). In contrast, IL-6 (27) and certain peptide fragments of TNF-a! (lOa) are pyrogenic, but lack sleep-promoting activity. Furthermore, corticotropin-releasing factor induces hyperthermia while decreasing sleep (8); cholecystokinin induces hypothermia while increasing sleep (11). Finally, during the course of bacterial infection, sleep responses are not correlated with febrile responses (36). Icv bolus injection of 100 ng TNF-P suppressed the 12and 24-h food intake by 39 and 33%, respectively, in rats. Plata-Salaman et al. (31) using a very similar method to ours reported 43% overnight and 31% daily food intake suppression after the icv injection of 100 ng TNF-a! at dark onset in rats. Although we tested only one dose of TNF-fl, these results indicate that the anorectic potencies of TNF-cu and -p are in the same range. It has been hypothesized that TNF-cu has a direct central effect on food intake (31, 39). In addition, it inhibits gastric emptying (29), elicits gastrointestinal lesions (29, 38), and stimulates other hormones, e.g., IL-l, known to suppress food intake (31). These peripheral effects may also contribute to the anorectic actions of TNF-a; similar mechanisms may account for the anorectic actions of TNF-P as well. It is also possible that the decrease in food intake is a consequence of increased sleep. However, it is difficult to correlate the food intake and sleep responses, since sleep was measured for only 6 h, whereas the anorectic effects lasted for at least 12 h and different species were used in the sleep and food intake experiments. It is not likely that fever may be a factor in the suppression of food intake after TNF-P injection, since fever per se does not affect food intake. For example, pyrogenic doses of IL-l and endotoxin (22) or pyrogenic fragments of TNF-CY (lOa) did not suppress eating in rats. More recent experiments in which TNF-a! was used under identical conditions as TNF-@ was in the present study indicated that the pyrogenic, hypnogenic, and anorectic potencies of TNF-cu and -p are in the same range (lOa). The similar patterns of the effects of TNF-cu and -p and the similar potencies suggest that the in vivo central effects of the two related cytokines may be mediated by common (receptor) mechanisms. TNF-P strongly upregulates TNF-cu gene expression (28); thus it is possible that the effects of TNF-P are partially due to simulated TNF-CY secretion. In summary, TNF-P elicits symptoms characteristic for generalized inflammations, such as increases in sleep and fever and suppression of food intake. The authors thank Drs. M. Kimura-Takeuchi, F. Obal, Jr., and M. Opp for reviewing the manuscript. The technical assistance of Gail Richmond and the secretarial assistance of Collean Payne are gratefully acknowledged. This work was supported by the Office of Naval Research (NOOOl490-J-1069), the U.S. Army Medical Research and Development Command (DAMD-17-86-C-6194), and the National Institutes of Health (NS-25378 and NS-27250). L. Kapas was on leave from the Dept. of Physiology, Albert SzentGyorgyi Medical Univ., Szeged, Hungary. Address reprint requests to L. Kapas. Received
28 October
1991; accepted
in final
form
17 February
1992.
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R706
TNF-P,
SLEEP,
FEVER,
AND
concerning 1990.
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266: 7313-7316,
1991.
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necrosis factor-p LEVENTE
KAPAS
Department
of Physiology
AND JAMES
induces M. KRUEGER
and Biophysics,
University
Kapbs, Levente, and James M. Krueger. Tumor necrosis factor-p induces sleep, fever, and anorexia. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R703-R707, 1992.-The enhanced sleep, fever, and anorexia experienced during general infections are attributed to the increased production of cytokines. Cytokines such as interleukin-1 and tumor necrosis factor-a (TNF-cu) have characteristic somnogenic, pyrogenic, and anorectic effects. TNF-P is closely related to TNF-cu, and they share common receptors. The effects of TNF-P on sleep-wake activity, brain temperature (Tbr), and food intake were, however, heretofore unknown. We injected 0.5-200 ng TNF-P into rabbits intracerebroventricularly (icv) in the light period, and the electroencephalogram, movement, and Tbr were recorded for 6 h from rabbits. The highest dose, 200 ng TNF-P, induced increases in non-rapid-eye-movement sleep and decreases in rapid-eye-movement sleep accompanied with biphasic febrile responses. Icv injection of 100 ng TNF-P at dark onset suppressed 12-h and 24-h food intake in rats. These data suggest to us that TNF-P may belong to the group of endogenous pyrogens/sleep factors. lymphotoxin; rat; rabbit; thermoregulation; food intake; rapideye-movement sleep; non-rapid-eye-movement sleep GENERALIZED INFECTIONS Central nervous system symptoms often observed include excess sleep, fever, and anorexia. These symptoms seem to result from the actions of a complex array of cytokines (17). Cytokines are best known as immunocyte products mediating inflammatory responses and immune functions, though they are also produced by neurons and glia cells (4). Regulatory relationships between cytokines are very complex and incompletely understood. Nevertheless, systemic or central injections of certain cytokines, such as tumor necrosis factor-a (TNF-(u), induce sleep (34), fever (7, 23, 24, 34), and anorexia (6, 26, 31). The objective of the present study was to investigate whether a related cytokine, TNF-P, has similar effects on sleep, thermoregulation, and food intake. TNF-/3 has about a 30% homology with TNF-a at the amino acid level (30). Although TNF-cu and -6 share the same receptors (1,9), their bioactivities are not identical (see Ref. 40 for a review). For example, there are differences between TNF-a and -0 in their cytotoxic effects (3,5), effects on sympathetic nervous system (IO), and on interleukin-1 (IL-l) secretion (21). We report herein that TNF-P promotes non-rapid-eye-movement sleep (NREMS), induces fever, and suppresses food intake. DURING
MATERIALS
AND
METHODS
Sleep experiments. Male New Zealand rabbits (3-4 kg) were provided with a lateral cerebral ventricular guide cannula and stainless steel electroencephalographic (EEG) electrodes using ketamine-xylazine (35 and 5 mg/kg) anesthesia. A calibrated thermistor was implanted over the parietal cortex to measure brain temperature (Tbr). EEG electrodes were placed over the frontal and parietal cortices. The leads from EEG electrodes and the thermistor were routed to a Teflon plug; the wires, electrodes, and guide tube were held in place with dental acrylic. Animals were allowed to recover from the surgery for at least 0363-6119/92
$2.00
sleep, fever, and anorexia
Copyright
of Tennessee, Memphis,
Tennessee 38163
2 wk. A 12:12-h light-dark cycle was maintained (light onset at 0600 h) at an ambient temperature of 21 & l°C in the recording chambers and the housing facility. Food and water were provided ad libitum. The rabbits were placed in the recording chambers (Hotpack 352600, Philadelphia, PA) for at least two 24-h habituation sessions before recordings were taken from the animals for the first time. Before use in an experiment, the rabbits were placed in the recording chambers the preceding evening. A flexible tether connected the electrode and thermistor leads mounted on the rabbit head to an electronic swivel. The rabbits were relatively free to move within the experimental cages; body movements were detected by ultrasonic motion sensors. The EEG, Tbr, and body movements were recorded on Grass 7D polygraphs placed in an adjacent room. In addition, the EEG signal was led through two band-pass filters (0.5-3.5 Hz, 6, and 4.0-7.5 Hz, 0), the signals were rectified, and the ratio of 8 to 8 activity was continuously computed and recorded on the polygraphs. The Tbr values taken every 10 min were also recorded on computer. Rapid-eye-movement sleep (REMS), NREMS, and wakefulness (W) were visually identified in 12-s epochs by an experimenter who was not aware of the treatment the rabbits had received. In brief, W was characterized by fast, low-amplitude EEG waves, relative high o-to-6 ratio, slowly increasing Tbr, and high incidence of gross body movements. NREMS was characterized by slow, high-amplitude EEG waves, low o-to-6 ratio, decreasing Tbr, and lack of body movements. REMS was characterized by fast, low-amplitude EEG waves, high e-to-6 ratio, sharply increasing Tbr at REMS onset, and lack of motor activity interrupted by occasional twitches. The percentages (duration) of NREMS and REMS (&SE) were calculated for l-h and 6-h periods. TNF-P was injected intracerebroventricularly (icv) in a volume of 25 ~1 into the cerebral ventricle (0.5 ng, n = 7; 5 ng, n = 6; 50 ng, n = 7; 200 ng, n = 6) between 0845 and 0915 h; each injection took ~2 min. After injections, animals were returned to the recording chambers and were recorded for 6 h. For control experiments, equal amounts of artificial cerebrospinal fluid (aCSF) containing dimethyl sulfoxide (DMSO) was used as injectant. These recordings were obtained from the same animal; thus matched-pairs design was used. A total number of 12 rabbits was used. Some of the rabbits were used for testing two or three different doses of TNF-P. In these cases, the TNF-P treatments were separated by at least 1 wk. Food intake measurements. The method previously used to determine the anorectic effects of TNF-cu in rats was used (31). Seven male Sprague-Dawley rats (260-310 g) were provided with lateral icv cannula using ketamine-xylazine (87 and 13 mg/kg, respectively) anesthesia. The animals were kept on 12:12-h dark-light cycle (light on at 0730 h) at 23 t l°C. Food and water were provided ad libitum. After the stabilization of daily food intake, two experimental days, separated by a recovery day, followed. Each rat was injected icv (5 ~1) in a random order with vehicle on one day (baseline food intake) and with 100 ng TNF-P on the other day at dark onset. After the injection, premeasured solid rat food pellets (Purina Rat Chow) were placed in the cages. The food intake [g/kg body wt (&SE)] was determined 12, 24, and 48 h after the treatments. Sleep-wake activity and Tbr were not recorded in these rats. Statistics. In case of the sleep experiments, differences between the experimental and control days were evaluated by analysis of variance (ANOVA) across the 6-h recording period,
0 1992 the American
Physiological
Society
R703
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R704
TNF-P, SLEEP, FEVER, AND ANOREXIA
basedon the hourly values. This was followed by paired Student’s t test. Temperature data, collected at IO-min intervals, were comparedbetweenvehicle- and TNF-treated groupsacross the 6-h recording period by ANOVA. To detect dose-dependent effects, hourly differences in sleep, and IO-min differences in Tbr between the control and TNF treatments, were computed for each dose.Thesevalues were comparedby ANOVA. In case of the food intake experiments, the differences between the effects of vehicle and TNF-P 12, 24, and 48 h after the treatments were evaluated by paired Student’s t test. Materials. Human recombinant TNF-P (R & D Systems, Minneapolis, MN) was dissolved in a mixture of DMSO and aCSF such that the specimenany rabbit or rat received contained 20% DMSO. Separate,supplementary experimentsindicated that icv injection of aCSF containing 20% DMSO does not affect sleepand Tbr in rabbits (25 ~1)or food intake in rats (5 ~1)per secomparedwith the effects of pure aCSF [percent of NREMS t SE (n = 5) during 6-h period after aCSF, 46.6 t 2.6; after DMSO, 49.0 t 1.8; percent of REMS after aCSF, 13.1 t 1.3; after DMSO, 10.0 t 0.6; maximum Tbr (n = 6) after aCSF, 38.2 & 0.2”C; after DMSO, 38.3 t 0.2”C; 24-h food intake (g/kg, = 7) after aCSF, 86.5 t 10.6; after DMSO, 97.7 t 8.9, NS, Jlaired t test]. RESULTS
TNF-@ elicited dose-dependent increases in Tbr and NREMS (Fig. 1). The three lowest doses induced slight increases in NREMS, although only the increase in NREMS after the lowest dose (0.5 ng) was significant (significant TNF effect across 6-h by ANOVA, signifi-
DISCUSSION
cant effect in postinjection hour 4 and 6 by paired t test). The highest dose of TNF-P (200 ng) elicited a robust increase in NREMS and induced a slight but statistically significant decrease in REMS (percent of REMS, 6.3 t 0.7 after vehicle vs. 3.5 t 0.6 after TNF-fl) across the 6-h 80
0.5
experimental period (Fig. 1). The effects of TNF-fi on sleep were first evident during the second postinjection hour, then persisted for the remainder of the experimental period. Increases in Tbr paralleled the somnogenic actions of TNF-p; 50 ng TNF-P slightly increased Tbr, whereas 200 ng elicited a strong biphasic fever (Fig. 1). The first peak in Tbr was during the first postinjection hour. During the second postinjection hour, Tbr increased again, and thereafter Tbr did not return to baseline levels during the 6-h experimental period. Tbr changes, associated with vigilance state transitions (i.e., transitions from W to NREMS, NREMS to REMS or W, and from REMS to NREMS or W), persisted during the fever. Icv injection of 100 ng TNF-P at dark onset significantly suppressed food intake in rats for 24 h (control, 67.6 t 5.97 vs. TNF-& 45.6 t 1.37 g/kg, P < 0.05). The suppression occurred during the dark period, the period that immediately followed the injection of TNF-/3; during the light period no significant effects were detected (dark control, 44.6 t 4.16 vs. TNF-P, 27.1 t 2.73 g/kg, P < 0.05; light control, 23.1 t 3.22 vs. TNF-P, 18.4 t 1.72 g/kg, NS). On the recovery day, the food intake returned to the baseline level (dark, 75.3 t 5.3; light, 15.3 t 2.1 g/kg). TNF-P did not induce gross behavioral abnormalities in rats or rabbits, although behavioral responses were not systematically evaluated. Two forms of TNF have been identified; TNF-cu primarily of monocyte/macrophage origin and its lymphocyte-derived homologue, TNF-P (see Ref. 40 for a review). The role of TNFs in inflammatory and immunological 50 ng
ng
200
ng
70 W I F
cl z 0 g 0 k k x
60
50 40
30 20 10
t
I
I
I
I
1
1
I
I
I
I
I
0
60
120
180
240
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360
0
60
120
180
240
POSTINJECTION
MINUTES
POSTINJECTION
I1
300
MINUTES
360
I
I
I
I
1
I
1
r
I
I
I
I
l
I
0
60
120
180
240
300
360
0
60
120
180
240
300
360
POSTINJECTION
MINUTES
POSTINJECTION
MINUTES
Fig. 1. Effects of intracerebroventricular injection of various doses of TNF-P (solid symbols) and vehicle (open symbols) on sleep and brain temperature in rabbits. Injections were done at time 0. Error bars indicate SE. Squares, brain temperature; circles, non-rapid-eye-movement sleep (NREMS); triangles, rapid-eye-movement sleep (REMS). Highest dose of TNF-P elicited a biphasic fever, promoted NREMS, and suppressed REMS. Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (018.218.056.169) on September 30, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
TNF-fi,
SLEEP,
FEVER,
processes are under extensive investigation, although their effects on brain functions are much less understood. The capacity of astrocytes to produce TNF-cu and -p (20) and direct modulatory effects of TNF-cx (31, 33) and TNF-P (25) on hypothalamic neurons indicate that TNFs may be involved in central regulatory mechanisms. Despite the sharing of common receptors by TNF-cx and -p (1, 9) there are differences in the effects of these two related cytokines. TNF-a and -p have disparate effects on sympathetic efferents in rats (10). They have different cytotoxic potencies in several tumor lines (3,5). TNF-a! is more active in inducing IL-l secretion (21) and granulocyte colony-stimulating factor secretion (15) than TNF-P, whereas TNF-P, but not TNF-a, causes inflammatory reaction in normal skin (2). Although it is known that TNF-cu promotes NREMS (34), fever (7,23,24,34), and suppresses food intake (6,26,31), these effects of the related cytokine TNF-P were previously not studied. In the present experiments, TNF-P elicited dose-dependent fevers that were biphasic after the highest dose. Similar biphasic fevers were reported after the administration of TNF-a (7, 23, 24, 34). It has been postulated that the first peak of the febrile response after TNF-cr injection can be attributed to a central effect of TNF-cx on prostaglandin synthesis (7, 24), whereas the second peak is due to TNF-a-induced IL-l secretion (7). TNF-P also induces IL-l secretion (21, 32) and, acting on central sites, increases the sympathic output to the brown adipose tissue, resulting in elevated body temperature in anesthetized rats (10). Thus two physiological mechanisms might also be involved in the pyrogenic actions of TNF-& During infections, TNF-P levels are elevated (19) as are other pyrogenic cytokines (see Ref. 14 for a review). It is very likely that TNF-P also contributes to the development of naturally occurring fever; i.e., TNF-P is possibly an endogenous pyrogen. TNF-P induced increases in NREMS and decreases in REMS. Similar sleep patterns were observed during the initial phase of generalized bacterial or fungal (37) infections. NREMS increase and REMS suppression were reported after the injection of other immunoactive sleep factors such as TNF-CY (34), IL-l (18), and interferon-a2 (16). It is assumed that a cascade-activation of the cytokine system brings about the characteristic autonomic and behavioral responses, such as excess sleep during infections. The relative long latency to the somnogenic response to TNF-P indicates that the increased sleep might be a secondary effect mediated via the release of other somnogenic substance(s). We hypothesize that TNF-P, as one of the cytokines released during infections, in concert with the other immunoactive sleep factors may contribute to the excess sleep during infections. It is unlikely that TNF-P-enhanced NREMS is a result of TNF-P-enhanced body temperature; there is much evidence showing a separation of the effects of a variety of substances on sleep and body temperature. For example, the febrile effects of IL-lp can be blocked by a protein synthesis inhibitor (18) or a cyclooxygenase inhibitor (12) without affecting sleep responses. In rats, low doses of IL-l promote sleep without having effects on Tbr (13). In rabbits, muramyl dipeptide induces both sleep and
AND
R705
ANOREXIA
febrile responses during the day, whereas at night certain doses induce enhanced NREMS without affecting Tbr (35). In contrast, IL-6 (27) and certain peptide fragments of TNF-a! (lOa) are pyrogenic, but lack sleep-promoting activity. Furthermore, corticotropin-releasing factor induces hyperthermia while decreasing sleep (8); cholecystokinin induces hypothermia while increasing sleep (11). Finally, during the course of bacterial infection, sleep responses are not correlated with febrile responses (36). Icv bolus injection of 100 ng TNF-P suppressed the 12and 24-h food intake by 39 and 33%, respectively, in rats. Plata-Salaman et al. (31) using a very similar method to ours reported 43% overnight and 31% daily food intake suppression after the icv injection of 100 ng TNF-a! at dark onset in rats. Although we tested only one dose of TNF-fl, these results indicate that the anorectic potencies of TNF-cu and -p are in the same range. It has been hypothesized that TNF-cu has a direct central effect on food intake (31, 39). In addition, it inhibits gastric emptying (29), elicits gastrointestinal lesions (29, 38), and stimulates other hormones, e.g., IL-l, known to suppress food intake (31). These peripheral effects may also contribute to the anorectic actions of TNF-a; similar mechanisms may account for the anorectic actions of TNF-P as well. It is also possible that the decrease in food intake is a consequence of increased sleep. However, it is difficult to correlate the food intake and sleep responses, since sleep was measured for only 6 h, whereas the anorectic effects lasted for at least 12 h and different species were used in the sleep and food intake experiments. It is not likely that fever may be a factor in the suppression of food intake after TNF-P injection, since fever per se does not affect food intake. For example, pyrogenic doses of IL-l and endotoxin (22) or pyrogenic fragments of TNF-CY (lOa) did not suppress eating in rats. More recent experiments in which TNF-a! was used under identical conditions as TNF-@ was in the present study indicated that the pyrogenic, hypnogenic, and anorectic potencies of TNF-cu and -p are in the same range (lOa). The similar patterns of the effects of TNF-cu and -p and the similar potencies suggest that the in vivo central effects of the two related cytokines may be mediated by common (receptor) mechanisms. TNF-P strongly upregulates TNF-cu gene expression (28); thus it is possible that the effects of TNF-P are partially due to simulated TNF-CY secretion. In summary, TNF-P elicits symptoms characteristic for generalized inflammations, such as increases in sleep and fever and suppression of food intake. The authors thank Drs. M. Kimura-Takeuchi, F. Obal, Jr., and M. Opp for reviewing the manuscript. The technical assistance of Gail Richmond and the secretarial assistance of Collean Payne are gratefully acknowledged. This work was supported by the Office of Naval Research (NOOOl490-J-1069), the U.S. Army Medical Research and Development Command (DAMD-17-86-C-6194), and the National Institutes of Health (NS-25378 and NS-27250). L. Kapas was on leave from the Dept. of Physiology, Albert SzentGyorgyi Medical Univ., Szeged, Hungary. Address reprint requests to L. Kapas. Received
28 October
1991; accepted
in final
form
17 February
1992.
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R706
TNF-P,
SLEEP,
FEVER,
AND
concerning 1990.
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