Systemic injection of TNF-a attenuates due to IL-lp and LPS in rats NANCY Department

C. LONG,

AK10

of Physiology,

MORIMOTO, Yamaguchi

TOMOKI Medical

Long, Nancy C., Akio Morimoto, Tomoki Nakamori, and Naotoshi Murakami. Systemic injection of TNF-cu attenuates fever due to IL-l/3 and LPS in rats. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R987-R991, 1992.-The effect of tumor necrosis factor-a (TNF-cu) on the febrile response to interleukin-ID (IL-l@) was investigated in rats. While both of these substances are capable of causing fever when injected into rats, an earlier study showed that the injection of antiserum against TNF-a( enhanced endotoxin [lipopolysaccharide (LPS)] fever, suggesting that physiological levels of circulating TNF may act to limit the magnitude of fever. In the present study, the intraperitoneal injection of 1 attenuated the fever due to the ,ug/kg of TNF- cy significantly intraperitoneal injection of 10 ,uglkg of IL-l& Higher doses of TNF-cu (10 and 50 hg/kg injected ip) slightly lowered the febrile response to this dose of IL-lp, but these changes were not significant. None of these doses of TNF-ar alone significantly altered body temperature. The injection of 1 pg/kg of TNF-a also significantly lowered the febrile response to the intraperitoneal injection of 10 pg/kg of LPS. The febrile responses to the preoptic area (POA) or intraperitoneal injection of IL-16 were not changed when a nonpyrogenic dose of TNF-cu was simultaneously injected into the POA. Further studies are needed, however, before we can conclude that TNF does not act in the central nervous system to control the febrile response. These data support the hypothesis that nonpyrogenic levels of TNF act in the systemic circulation to suppress the development of fever. tumor necrosis factor-a; cachectin; interleukin-lp; charide; endogenous pyrogen; antipyretic

lipopolysac-

OF FEVER, and its association with disease, has been recognized for centuries. However, the physiological mechanism of fever is still not known. At the present time, many researchers believe that fever due to lipopolysaccharide (LPS) or other exogenous pyrogens is caused by the release of an endogenous pyrogen or pyrogens (EP) into the circulation (1). These pyrogens, in turn, are thought to act on the brain to cause the release of prostaglandins, presumably of the E series, which cause an elevation in thermal set point, and, ultimately, fever (4). Many scientists believe that the active component of EP includes one or more immune cytokines. Over the past decade, researchers have discovered a number of cytokines that are capable of causing fever when injected into animals. However, the exact physiological role of these molecules in fever is not yet known. Recently, Long et al. (18) reported that the injection of rats with antiserum against interleukin-lp (IL-l@) before the injection of LPS blocked up to 60% of the resulting fever. These data support the hypothesis that IL-lp is responsible for a large portion of the fever due to the injection of LPS. Tumor necrosis factor (TNF) is another candidate for the role of circulating EP. Evidence that TNF is an endogenous mediator of fever includes the following: 1)

THE PHENOMENON

0363-6119/92

NAKAMORI,

School, Yamaguchi

fever AND NAOTOSHI

MURAKAMI

755, Japan

The injection of TNF-cu can induce fever (8, 15, 21), 2) the plasma concentration of TNF rises shortly after injections of LPS (5, 10, 12, 17, 20, 21, 29), 3) in humans the intravenous infusion of TNF-a resulted in plasma TNF levels and fevers that are similar to those seen after the injection of 4 rig/kg of LPS (21), and 4) injection of rabbits with antibody to TNF resulted in significantly smaller fevers in response to the injection of LPS (14, 22). However, recent studies show that the actions of TNF may be more complex. Long et al. (17) reported that when antiserum against TNF-cu is injected intraperitoneally into rats 2 h before the intramuscular injection of LPS, the resulting fevers were enhanced, not diminished. A subsequent study in which rats received anti-TNF-a! intravenously 3.5 days before the intraperitoneal injection of LPS gave similar results (18). Taken together, these data support the hypothesis that at physiological levels, TNF acts as an endogenous antipyretic in rats. The purpose of the, present study is to take this observation one step further and determine whether the injection of low doses of TNF-a along with a pyrogenic dose of IL-ID or LPS lowers the magnitude of the subsequent fever. METHODS Male albino (Wistar strain) rats weighing between 270 and 320 g were used in this study. The rats were housed in individual plastic cages in a room maintained at 26 t l°C, a temperature within the thermoneutral zone for rats, with a 12:12-h lightdark photoperiod, with lights on at 0700 h. To minimize the confounding effects of the rats’ circadian rhythm, all experiments were started between 1030 and 1330 h. When individual rats were exposed to multiple treatments, the order in which the animals received each treatment was randomized. The rats were allowed at least 2 days to recover between experiments. Body temperature was measured using a biotelemetry system (Data Sciences, St Paul, MN). Rats were implanted intraperitoneally with battery-operated transmitters. The output of the transmitters (frequency in Hz) was monitored by antennae mounted in a receiver board (model CTR86) that was placed under each animal’s cage. The data were then fed into a peripheral processor (matrix model BCMlOO) that was connected to a Sanyo MBC-175 AX computer (IBM compatible). Each rat was anesthetized (pentobarbital sodium, 50 mg/kg), implanted with a transmitter (model TAlOTA-F40), and then allowed at least 1 wk to recover before experimentation began. Recombinant human IL-l@ and TNF-cu were used in these studies. The IL-l@ was a kind gift of Otsuka Pharmaceutical. It was shipped to us in highly concentrated solution on dry ice and then thawed, aliquoted, and refrozen on arrival. Each aliquot was thawed and diluted just before use. The TNF-a was kindly provided by Dainippon Pharmaceutical. It was shipped and stored under the same conditions as was the IL-l& One microgram of the IL-l@ represented 2 x lo4 U of IL-1 activity, and 1 pg of the TNF-(U had an activity of 3.15 x lo3 U. On the days of the experiments, rats were gently lifted and

$2.00 Copyright 0 1992 the American Physiological

Society

R987

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R988

TNF

AND

their transmitters were switched on with a magnet. The rats were then left undisturbed for at least 30 min, or until each animal’s body temperature was stable for at least six readings at 5min intervals. The injection procedure began immediately after the computer recorded the zero time point and took between 5 and 12 min for all of the animals in any given experiment. In each experiment, the body temperature of the rats was monitored for 7 h after the injection. To study the effect of systemically administered TNF-a on the fever due to IL-l& rats were injected intraperitoneally with 10 pg/kg of IL-lfi (IO pg/ml in saline) plus 1 ml/kg saline or with 10 pg/kg of IL-l@ plus 1, 10, or 50 pg/kg of TNF-cu (in saline; injection volume 1 ml/kg). We also determined the effect of each dose of TNF-cu alone and of 1 ml/kg of saline on the body temperature of the rats. This experiment was performed in two separate trials with different groups of six and eight rats, respectively. Each animal received up to three injections with IO rug/kg IL-lp and up to four injections with TNF-ac. In our study of the effect of TNF on LPS fever, we used two separate groups of animals. The first group (n = 6) received an intraperitoneal injection of 1 pg/kg of TNF-cu plus a separate injection of 10 pg/kg of LPS ip and, on a different day, 1 ml/kg of saline ip plus 10 pg/kg of LPS ip. The second group (n = 5) of rats received 10 pg/kg of TNF-cu ip plus IO pg/kg of LPS ip on one day and saline plus the same dose of LPS on a different day. Hence, each rat was injected twice with LPS and once with TNF-cu. The LPS used in this study was from Salmonella typhosa (Difco, Detroit, MI). The LPS was dissolved in sterile saline to a concentration of 10 pg/ml. To investigate whether the injection of TNF-cu into the preoptic area (POA) altered the fever due to the intraperitoneal or POA injection of IL-l& rats that had been implanted with stainless steel cannulas (0.8 mm OD) into the POA region were used. Each rat was anesthetized (pentobarbital sodium, 50 mg/ kg), and the cannula was implanted at coordinates (in mm) 2 anteroposterior, 1.5 lateral, and 8.5 ventral with respect to the bregma, according to the rat brain atlas (26) by standard stereotaxic techniques. The rats were allowed at least 10 days to recover before experimentation began. A group of 5 rats was used to test the effect of the POA injection of TNF-cu on the fever due to the intraperitoneal injection of IL-l& In separate trials, each rat received the following three treatments: 0.2 ng of TNF-cu (in saline; vol = 1~1) into the POA + IO pg/kg of IL-l ip; 0.2 ng of TNF-cu into the POA + saline (1 ml/kg) ip; or saline (1 ~1) into the POA + 10 pg/kg of IL-lp ip. A separate group of rats was used to study the effect of the POA injection of TNF-(U on the fever due to the POA injection of IL-ID. On the day of the experiment, the rats were injected with 0.2 ng of IL-l@ alone (in saline; vol = 1 pl), or this dose of IL+ plus a separate injection of 0.2 ng of TNF-cr (in saline; vol = 1 ~1). We also tested the effect of 0.2 ng of TNF-cu injected alone, to confirm that this dose of TNF-cu had no effect on body temperature. In the analysis of the data, the change in body temperature was calculated by subtracting the baseline temperature of each rat (the average of the rats’ temperature 30,15, and 0 min before the injection) from each subsequent time point. Statistical comparisons were made between the mean changes in body temperature of the rats over a preselected time period. This value was calculated for each rat by simply summing the temperature changes over the time period of interest and dividing by the number of points. The mean changes in body temperature were then compared by paired, one-tailed Student’s t tests, with the exception of the first study, which was analyzed by analysis of variance followed by Scheffe’s F test. The time intervals for comparison were selected based on pilot studies before the experiments were completed.

FEVER RESULTS

The changes in body temperature of rats after the intraperitoneal injection of IL-lb plus saline or IL-l@ plus TNF-cw together are shown in Fig. IA. Before the rats received IL-l@ and saline, their baseline temperature was 37.32 t 0.14”C. B ef ore the injection of IL-l@ together with 1, 10, or 50 pg/kg of TNF-cw, their baseline temperatures were 38.00 t 0.21, 37.19 t 0.09, and 38.01 t 0.012°C, respectively. All of the animals showed an acute rise i n temperature during the first hour after the injection. This was followed by a fall in temperature during the second hour. This pattern is commonly seen after the intraperitoneal injection of pyrogen. The rats that were injected with IL-lfl and saline went on to develop fevers with an average magnitude of 1.10 t 0.14”C over the period from 120 to 420 min after injection. The rats that received IL-1p and 1 pg/kg of TNF-cu, however, developed significantly lower fevers during this time period, with an average magnitude of 0.31 t 0.21”C (P 5 0.05). The rats that received 10 and 50 pg/kg of TNF-a along with IL-10 developed intermediate fevers, with average magnitudes of 0.74 t 0.17 and 0.78 t O.l3”C, respectively. These temperature changes did not differ significantly from those of the rats that had received IL-l@ with saline. The change in temperature of rats injected with TNF-a alone or saline is plotted in Fig. 1B. Before the injection of 1, 10, and 50 pg/kg of TNF-a or saline, the rats’ baseline temperatures were 38.02 t 0.15,37.08 t 0.16,38.01 t 0.26, and 37.18 t O.l5”C, respectively. Rats injected with these doses of TNF-cr or saline experienced only minor oscillations in body temperature throughout the recording period. In Fig. 2A, we have compared the febrile responses of rats injected intraperitoneally with IO pg/kg of LPS plus 1 pg/kg of TNF-a, or this dose of LPS plus saline. The baseline temperatures before the injections of LPS with saline and LPS with 1 pg/kg TNF-cu were 37.09 t 0.05 and 37.18 t O.O6”C, respectively. During the first 2 h after ----+---

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Fig. 2. A: mean change in body temperature of rats after intraperitoneal injection of 1 pg/kg TNF-cu plus a separate intraperitoneal injection of 10 pg/kg lipopolysaccharide (LPS), or with saline plus same dose of LPS. B: mean change in body temperature of rats after intraperitoneal injection of 10 pg/kg TNF-cr plus a separate injection of 10 pg/kg LPS, or with saline plus same dose of LPS. Data were analyzed by paired one-tailed Student’s t tests.

the injections, the rats showed the typical transient rise and fall in body temperature. The rats that had received LPS with saline developed moderate fevers, with a mean change in body temperature of 0.98 t O.OS°C between 120 and 240 min after the injection. After the injection of 1 hg/kg TNF-ar + LPS, the same group of rats showed a mean change in temperature of 0.63 t O.l6”C, which, by paired t test, was significantly lower than that seen after LPS and saline (P = 0.03). Figure 2B shows the effect of 10 pg/kg of TNF-a injected intraperitoneally on the febrile response to the intraperitoneal injection of 10 pg/kg of LPS. Before the injection of saline with 10 pg/kg of LPS or of 10 pg/kg of TNF-a with the same dose of LPS, the mean baseline temperatures of the rats were 37.13 t 0.2l”C (P = 0.16) and 38.14 t O.M”C, respectively. After the injection, both groups of rats developed fevers of similar magnitude and duration. Between 120 and 240 min after injection, the rats that received LPS and TNF-cw showed a mean change in body temperature of 0.80 t 0.19°C. With the use of a paired t test, this value did not differ significantly from that seen after the injection of LPS and saline (0.90 t O.l9OC, P = 0.26). The mean change in body temperature of rats that were injected with 0.2 ng of TNF-a into the POA immediately followed by 10 ,ug/kg of IL-lp ip, or an equal volume of saline into the POA followed by the same dose of IL-lfl ip, is plotted in Fig. 3A. Before the injection of TNF-cu and IL-l& the baseline temperature of the rats was 37.64 +- O.l4”C, and before the injection of saline and IL-l@ the baseline value was 37.71 t 0.17”C. The mean change in body temperature of the rats between 120 and 420 min after the POA injection of TNF-cu and the intraperitoneal injection of IL-l@ was 1.17 t 0.42OC. During this time

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after injection of ip, or with 0.2 ng change in body and saline intraStudent’s t tests.

period after the POA injection of saline and the intraperitoneal injection of IL-l& the mean temperature change was 1.38 t 0.32OC. There is no significant difference between these values (P = 0.20). Figure 3B shows the change in temperature of the rats after the POA injection of 0.2 ng of TNF-ar and the intraperitoneal injection of saline. Before the rats were injected with TNF, their mean body temperature was 37.83 t 0.25OC. After this treatment, the animals tended to show a gradual rise in temperature. Between 120 and 420 min after injection, their mean change in body temperature was 0.75 t 0.38"C. The febrile response of rats injected with 0.2 ng of IL-l@ alone or this dose of IL-lp plus 0.2 ng of TNF-cu into the POA is shown in Fig. 4. The baseline body temperatures of the rats before injection were 36.66 t 0.14 and 36.53 t O.O5”C, respectively. Between 120 and 420

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R990

TNF

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tor or by stimulating the synthesis of the IL-1 inhibitor. TNF may also act to stimulate the release of some other endogenous antipyretic, such as adrenocorticotropic hormone (ACTH; ll), cx-melanocyte-stimulating hormone (a-MSH; 2), or perhaps arginine vasopressin (24). This possibility is supported by the observation that central administration of corticotropin-releasing factor, which stimulates ACTH and a-MSH release, has been shown to attenuate the febrile response due to the injection of IL-l DISCUSSION in rabbits (3, 25). The results of this study are consistent with the hyThese data also demonstrate the importance of distinpothesis that nonpyrogenic levels of TNF act in the sys- guishing between physiological and pharmacological temic circulation to lower the febrile response to injected doses of cytokines. In this study, we found that rats inpyrogens. jected intraperitoneally with 1 pg/kg of human TNF-cu, Comparison of the febrile response of rats injected inwhich is equivalent to -3,160 U/kg body wt or about traperitoneally with IL-l@ plus saline, or with IL-10 plus 1,000 U/rat, lowered the febrile response to the injection various doses of TNF (injected ip), shows that very low of IL-l& Although it is not possible to compare units of levels of TNF (1 pg/kg) decreased the febrile response to human and rat cytokine directly, this dose is within the IL-l& Higher doses of TNF tended to lower the febrile range of circulating levels of endogenous TNF seen in rats response to IL-l& but this effect was not significant. injection of IO pg/kg of LPS. These data are in keeping with earlier observations show- after the intraperitoneal During the first 4 h after injection, rats showed plasma ing that the injection of antiserum against TNF signifilevels of TNF that ranged from - 1 to 700 U/ml (17). On cantly enhanced the febrile response of rats to the injection of LPS (17, 18). Similar results have been seen in the assumption that the rat’s plasma volume is equal to 5% of its body weight, a 300-g rat would have between 15 rabbits as well (19). and 10,500 U of rat TNF in its bloodstream during this Because the febrile response induced by LPS is significantly suppressed by antiserum against IL-l@ (17)) it is time period. An earlier study by Kettelhut and Goldberg likely that LPS-induced fever in rats is caused primarily (15) demonstrated that the injection of 1 X lo8 U/kg of by this cytokine. Therefore, the next step in this study human TNF-cu caused fever, a dose >30,000 times higher was to determine whether the intraperitoneal injection of than we injected. low doses of TNF-cu alters LPS-induced fever. We found It is perhaps because of the dose-dependent nature of that the injection of 1 pg/kg of TNF-a significantly low- the actions of TNF that no consensus has emerged in the ered the fever due to the intraperitoneal injection of LPS literature concerning the physiological role of TNF. as well. It is interesting to note that this dose of TNF did While some reports have shown that antibodies against not attenuate the febrile response to LPS as strongly as it TNF block the lethal effects of a large dose of endotoxin did the response to IL-l@ the rats that received 1 pg/kg (6, 28), another study showed that low doses of TNF of TNF + LPS developed fevers that were 64% as high as given before or up to 6 h after exposing rats to cecal those seen in rats injected with saline and LPS; however, contents actually decreased the subsequent mortality in this dose of TNF lowered the febrile response to IL-lp to these animals (27). In addition, TNF has also been shown just 28% of the level seen after the injection of saline and to play a role in protecting an animal against infection (9, IL-l& This discrepancy could be the result of endogenously produced TNF adding to the injected TNF-cu to 23). This duality is not unexpected because the immune produce levels of this cytokine somewhat higher than the response to bacterial products such as endotoxin, which optimal antipyretic range. Further studies using even presumably evolved as a protective mechanism, is also lower doses of TNF-cu would enable us to test this possi- thought to be responsible for endotoxic shock (9). Although fever has been shown to help the infected bility. host fight off the invading pathogen (7, 16), some negaHolt et al. (13) showed that the injection of 100 and 200 ng of TNF-cu into the third ventricle resulted in a dose- tive feedback mechanism must be in place to keep body dependent drop in rectal temperature. In our study, how- temperature from becoming dangerously high. Our data ever, the injection of 0.2 ng of TNF-a directly into the support the hypothesis that at physiological levels in the systemic circulation TNF participates in this negative POA caused a slight rise in body temperature. The injection of this dose of TNF-a into the POA did not alter the feedback response by inhibiting the fever-inducing capacity of IL-l@. febrile response to IL-l& injected either intraperitoneally or into the POA. It is possible that the action of TNF on brain regions other than the POA is responsible for the The authors thank Dr. M. J. Kluger for critically reading this manuantipyresis that was seen in the study by Holt et al. (13). script. This work was supported by Grant-in-Aid A6244025 for scientific It is also possible that our dose of TNF-c\! was too high or research from the Ministry of Education, Science, and Culture of Japan. too low for this response to occur. Present address for N. C. Long: Dept. of Environmental Health and The mechanism by which the intraperitoneal injection Physiology, Respiratory Biology Program, Harvard School of Public of TNF suppresses fever due to intraperitoneal IL-16 or Health, 665 Huntington Ave., Boston, MA 02115. Address for reprint requests: A. Morimoto, Dept. of Physiology, LPS is not clear. It is possible that TNF is involved in a negative feedback loop to limit the action of IL-1p, per- Yamaguchi Univ. School of Medicine, Ube, Yamaguchi 755, Japan. haps by interfering with the binding of IL-1 to its recep- Received 4 September 1990; accepted in final form 30 April 1992. min after the injection of IL-l@ alone, the rats showed a mean temperature change of 1.43 t 0.16OC. This was not significantly different from that seen after the injection of IL-l/3 and TNF -CYtogether (1.69 t 0.14, P = 0.16). Figure 4B shows the change in temperature of the rats after the injection of 0.2 ng of TNF alone. Before receiving TNF-a, the rats had a mean body temperature of 36.60 t 0.15”C.

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REFERENCES 1. Beeson, P. B. Temperature-elevating effect of a substance obtained from polymorphonuclear leukocytes (Abstract). J. Clin. Invest. 27: 524, 1948. 2. Bell, R. C., and J. M. Lipton. Pulsatile release of antipyretic neuropeptide cu-MSH from septum of rabbits during fever. Am. J. Physiol. 252 (Regulatory Integrative Comp. Physiol. 21): R1152Rl157, 1987. 3. Bernardini, G. L., D. B. Richards, and J. M. Lipton. Antipyretic effect of centrally administered CRF. Peptides 5: 57-59, 1984. 4. Bernheim, H. A., T. M. Gilbert, and J. T. Stitt. Prostaglandin E levels in the third ventricular cerebrospinal fluid of rabbits during fever and change in body temperature. J. Physiol. Lond. 301: 69-78, 1980. 5. Beutler, B. A., I. W. Milsark, and A. Cerami. Cachectin/ tumor necrosis factor: production, distribution and metabolic fate in vivo. J. Immunol. 135: 3972-3977, 1985. 6. Beutler, B. A., I. W. Milsark, and A. Cerami. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science Wash. DC 229: 869-871, 1985. 7. Covert, J. B., and W. W. Reynolds. Survival value of fever in fish. Nature Lond. 267: 43-45, 1977. 8. Dinarello, C. A., J. G. Cannon, S. M. Wolff, H. A. Bernheim, B. Beutler, A. Cerami, I. S. Figari, M. A. Palladino, Jr., and J. V. O’Connor. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces the production of interleukin-l. J. Exp. Med. 163: 1433-1450, 1986. 9. Ghiara, P., D. Boraschi, L. Nencioni, P. Ghezzi, and A. Tagliabue. Enhancement of in vivo immune response by tumor necrosis factor. J. ImmunoZ. 139: 3676-3679, 1987. 10. Gifford, G. E., and D. A. Flick. Natural production and release of tumor necrosis factor. In: Tumor Necrosis Factor and Related Cytokines, edited by G. Bock and J. Marsh. New York: Wiley, 1987, p. 3-20. (Ciba Foundation Symp. 131) 11. Glyn, J. R., and J. M. Lipton. Hypothermic and antipyretic effects of centrally administered ACTH (l-24) and cu-melanotropin. Peptides 2: 177-187, 1983. 12. Hesse, D. G., K. J. Tracey, Y. Fong, K. R. Manogue, M. A. Palladino, Jr., A. Cerami, G. T. Shires, and S. F. Lowry. Cytokine appearance in human endotoxemia and primate bacteremia. Surg. Gynecol. Obstet. 166: 147-153, 1988. 13. Holt, S. J., R. F. Gimble, and D. A. York. Tumour necrosis factor a and lymphotoxin have opposite effects on sympathetic efferent nerves to brown adipose tissue by direct action in the central nervous system. Brain Res. 497: 183-186, 1989. 14. Kawasaki, H., M. Moyiyama, Y. Ohtani, M. Naitoh, A. Tanaka, and H. Nariuchi. Analysis of endotoxin fever in rabbits using a monoclonal antibody to tumor necrosis factor (cachectin). Infect. Immunol. 57: 3131-3135, 1989. 15. Kettelhut, I. C., and A. L. Goldberg. Tumor necrosis factor can induce fever in rats without activating protein breakdown in muscle or lipolysis in adipose tissue. J. C&n. Invest. 81: 1384-1389, 1988.

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Systemic injection of TNF-alpha attenuates fever due to IL-1 beta and LPS in rats.

The effect of tumor necrosis factor-alpha (TNF-alpha) on the febrile response to interleukin-1 beta (IL-1 beta) was investigated in rats. While both o...
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