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Interleukin (IL)-6, But Not IL-1, Induction in the Brain Downstream of Cyclooxygenase-2 Is Essential for the Induction of Febrile Response against Peripheral IL-1

Division of Cell Biology, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Address all correspondence and requests for reprints to: Yoichiro Iwakura, D.Sc., Professor, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail: iwakura{at}ims.u-tokyo.ac.jp.

	Abstract

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IL-1 is an endogenous pyrogen produced upon inflammation or infection. Previously, we showed that, upon injection with turpentine, IL-1 is induced in the brain in association with the development of fever. The role of endogenous IL-1 in the brain and the signaling cascade to activate thermosensitive neurons, however, remain to be elucidated. In this report, febrile response was analyzed after peripheral injection of IL-1. We found that a normal febrile response was induced even in IL-1/ß-deficient mice, indicating that production of IL-1 in the brain is not necessarily required for the response. In contrast, IL-6-deficient mice did not exhibit a febrile response. Cyclooxygenase (Cox)-2 expression in the brain was strongly induced 1.5 h after injection of IL-1, whereas IL-6 expression was observed 3 h after the injection. Cox-2 expression in the brain was not influenced by IL-6 deficiency, whereas indomethacin, an inhibitor of cyclooxygenases, completely inhibited induction of IL-6. These observations suggest a mechanism of IL-1-induced febrile response in which IL-1 in the blood activates Cox-2, with the resulting prostaglandin E₂ inducing IL-6 in the brain, leading to the development of fever.

	Introduction

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IL-1 IS A MAJOR mediator of inflammation, performing numerous functions related to host defense mechanisms by regulating not only the immune system but also the neuronal and endocrine systems (1). Two molecular species, IL-1 and IL-1ß, are known as agonists and an antagonist, IL-1 receptor antagonist (IL-1Ra), which binds to the same receptors, is also known. Two IL-1 receptors, the type I IL-1 receptor (IL-1RI) and type II (IL-1RII), exist; only the former transduces IL-1 signaling and the latter rather acts as a decoy. IL-1 is produced by a large variety of cells, including monocytes and macrophages, and IL-1Rs are expressed on a wide range of cells in the immune, neural, and endocrine systems. Because IL-1Rs are induced upon peripheral inflammation in the brain, particularly the hypothalamus, hippocampus, and choroid plexus (2, 3, 4), a role for IL-1 has been suggested in the neuronal system.

Fever is a common response of the body to various stresses such as infection and inflammation. Such peripheral stimuli are transmitted to the brain through the nervous system and also by "endogenous pyrogens" (5). Although it is well known that circulating cytokines such as IL-1 and tumor necrosis factor (TNF) are important endogenous pyrogens, the precise mechanism by which these cytokines induce fever through activation of the thermoregulatory neurons in the hypothalamus remains to be elucidated. It is especially interesting to elucidate how these cytokines stimulate relevant thermoregulatory brain structures, because these large hydrophilic polypeptides hardly penetrate the blood-brain barrier (BBB) (6, 7).

We showed previously that IL-1 expression was induced in the diencephalon of the brain upon injection with turpentine, and that the febrile response to turpentine was abolished in IL-1/ß-deficient mice, suggesting involvement of IL-1 in the brain in the development of fever (8). Consistently, IL-1RI-deficient mice also failed to respond to turpentine (9). On the other hand, it has been demonstrated that endogenous hypothalamic IL-1ß is not necessary for the development of IL-1-, IL-1ß- or lipopolysaccharide (LPS)-induced fever (10). It is not known, however, whether or not a febrile response can be induced in the complete absence of both IL-1 and IL-1ß in the brain.

It is known that prostaglandin (PG)E₂ is involved in the development of fever during inflammation, because inhibitors of cyclooxygenases, which catalyze synthesis of PGH₂, a precursor of PGE₂, can suppress febrile response (11), and mice lacking the EP₃ receptor, one of the receptors for PGE₂, showed an impaired febrile response during the first hour after IL-1ß injection (12). Although two types of cyclooxygenases (Cox) are known, it was suggested that only Cox-2 is involved in the febrile response upon inflammation (8, 13, 14, 15). Furthermore, endogenously induced IL-6 has also been suggested to be involved in the febrile response induced by IL-1 (16). However, the relationship among IL-1, IL-6, and Cox-2 in the brain has not been established conclusively.

In this report, to elucidate the roles of IL-1, which is endogenously induced in the brain during fever, we examined the febrile response in IL-1/ß-deficient mice upon peripheral administration of IL-1. Furthermore, we analyze the signaling cascade in the brain using IL-1/ß- and IL-6-deficient mice.

	Materials and Methods

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Reagents
Recombinant murine IL-1 was obtained from Pepro Tech EC LTD (London, UK). The lyophilized protein was dissolved in pyrogen-free 0.9% NaCl (saline) containing 0.1% BSA (A9306; Sigma, St. Louis, MO). Indomethacin was obtained from Sigma.

Animals
IL-1/ß-doubly deficient mice were produced as described (8), and IL-6-deficient mice were kindly provided by Dr. Manfred Kopf (17). These mice were backcrossed to C57BL/6J mice for eight generations, and C57BL/6J mice were used as controls. Mice were housed individually from weaning at 4 wk of age, and sex- and age-matched adult (9–15 wk of age) male mice were used for each experiment. Mice were kept under specific, pathogen-free conditions in an environmentally controlled clean room at the Center for Experimental Medicine, Institute of Medical Science, University of Tokyo. They were housed at an ambient temperature of 24 C and a daily cycle of 12-h light/dark (0800–2000 h light). All experiments were carried out both according to the institutional ethical guidelines for animal experiments and the safety guidelines for gene manipulation experiments.

Measurement of body temperature
Intraperitoneal temperature of mice was measured using an electric thermometer and tips (ELAMS system; BioMedic Data System, Inc., Maywood, NJ) with an accuracy of 0.1 C. All the tips were tested and adjusted before use. Mice were anesthetized with Nembutal, and the tip was implanted chronically into their peritoneal cavity and ligated to the peritoneum. The position of the tips was verified by postmortem examination. These mice were used for experiments 18 d after the thermometer implantation. IL-1 [1 µg/kg body weight (BW)] was injected iv at 1100 h, and the temperature was measured every 15 min by a person who was accustomed to using the system.

Northern blot hybridization analysis
Northern blot hybridization was performed as described previously using mouse IL-1, IL-1ß, Cox-2, IL-6, and ß-actin cDNA as probes (8). Wild-type, IL-1/ß-deficient, and IL-6-deficient mice were injected with IL-1 (1 µg/kg BW). Mice were killed 1.5 and 3 h after injection, and poly-A⁺ RNA was isolated from the diencephalons. Samples from four mice were pooled for each genotype. Poly-A⁺ RNA (8–11 µg) was electrophoresed on a denatured agarose gel and hybridized with specific probes; ß-actin was used as a control. Relative radioactivities of the IL-1, IL-1ß, IL-6, and Cox-2 bands were compared after normalization with the intensity of the ß-actin band.

Indomethacin treatment
Mice were injected with indomethacin (10 mg/kg BW, ip injection) dissolved in a buffer containing 0.9% NaCl, 5% ethanol, and 4% sodium hydrogen carbonate, or the buffer only 30 min before IL-1 (1 µg/kg BW, iv) injection or saline injection, and IL-6 and Cox-2 mRNA levels were measured 3 h after the treatment by Northern blot hybridization.

Statistical analysis
Averages ± SD are shown. In Fig. 1, Student’s t test was used to evaluate statistical significance. Animals with consecutive missing temperature recordings, due to failure of the telemetry system, were excluded from the statistical analysis. In Fig. 2, Student’s paired t test was performed to compare before (basal) and after (1.5 h or 3 h after IL-1 injection) data for each genotype.

View larger version (37K): [in this window] [in a new window]   FIG. 1. Effects of IL-1/ß or IL-6 deficiency on fever development after injection with IL-1 (1 µg/kg BW, iv injection). The body temperatures relative to that at the time of IL-1 injection are shown. A, IL-1-injected wild-type mice (n = 4; ); saline-injected wild-type mice (n = 4; ); IL-1-injected IL-1/ß-deficient mice (n = 3; ); and saline-injected IL-1/ß-deficient mice (n = 3; ). B, IL-1-injected IL-6-deficient mice (n = 3; ); and saline-injected IL-6-deficient mice (n = 3; ). Averages ± SD are shown. *, P < 0.05, IL-1-injected wild-type mice vs. IL-1-injected IL-1/ß-deficient mice; #, P < 0.05, IL-1-injected IL-1/ß-deficient mice vs. saline-injected IL-1/ß-deficient mice; **, P < 0.05, IL-1-injected wild-type mice vs. saline-injected wild-type mice.

View larger version (54K): [in this window] [in a new window]   FIG. 2. Expression of the mRNA for IL-6, IL-1, IL-1ß, and Cox-2 in the diencephalon after iv injection with IL-1. A, Northern blot hybridization. B-E, relative radioactivity of the bands corresponding to IL-1, IL-1ß, IL-6, and Cox-2 mRNA normalized against the intensity of the ß-actin band. Data show the averages and the SD of three independent experiments. WT, Wild-type mice (open bars); IL-1–/–, IL-1/ß-deficient mice (stripe bars); IL-6–/–, IL-6-deficient mice (filled bars). *, P < 0.05; **, P < 0.001.

	Results

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Febrile response to IL-1 in IL-1/ß-deficient and IL-6-deficient mice

Induction of IL-6, IL-1, IL-1ß, and Cox-2 expression in the brain by IL-1
We next examined the time course of mRNA expression for the IL-6, IL-1, IL-1ß, and Cox-2 genes in the brain after IL-1 injection (Fig. 2). In wild-type mice, Cox-2 and IL-1ß were already strongly induced 1.5 h after injection of IL-1, followed by IL-6 and IL-1 induction after 3 h. Similarly, in IL-1/ß-deficient mice, Cox-2 was strongly induced 1.5 h after the injection and IL-6 induction followed 3 h after the injection, as observed in wild-type mice. In the case of IL-6-deficient mice, Cox-2 and IL-1ß were also induced 1.5 h after the injection and IL-1 was induced 3 h after the injection, as in wild-type mice. Similar results were obtained in two additional independent experiments using mRNAs from the whole brains. These results show that endogenous IL-1 and IL-6 are not necessary for the induction of Cox-2 and that IL-6 induction occurs later than that of Cox-2, suggesting that IL-6 is induced downstream of PGE₂.

Suppression of IL-1-induced IL-6 expression by indomethacin
We next analyzed the effect of indomethacin, an inhibitor of cyclooxygenases, on the expression of IL-6 to examine PGE₂ dependency of the IL-6 expression. The expression of IL-6 was measured at 0 h (basal level) and 3 h after IL-1 injection with or without indomethacin treatment. The administration of indomethacin 30 min before IL-1 injection strongly suppressed IL-6 transcription (Fig. 3). By this treatment, the Cox-2 expression was not inhibited and was rather induced by the treatment itself, even in the absence of IL-1 treatment. Under these conditions, fever development was completely suppressed, in agreement with previous reports (data not shown; see Refs. 14 , 18). These results suggest that IL-6 expression is dependent on PGE₂ production.

View larger version (40K): [in this window] [in a new window]   FIG. 3. The effect of indomethacin treatment on the expression of IL-6 after injection with IL-1. Wild-type mice were treated with indomethacin 30 min before IL-1 injection and after 3 h; relative IL-6 mRNA levels in the diencephalon were analyzed by Northern blot hybridization. A, Northern blot hybridization profile. 1, nontreated mice; 2, 3 h after saline injection without pretreatment with indomethacin; 3, 3 h after IL-1 injection without pretreatment with indomethacin; 4, 3 h after saline injection with pretreatment with indomethacin; and 5, 3 h after IL-1 injection with pretreatment with indomethacin. mRNAs from four mice were used for each lane. B, Relative radioactivity of the bands corresponding to IL-6, normalized against the intensity of the ß-actin bands. Similar results were obtained in another experiment.

	Discussion

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We observed rather higher febrile response in IL-1/ß-deficient mice than in wild-type mice. This result is consistent with the hyperresponsive febrile reaction of IL-1ß-deficient mice by ip injection of IL-1, IL-1ß, or LPS (10). The increased febrile response could be explained by the number or the affinity of IL-1Rs in IL-1/ß-deficient mice, although no such differences in IL-1Rs were reported in IL-1ß-deficient mice (10). The hyperresponsive febrile response may also reflect lower levels of IL-1Ra in the brain. Consistent with this notion, we reported that IL-1Ra levels in the brain were decreased in IL-1- or IL-1ß-deficient mice (8).

Then, we analyzed the signal transduction mechanisms during febrile response in the brain. It has been reported that Cox-2 is induced by IL-1 (19, 20, 21, 22), that Cox-2 null mutant mice failed to show a febrile response to IL-1ß (15), and that various Cox-2 inhibitors including indomethacin suppress the development of fever upon inflammation (15), suggesting involvement of PGE₂ in IL-1-induced febrile response. Endogenously induced IL-6 has also been suggested to be involved in the febrile response induced by IL-1, because IL-6 null mutant mice failed to mount a febrile response to peripherally injected IL-1ß (16) or IL-1 (Fig. 1B). In this report, we have analyzed the relationship among IL-1, IL-6, and Cox-2, and demonstrated that: 1) Cox-2 is strongly induced 1.5 h after iv injection of IL-1, followed by IL-6 at 3 h after injection; 2) Cox-2 induction in the brain is not affected by deficiencies in IL-1 or IL-6; 3) no fever development is observed in IL-6-deficient mice, although Cox-2 is induced in the brain; and 4) inhibition of Cox activity by indomethacin suppresses both IL-6 induction and fever development. These results suggest the following signaling cascade in the febrile response: peripheral IL-1 Cox-2 activation in the brain PGE₂ IL-6 induction fever development. It has been well documented that IL-1 can induce Cox-2 expression both in vitro and in vivo (19, 20, 21, 23). The endothelium of the cerebral vasculature may be the site where circulating IL-1 interacts with its receptors. Indeed, we and other investigators (4, 24) observed expression of IL-1RI on cerebral blood vessels after treatment with IL-1 (data not shown) (4, 24). Because Cox-2 is induced in the microvessels of the brain upon IL-1 injection (24, 25, 26), PGE₂ may be released inside the brain through the BBB to induce IL-6 inside the brain. It was also suggested that IL-1 might penetrate the fenestrated endothelia of capillaries of organum vasculosum laminae terminalis, bind to their receptors located on astrocytes that tightly surround the vascular network, and trigger the synthesis and release of PGE₂ (5, 27).

There has been some confusion among data relating to the signaling cascade in the brain that occurs during inflammation. It was reported that intracerebroventricular injection of IL-6 induces an increase of PGE₂ levels in the cerebrospinal fluid in parallel with the rise in body temperature in cats (28), suggesting that IL-6 induces Cox-2. Another study has also demonstrated that PGE₂ release from rat hypothalamic explants is increased by both IL-1ß and IL-6 in vitro (29). In contrast, this report shows that peripherally injected IL-1 can induce Cox-2 in IL-6-deficient mice without fever development, and indomethacin inhibits IL-6 induction, suggesting that IL-6 is induced downstream of Cox-2. In support of this notion, several reports have demonstrated that IL-6 is induced by PGE₂ in activated peritoneal macrophages (30, 31). The expression of IL-6 in the brain has also been suggested to be downstream of PGE₂; one such study reported that hyperthermia induced by PGE₂ was markedly suppressed by the microinjection of anti-IL-6 directly into the anterior hypothalamic preoptic area (32). Furthermore, PGE₂ induces IL-6 in U373 MG human astroglioma cells (33), and inhibition of Cox-2 reduces IL-6 synthesis in human postmortem astrocyte cultures (34). Intravenous administration of IL-6, however, did not induce Cox-2 expression in the rat brain. Thus, IL-6 may induce Cox-2, and vice versa, under artificial conditions, but only IL-6 induction by PGE₂ appears to occur in the brain during an in vivo febrile response against IL-1 in mice.

It is known that IL-1 induces other cytokines such as IL-6 or TNF in the periphery (35). IL-1 and TNF synergistically increase the production of IL-6 in human synovial fibroblast (36). Thus, it is possible that the febrile response is not caused directly by IL-1, but rather other cytokines that are induced by IL-1 in the periphery. Regarding this possibility, we could not detect any febrile response by the injection of IL-6 into wild-type mice, consistent with the previous observation (16). On the other hand, administration of TNF could evoke febrile response in IL-1-deficient mice as in wild-type mice. Thus, it is possible that the febrile response may actually be caused by other cytokines that are induced by IL-1 in the periphery.

Finally, we have shown that both early febrile response, which occurs during the 15–45 min after IL-1 administration, and late response, which occurs after 1 h 45 min, were abolished in IL-6-deficient mice. However, suppression of the early response is rather unexpected, because IL-6 induction was only low during the early phase. It is possible that only low levels of IL-6 are enough for the induction of fever. Consistent with our results, Chai et al. (16) reported that LPS- or IL-1ß-induced fever response was completely abolished in IL-6-deficient mice, although the early response was not clear. However, because the early febrile response against IL-1 in mice was very small compared with that of rabbits or rats against LPS or IL-1ß (5, 37), we might have failed to detect the response. We are now further analyzing the signaling mechanism of the early-phase febrile response.

In conclusion, we have shown that endogenous brain IL-1 is not necessary for IL-1-induced fever development. We suggest that the signaling cascade for the febrile response in the brain is as follows: peripheral IL-1 Cox-2 activation PGE₂ IL-6 induction fever. We are now analyzing the roles of other cytokines in the brain in the development of fever.

	Footnotes

 
Current address for T.S.: Department of Developmental Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan.

Current address for M.A.: Division of Transgenic Animal Science, Kanazawa University Advanced Science Research Center, 13-1 Takaramachi, Kanazawa 920-8640, Japan.

This work was supported by the grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Ministry of Health, Labor and Welfare of Japan, and Pioneering Research Project in Biotechnology.

Abbreviations: BBB, Blood-brain barrier; BW, body weight; Cox, cyclooxygenase; IL-1R, IL-1 receptor; IL-1Ra, IL-1R antagonist; LPS, lipopolysaccharide; PG, prostaglandin.

Received January 19, 2004.

Accepted for publication July 12, 2004.

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