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Effect of IL-1α on the release of norepinephrine in rat hypothalamus
Journal of Neuroimmunology 90 Ž1998. 122–127
Effect of IL-1 a on the release of norepinephrine in rat hypothalamus Daljit Kaur a
a,)
, David F. Cruess b, William Z. Potter
c
Section on Clinical Pharmacology, Experimental Therapeutics Branch, NIMH, National Institute of Health, Bethesda, MD 20892, USA b DiÕision of Public Health and Biometrics, Uniformed SerÕices UniÕersity of Health Sciences, Bethesda, MD 20892, USA c A DiÕision of Elly Lilly and, Lilly Corporate Center, Indianopolis, IN 46285, USA Received 25 April 1997; revised 25 February 1998; accepted 26 February 1998
Abstract The increased release of norepinephrine ŽNE. in the brain as part of the ‘acute phase response’ has been postulated to result from a direct action of IL-1 on the hypothalamus. To test whether the effects of IL-1 a were direct, we carried out in vivo experiments using microdialysis and measured NE release in the hypothalamus using high pressure liquid chromatography ŽHPLC.. Two groups of male Sprague Dawley rats were either injected intraperitoneally with 1 ml of IL-1 a Ž2 m grml. or had IL-1 a 2 m l Ž100 ngrml. infused directly into the medial hypothalamus. A significant increase in extracellular hypothalamic NE was observed in the animal group treated with IL-1 a intraperitoneally and not in the controls or the group treated with IL-1 a intracerebrally. One-way ANOVA showed a significant effect of drug and route of administration with the ip IL-1 a treated group, differing from all other groups Žvehicle ip, IL-1 a ic, and vehicle ic.. Therefore these findings suggest that some aspects of IL-1 a actions on the HPA may be indirect requiring other intermediate steps or mediators outside the central nervous system. q 1998 Published by Elsevier Science B.V. All rights reserved. Keywords: Hypothalamus; HPLC; Norepinephrine; Rat
1. Introduction: The ‘acute phase response’ is an inflammatory as well as an immunological response mounted by an animal when exposed to infection and stress Žfor review see Dinarello, 1984, pp 57–59; and Blatteis, 1988.. A further extension of the ‘acute phase response’ include the release of cytokines such as Žinterleukin-1. IL-1, interleukin-6 ŽIL-6. and tumour necrosis factor a ŽTNFa . as well as neurohormones such as corticotrophin-releasing hormone ŽCRF., corticosteroids Žfor review see Sapolsky et al., 1987; Rivier and Rivest, 1993 pp. 205–208. and norepinephrine ŽDunn, 1988; Mefford and Heyes, 1990.. The actions of systemically delivered IL-1 on the central nervous system are known and intra-cerebroventricular delivery of IL-1 a and IL-1 b have systemic effects ŽDunn, 1988. confirming a bidirectional interaction by this cytokine ŽBanks et al., 1989.. Both indirect and direct mechanisms, by which these cytokines effect the release of norepinephrine ŽNE. and its metabolites in the hypothalamus, have been impli-
)
Corresponding author. Tel.rfax: q1 301 5306594.
cated ŽDunn, 1988; Kabiersch et al., 1988; Rivier et al., 1989; Mefford and Heyes, 1990.. However there remains a controversy about the exact mechanisms by which these central effects of IL-1 are mediated and how IL-1 accesses the brain. It has been suggested that a part of its central actions is a result of a direct effect of IL-1 on the hypothalamus either after having traversed the organum vasculosum laminae terminalis Ža blood brain deficient site. ŽBanks et al., 1989, 1991; Katsuura et al., 1990. or by release of endogenous IL-1. However given that IL-1 is a 17.5 kDa protein, it is considered unlikely that it can cross the blood-brain barrier in any appreciable amounts. Thus, the exact mechanism of action of IL-1 in the central nervous system ŽCNS. causing the release of NE is unknown despite in vivo studies ŽSmagin et al., 1996.. To explore whether this effect of IL-1 is by direct central action, experiments were performed in which IL-1 a or vehicle was given either systemically Žintraperitoneal injection. or centrally Žvia a cannula. to four groups of male Sprague Dawley rats. Microdialysis, followed by high performance liquid chromatography ŽHPLC. of the dialysate was used to measure the extracellular NE from the medial hypothalamus. Both IL-1 a ŽMefford and Heyes, 1990. and IL-1 b ŽDunn, 1988, Rivier et al., 1989. have
0165-5728r98r$ - see front matter q 1998 Published by Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 5 7 2 8 Ž 9 8 . 0 0 0 6 2 - 9
D. Kaur et al.r Journal of Neuroimmunology 90 (1998) 122–127
been shown to increase hypothalamic catecholamine turnover whether given via an intra-cerebroventricular or peripheral Žip or iv. route. We used IL-1 a instead of IL-1 b , because of our prior experience with it in this laboratory ŽMefford and Heyes, 1990.. Although IL-1 a and IL-1 b have a low homology ŽMarch et al., 1985. their biological functions are similar Žfor review see Dower et al., 1986; Dunn, 1992; Dinarello, 1994.. The main differences are that compared to IL-1 b , larger doses of IL-1 a Ž100 fold. are necessary to cause the same biological effect and that IL-1 a uses the more ubiquitous type I receptor ŽIL-1RI. while IL-1 b uses the type 2 receptor ŽIL-1RII. as well, for its actions ŽLuheshi et al., 1993; Dinarello, 1994.. However, the main signal transducer for both the interleukins is IL-1RI Žfor review see Dinarello, 1994.. We have therefore referenced experiments using IL-1 b and extrapolated some of its actions to IL-1 a .
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basal NE release. Basal NE values were taken as the average NE concentration of three consecutive samples collected 1 h 40 min after insertion of the probe and 1 h Ž60 min. immediately prior to challenge with IL-1 a . Two ml of human recombinant IL-1 a ŽhrIL-1 a R & D Systems Minneapolis, MN. at a concentration of 100 ngrml in ACSF, was infused through the cannula at a rate of 0.1 mlrmin over a 20 min period using a BAS infusion pump ŽBioanalytical Systems, IN.. Because of its large molecular weight IL-1 a was infused through the cannula instead of the microdialysis membrane to ensure its delivery to the hypothalamus. Intraperitoneal Žip. IL-1 a was given at a dose of 2 m granimal. Twenty minute samples were collected for three h after treatment with IL-1 a or vehicle for a total of 15 samples per animal. NE concentrations obtained from the post-treatment infusion samples included those in the samples obtained during the infusion of IL-1 a . 2.2. High performance liquid chromatography
2. Materials and methods 2.1. Microdialysis Male Sprague Dawley rats ŽTaconic Farms. weighing 230–350 g were housed at the NIH Animal Housing Facility, given water and food provided ad libitum and maintained on a 12:12 h light:dark cycle. Rats were anesthetized with 8% chloral hydrate in normal saline Ž450 mgrkg. with an initial dose of 0.6 mlr100 g given intraperitoneally and anaesthesia was maintained with periodic subcutaneous injections of 0.4 ml of the same chloral hydrate. Animals were then placed in a stereotaxic small animal instrument ŽDavid Kopf Instruments. and a burr hole was drilled into the skull at the appropriate stereotaxic location for the medial hypothalamus. A specially constructed microdialysis probe ŽCarnegie Medicine. with 3 mm membrane tip, ŽBioanalytical SystemsrCarnegie Medicine, West Lafayette, IN. with an adjacent cannula was then placed into the medial hypothala-mus using the following coordinates with bregma as reference: anteroposterior—3.3 mm, lateral—1.0 mm, vertical—9.6 mm ŽPaxinos and Watson, 1986.. IL-1 a was prepared in sterile-filtered phosphate-buffered saline ŽPBS. containing 0.1% bovine albumin ŽBSA., aliquotted in 1 ml volumes Žconcentration of 2 m grml. and kept frozen at y708C until used. For perfusion of IL-1 a the aliquots were further diluted to a concentration of 100 ngrml in artificial cerebrospinal fluid. Artificial cerebrospinal fluid ŽACSF.: 1.2 mM CaCl 2 , 120 mM MgCl 2 , 3.0 mM KCL, 120 mM NaCl, 3.0 mM sodium phosphate, ŽpH adjusted to 7.4., was perfused through the probe at a flow rate of 2 m lrmin after which 20 minute samples Ž40 m l. were collected in 40 m l of perchloric acid ŽHCLO4 . and immediately frozen until analysis for norepinephrine ŽNE.. The first three samples were not analyzed, but 2 h of sample collections prior to challenge were retained for analysis to establish
The dialysate was analyzed using HPLC with amperometric detection and samples were analyzed for norepinephrine. Separation was achieved using a 10 cm Spherisorb ODS2 column; ID 4.6rmm ŽThomson, Instrument, Springfield, VA.. The mobile phase consisted of 30 gm of sodium monophosphate ŽNaH 2 PO4 ., 100 mgrl EDTA, 100 mgrl of sodium dodcyel sulphate ŽSigma, St. Louis, MO. and 10% methanol. Detection was achieved using a glassy carbon electrode ŽTL-8A, Bioanalytical Systems, West Lafayette, IN. at q0.65 V vs. a AgrAgCl reference electrode. Standard solutions of NE were run on HPLC before and after sample runs. The averaged basal and post-treatment values were expressed as fmolr20 min collection. Post-treatment values were expressed as percent change relative to the basal values. Randomly selected animals were decapitated, and the brains removed and fixed in formalin. The brain was sectioned to locate the cannula track to confirm proper cannula placement. The NE content was calculated for a total of 15 twenty minute collection fractions. Basal values for each animal were defined as the average from 3 twenty minute fractions taken immediately before treatment and designated as zero time ŽT0 .. Further twenty minute collection fractions were assigned as T20 to T180 . Because of the large inter-animal variability in basal NE values, the latter were expressed as the percentage change relative to the basal value for each time point after IL-1 a or vehicle administration. The Scheffe’s ˆ test was applied to data using a one-way analysis of variance ŽANOVA. using StatView 4.0 ŽAbacus Concepts, Berkeley, CA..
3. Results IL-1 a did not affect extracellular NE when infused directly into the rat medial hypothalamus but produced an
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Fig. 1. Mean percentage change "SEM of intracellular hypothalamic norepinephrine release following IL-1 alpha or vehicle administered intraperitoneally Žip. or directly into the hypothalamus Žic..
increase when given intraperitoneally over values observed in rats administered vehicle by either route or IL-1 a intracerebrally Žic. ŽFig. 1.. This increase occurred in the first 60 min after intra-peritoneal injection of IL-1 a with a second smaller peak at 120 min and a gradual return to baseline values by approximately 180 min ŽFig. 1.. Because the major effect is within the first 60 min we decided to focus on the time period T20 to T60 . The average basal value of all groups Žboth treatment and control. was 453.8 " 55.7 fmol Ž n s 25. and the significant increase in NE observed in the intraperitoneal Žip. IL-1 a treated group reflected a post treatment value of 957.4 " 175.0 fmol Ž n s 6. at T60 . This reflected a percentage increase of approximately 110%. Both normalized and absolute percentage differences values for all time points were subjected to ANOVA comparing the two treatment groups and their controls, followed by Scheffe’s ˆ test. Significant P-Values ŽScheffe’s ˆ test. were only seen in the IL-1 a ip treated group of animals compared to other groups ŽVehicle ip, Vehicle ic and IL-1 a ic. for time points T20 , T40 and T60 . P-values ŽScheffe’s ˆ test. for comparisons of absolute percentage change ranged from
0.0008-0.0191 for the same time period ŽT60 .. The maximal increase in NE was during the 60 min ŽT60 . period. There were no significant differences for any of the following group comparisons: ŽVehicle icrIL-1 a ic; Vehicle icrVehicle ip; IL-1 a icrVehicle ip. for any of the time points ŽT20 , T40 and T60 ..
4. Discussion We found that IL-1 a produced an increase in extracellular hypothalamic NE when administered intraperitoneally but not when it was infused intracerebrally directly into the hypothalamus at a dose of 100 ngrml. This dose, which is in excess of what is accepted as bio-logically active in the central nervous system, was chosen because prior trials with IL-1 a at doses of 1 ngrml and 10 ngrml did not elicit an effect on direct perfusion Žunpublished data.. This finding is consistent with previous reports showing that peripherally delivered IL-a produced increased central catecholamine turnover in the central nervous system
D. Kaur et al.r Journal of Neuroimmunology 90 (1998) 122–127
ŽDunn, 1988; Kabiersch et al., 1988; Mefford and Heyes, 1990.. Our findings argue against the possibility that, this increased catecholamine turnover is a consequence of a direct action of IL-1 a in the hypothalamus. Despite the fact that large immunologically active molecules cannot readily access the brain under normal conditions, there is evidence that the blood brain barrier ŽBBB. deficient areas, such as the organum vasculosum laminae terminalis ŽOVLT., allow large molecules like IL-1 the opportunity to enter the brain ŽKatsuura et al., 1990; Banks et al., 1991.. Furthermore, Banks et al. Ž1991. demonstrated that small amounts Ž0.06% to 0.08% of the total intravenous dose. of radiolabelled IL-1 a and IL-1 b were able to access the brain in mouse via a saturable mechanism without disruption to the blood–brain barrier. It is uncertain, however, if this small an amount is sufficient to activate the HPA. The findings of Hashimoto et al. Ž1991., demonstrate that IL-1 b could be internalized by the BBB endothelial cells, suggesting that cytokines can transported across the BBB by endocytosis. In addition, in an inflammatory response, a secondary disruption of the BBB can occur allowing the production of IL-1 a , IL-1 b and TNFa which initiate further interactions with the brain ŽDantzer, 1994; Fabry et al., 1994.. Centrally, IL-1 induces astrocytes and microglia to release endogenous IL-1 ŽCoceani et al., 1988.. Peripheral effects of IL-1 include activation of the sympathetic system in the spleen, liver and diaphragm thus effecting increased NE release centrally and peripherally. Whether these cytokines of central or peripheral origin, act separately or in concert, is unclear but the consequent central effects are an increased release of CRH, prostaglandins ŽPGD 2 and PGE 2 . ŽStitt, 1986; Terao et al., 1995. and NE. One possibility suggested by Terao et al. Ž1995. is that prostaglandins PGD 2 and PGE 2 mediate the action of intraperitoneally administered IL-1 with PGD 2 acting directly on the hypothalamus and PGE 2 enhancing IL-1’s effects by increasing sympathetic activity in the spleen. Sakata et al. Ž1994. found that neither ICV injection of IL-1 b nor intra-hypothalamic injection of PGE 2 failed to produce an increase in plasma NE increase supporting the view that systemically delivered IL-1 b acts through peripherally induced prostaglandins to cause increased plasma catecholamine turnover. In the same experiments increased plasma NE and epinephrine induced by intravenous LPS were blocked by pre-treatment with indomethacin suggesting that prostaglandins were essential to increased catecholamine turnover. Furthermore ŽKomaki et al., 1992. found raised PGE 2 in some brain areas including the OVLT, in response to intravenous injection of IL-1 b . This again suggests that the central effects of IL-1 b are at least in part mediated through prostaglandin release. Evidence for IL- a and IL-1 b mediated prostaglandin release and subsequent noradrenergic activation also emerges from studies in culture systems. Katsuura et al. Ž1989. demonstrated that although the effect of IL-1 a was 100-fold less
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effective, both IL-1 b and IL-1 a caused an increased release prostaglandin PGE 2 in cultured rat astrocytes. In addition, CRH has also been implicated in the mediation of IL-1’s effects centrally ŽBerkenbosch et al., 1987; Sapolsky et al., 1987; Uehara et al., 1987; for review see Rivier, 1995.. Besides its role as mediator of ACTH release and subsequent corticosterone release, CRH also has been shown to activate the central noradrenergic neurons. Valentino et al. Ž1983. demonstrated that application of CRF to the locus corereus ŽLC. neurons increased firing rates of the LC neurons suggesting noradrenergic activation. Emoto et al. Ž1993. also found an increase in 3m ethoxy-4-hydoxy-phenylethyleneglycol sulphate ŽMHPG-SO4; a major metabolite of NA. in several brain regions Žhypothalamus, amygdala, LC, medulla obloggata q pons. on ICV injection of CRF, thereby supporting CRFs function as a noradrenergic activator. Interleukin-1 is also involved in increasing nociceptive threshold in rats and the effect is mediated by the noradrenergic neurons and CRF. It has been shown that this effect is blocked completely when the animals are pretreated with 6-OHDA Žto deplete the catecholaminergic neurons., prazosin Žan a 1-adrenorecptor antagonist. and CRF antagonist, a-helical CRH-41, suggesting that both IL-1 a and CRF are capable of activating the noradrenergic system in the rat brain ŽBianchi and Panerai, 1995.. Intraventricular injections of IL-1 have been shown to increase NE turnover in the hypothala-mus and spleen which has remained resistant to intraperitoneal indomethacin Ža cyclooxyengase inhibitor., suggesting that the NE release in these organs is CRHmediated ŽTerao et al., 1993.. Contemporary experiments also show that pretreatment with antiserum to CRH can attenuate the IL-1-stimulated hypothalamic NE release ŽTerao et al., 1993., thereby, strengthening the role of CRH in mediating HPA activation. The results described in our study do not support a theory of direct action of IL-1 on the HPA and contrast those of Shintani et al. Ž1993.. The differences in technique between Shintani’s study and ours include the location of infusion Žanterior hypothalamus compared to medial hypothalamus., type of IL-1 used ŽIL-1 b versus IL-1 a ., dosage of IL-1 Ž0.1 nM versus 0.2 ng w2 m l of IL-1 @100 ngrmlx. and mode of delivery microinjection vs. slow infusion. may account for the outcome. Terrazzino et al. Ž1995. found an increase in NE release in the paraventricular nucleus of the hypothalamus on intracerebroventricular ŽICV. injection of IL-1 b Ž10 ng in 5m l. paralleling an adrenocorticotrophin response with peaks at 20 min and again at 140 min. The time course for increased NE release in their experiments approximates NE increases in our experiments Žsee Fig. 1., but only for the intraperitoneally Žip. injected IL-in our case. We did not observe any NE increase on intracerebral delivery. We are unable to explain this discrepancy, but whether an ICV route as opposed to a direct injection into the hypothalamus allows for sufficient time for induction and interac-
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tions of other hypothalamic intermediates such as CRF, prostaglandins, and endogenous IL-1 ŽFontana et al., 1982. Žsubstances which appear to be intimately involved in HPA activation., has to be considered. The question whether our use of IL-1 a as opposed to the more potent IL-1 b could somehow have contributed to our failure to induce NE release has been addressed in the introduction. There are reports suggesting differences between the actions of IL-1 a and IL-1 b centrally in the induction of thermogenesis and fever and that IL-1 a does not act through CRF to mediate ACTH release ŽBusbridge et al., 1989. but there is evidence to the contrary, demonstrating that IL-1 a is capable of CRF release in vitro from incubated hypothalami although the required molar concentration for IL-1 a is higher than IL-1 b ŽTsagarakis et al., 1989.. Therefore, it appears that one of the many effects of IL-1 is the production of itself, and a cascade of other cytokines and hormones among which are PGD 2 , PGE 2 and CRF in the brain, particularly in the HPA. The consequent increase in catecholamine turnover is in part facilitated by these intermediate products. The fact that antagonism of both prostaglandins and CRH can decreaserattenuate the noradrenergic effects of interleukin-1 suggests that these intermediate products and pathways are important for IL-1 to effect central NE release. Peripherally delivered IL-1 or other challenges such as stress or infectious agents probably serve as messengers for the initiation of crosstalk between the peripheral and CNS immune systems and perhaps endogenous IL-1 is the first essential step in this chain of events. 5. Unlinked reference Paxinos and Watson, 1986, Dunn, 1992 References Banks, W.A., Kastin, A.J., Durham, D.A., 1989. Bidirectional transport of interleukin-1 alpha across the blood-brain barrier. Brain Res. Bull. 23 Ž6., 433–437. Banks, W.A., Ortiz, L., Plotkin, S.R., Kastin, A.J., 1991. Human interleukin ŽIL. 1 a , murine IL-1 a nd murine IL-1 b are transported from blood to brain in mouse by a shared saturable mechanism. J. Pharmacol. Exp. Ther. 259 Ž3., 988–996. Berkenbosch, F., van Oers, J., del Rey, A., Tilders, F., Besedovsky, H., 1987. Corticotrophin-releasing factor-producing neurons in rat activated by interleukin-1. Science 238, 524–526. Bianchi, M., Panerai, A.E., 1995. CRH and the noradrenergic system mediate nociceptive effect of central interleukin-1a in the rat. Brain Res. Bull. 36 Ž1., 113–117. Blatteis, C.M., 1988. Neural mechanisms in pyrogenic and acute-phase responses to interleukin-1. Intern. J. Neurosci. 38, 223–232. Busbridge, N.J., Dascombe, M.J., Tilders, F.J.H., van Oers, J.W.A.M., Linton, E.A., Rothwell, N.J., 1989. Central activation of thermogenesis and fever by interleukin-1 b and interleukin-1 a involves different mechanisms. Biochem. Biophys. Res. Commun. 162 Ž2., 591–596.
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Effect of IL-1 a on the release of norepinephrine in rat hypothalamus Daljit Kaur a
a,)
, David F. Cruess b, William Z. Potter
c
Section on Clinical Pharmacology, Experimental Therapeutics Branch, NIMH, National Institute of Health, Bethesda, MD 20892, USA b DiÕision of Public Health and Biometrics, Uniformed SerÕices UniÕersity of Health Sciences, Bethesda, MD 20892, USA c A DiÕision of Elly Lilly and, Lilly Corporate Center, Indianopolis, IN 46285, USA Received 25 April 1997; revised 25 February 1998; accepted 26 February 1998
Abstract The increased release of norepinephrine ŽNE. in the brain as part of the ‘acute phase response’ has been postulated to result from a direct action of IL-1 on the hypothalamus. To test whether the effects of IL-1 a were direct, we carried out in vivo experiments using microdialysis and measured NE release in the hypothalamus using high pressure liquid chromatography ŽHPLC.. Two groups of male Sprague Dawley rats were either injected intraperitoneally with 1 ml of IL-1 a Ž2 m grml. or had IL-1 a 2 m l Ž100 ngrml. infused directly into the medial hypothalamus. A significant increase in extracellular hypothalamic NE was observed in the animal group treated with IL-1 a intraperitoneally and not in the controls or the group treated with IL-1 a intracerebrally. One-way ANOVA showed a significant effect of drug and route of administration with the ip IL-1 a treated group, differing from all other groups Žvehicle ip, IL-1 a ic, and vehicle ic.. Therefore these findings suggest that some aspects of IL-1 a actions on the HPA may be indirect requiring other intermediate steps or mediators outside the central nervous system. q 1998 Published by Elsevier Science B.V. All rights reserved. Keywords: Hypothalamus; HPLC; Norepinephrine; Rat
1. Introduction: The ‘acute phase response’ is an inflammatory as well as an immunological response mounted by an animal when exposed to infection and stress Žfor review see Dinarello, 1984, pp 57–59; and Blatteis, 1988.. A further extension of the ‘acute phase response’ include the release of cytokines such as Žinterleukin-1. IL-1, interleukin-6 ŽIL-6. and tumour necrosis factor a ŽTNFa . as well as neurohormones such as corticotrophin-releasing hormone ŽCRF., corticosteroids Žfor review see Sapolsky et al., 1987; Rivier and Rivest, 1993 pp. 205–208. and norepinephrine ŽDunn, 1988; Mefford and Heyes, 1990.. The actions of systemically delivered IL-1 on the central nervous system are known and intra-cerebroventricular delivery of IL-1 a and IL-1 b have systemic effects ŽDunn, 1988. confirming a bidirectional interaction by this cytokine ŽBanks et al., 1989.. Both indirect and direct mechanisms, by which these cytokines effect the release of norepinephrine ŽNE. and its metabolites in the hypothalamus, have been impli-
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Corresponding author. Tel.rfax: q1 301 5306594.
cated ŽDunn, 1988; Kabiersch et al., 1988; Rivier et al., 1989; Mefford and Heyes, 1990.. However there remains a controversy about the exact mechanisms by which these central effects of IL-1 are mediated and how IL-1 accesses the brain. It has been suggested that a part of its central actions is a result of a direct effect of IL-1 on the hypothalamus either after having traversed the organum vasculosum laminae terminalis Ža blood brain deficient site. ŽBanks et al., 1989, 1991; Katsuura et al., 1990. or by release of endogenous IL-1. However given that IL-1 is a 17.5 kDa protein, it is considered unlikely that it can cross the blood-brain barrier in any appreciable amounts. Thus, the exact mechanism of action of IL-1 in the central nervous system ŽCNS. causing the release of NE is unknown despite in vivo studies ŽSmagin et al., 1996.. To explore whether this effect of IL-1 is by direct central action, experiments were performed in which IL-1 a or vehicle was given either systemically Žintraperitoneal injection. or centrally Žvia a cannula. to four groups of male Sprague Dawley rats. Microdialysis, followed by high performance liquid chromatography ŽHPLC. of the dialysate was used to measure the extracellular NE from the medial hypothalamus. Both IL-1 a ŽMefford and Heyes, 1990. and IL-1 b ŽDunn, 1988, Rivier et al., 1989. have
0165-5728r98r$ - see front matter q 1998 Published by Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 5 7 2 8 Ž 9 8 . 0 0 0 6 2 - 9
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been shown to increase hypothalamic catecholamine turnover whether given via an intra-cerebroventricular or peripheral Žip or iv. route. We used IL-1 a instead of IL-1 b , because of our prior experience with it in this laboratory ŽMefford and Heyes, 1990.. Although IL-1 a and IL-1 b have a low homology ŽMarch et al., 1985. their biological functions are similar Žfor review see Dower et al., 1986; Dunn, 1992; Dinarello, 1994.. The main differences are that compared to IL-1 b , larger doses of IL-1 a Ž100 fold. are necessary to cause the same biological effect and that IL-1 a uses the more ubiquitous type I receptor ŽIL-1RI. while IL-1 b uses the type 2 receptor ŽIL-1RII. as well, for its actions ŽLuheshi et al., 1993; Dinarello, 1994.. However, the main signal transducer for both the interleukins is IL-1RI Žfor review see Dinarello, 1994.. We have therefore referenced experiments using IL-1 b and extrapolated some of its actions to IL-1 a .
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basal NE release. Basal NE values were taken as the average NE concentration of three consecutive samples collected 1 h 40 min after insertion of the probe and 1 h Ž60 min. immediately prior to challenge with IL-1 a . Two ml of human recombinant IL-1 a ŽhrIL-1 a R & D Systems Minneapolis, MN. at a concentration of 100 ngrml in ACSF, was infused through the cannula at a rate of 0.1 mlrmin over a 20 min period using a BAS infusion pump ŽBioanalytical Systems, IN.. Because of its large molecular weight IL-1 a was infused through the cannula instead of the microdialysis membrane to ensure its delivery to the hypothalamus. Intraperitoneal Žip. IL-1 a was given at a dose of 2 m granimal. Twenty minute samples were collected for three h after treatment with IL-1 a or vehicle for a total of 15 samples per animal. NE concentrations obtained from the post-treatment infusion samples included those in the samples obtained during the infusion of IL-1 a . 2.2. High performance liquid chromatography
2. Materials and methods 2.1. Microdialysis Male Sprague Dawley rats ŽTaconic Farms. weighing 230–350 g were housed at the NIH Animal Housing Facility, given water and food provided ad libitum and maintained on a 12:12 h light:dark cycle. Rats were anesthetized with 8% chloral hydrate in normal saline Ž450 mgrkg. with an initial dose of 0.6 mlr100 g given intraperitoneally and anaesthesia was maintained with periodic subcutaneous injections of 0.4 ml of the same chloral hydrate. Animals were then placed in a stereotaxic small animal instrument ŽDavid Kopf Instruments. and a burr hole was drilled into the skull at the appropriate stereotaxic location for the medial hypothalamus. A specially constructed microdialysis probe ŽCarnegie Medicine. with 3 mm membrane tip, ŽBioanalytical SystemsrCarnegie Medicine, West Lafayette, IN. with an adjacent cannula was then placed into the medial hypothala-mus using the following coordinates with bregma as reference: anteroposterior—3.3 mm, lateral—1.0 mm, vertical—9.6 mm ŽPaxinos and Watson, 1986.. IL-1 a was prepared in sterile-filtered phosphate-buffered saline ŽPBS. containing 0.1% bovine albumin ŽBSA., aliquotted in 1 ml volumes Žconcentration of 2 m grml. and kept frozen at y708C until used. For perfusion of IL-1 a the aliquots were further diluted to a concentration of 100 ngrml in artificial cerebrospinal fluid. Artificial cerebrospinal fluid ŽACSF.: 1.2 mM CaCl 2 , 120 mM MgCl 2 , 3.0 mM KCL, 120 mM NaCl, 3.0 mM sodium phosphate, ŽpH adjusted to 7.4., was perfused through the probe at a flow rate of 2 m lrmin after which 20 minute samples Ž40 m l. were collected in 40 m l of perchloric acid ŽHCLO4 . and immediately frozen until analysis for norepinephrine ŽNE.. The first three samples were not analyzed, but 2 h of sample collections prior to challenge were retained for analysis to establish
The dialysate was analyzed using HPLC with amperometric detection and samples were analyzed for norepinephrine. Separation was achieved using a 10 cm Spherisorb ODS2 column; ID 4.6rmm ŽThomson, Instrument, Springfield, VA.. The mobile phase consisted of 30 gm of sodium monophosphate ŽNaH 2 PO4 ., 100 mgrl EDTA, 100 mgrl of sodium dodcyel sulphate ŽSigma, St. Louis, MO. and 10% methanol. Detection was achieved using a glassy carbon electrode ŽTL-8A, Bioanalytical Systems, West Lafayette, IN. at q0.65 V vs. a AgrAgCl reference electrode. Standard solutions of NE were run on HPLC before and after sample runs. The averaged basal and post-treatment values were expressed as fmolr20 min collection. Post-treatment values were expressed as percent change relative to the basal values. Randomly selected animals were decapitated, and the brains removed and fixed in formalin. The brain was sectioned to locate the cannula track to confirm proper cannula placement. The NE content was calculated for a total of 15 twenty minute collection fractions. Basal values for each animal were defined as the average from 3 twenty minute fractions taken immediately before treatment and designated as zero time ŽT0 .. Further twenty minute collection fractions were assigned as T20 to T180 . Because of the large inter-animal variability in basal NE values, the latter were expressed as the percentage change relative to the basal value for each time point after IL-1 a or vehicle administration. The Scheffe’s ˆ test was applied to data using a one-way analysis of variance ŽANOVA. using StatView 4.0 ŽAbacus Concepts, Berkeley, CA..
3. Results IL-1 a did not affect extracellular NE when infused directly into the rat medial hypothalamus but produced an
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Fig. 1. Mean percentage change "SEM of intracellular hypothalamic norepinephrine release following IL-1 alpha or vehicle administered intraperitoneally Žip. or directly into the hypothalamus Žic..
increase when given intraperitoneally over values observed in rats administered vehicle by either route or IL-1 a intracerebrally Žic. ŽFig. 1.. This increase occurred in the first 60 min after intra-peritoneal injection of IL-1 a with a second smaller peak at 120 min and a gradual return to baseline values by approximately 180 min ŽFig. 1.. Because the major effect is within the first 60 min we decided to focus on the time period T20 to T60 . The average basal value of all groups Žboth treatment and control. was 453.8 " 55.7 fmol Ž n s 25. and the significant increase in NE observed in the intraperitoneal Žip. IL-1 a treated group reflected a post treatment value of 957.4 " 175.0 fmol Ž n s 6. at T60 . This reflected a percentage increase of approximately 110%. Both normalized and absolute percentage differences values for all time points were subjected to ANOVA comparing the two treatment groups and their controls, followed by Scheffe’s ˆ test. Significant P-Values ŽScheffe’s ˆ test. were only seen in the IL-1 a ip treated group of animals compared to other groups ŽVehicle ip, Vehicle ic and IL-1 a ic. for time points T20 , T40 and T60 . P-values ŽScheffe’s ˆ test. for comparisons of absolute percentage change ranged from
0.0008-0.0191 for the same time period ŽT60 .. The maximal increase in NE was during the 60 min ŽT60 . period. There were no significant differences for any of the following group comparisons: ŽVehicle icrIL-1 a ic; Vehicle icrVehicle ip; IL-1 a icrVehicle ip. for any of the time points ŽT20 , T40 and T60 ..
4. Discussion We found that IL-1 a produced an increase in extracellular hypothalamic NE when administered intraperitoneally but not when it was infused intracerebrally directly into the hypothalamus at a dose of 100 ngrml. This dose, which is in excess of what is accepted as bio-logically active in the central nervous system, was chosen because prior trials with IL-1 a at doses of 1 ngrml and 10 ngrml did not elicit an effect on direct perfusion Žunpublished data.. This finding is consistent with previous reports showing that peripherally delivered IL-a produced increased central catecholamine turnover in the central nervous system
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ŽDunn, 1988; Kabiersch et al., 1988; Mefford and Heyes, 1990.. Our findings argue against the possibility that, this increased catecholamine turnover is a consequence of a direct action of IL-1 a in the hypothalamus. Despite the fact that large immunologically active molecules cannot readily access the brain under normal conditions, there is evidence that the blood brain barrier ŽBBB. deficient areas, such as the organum vasculosum laminae terminalis ŽOVLT., allow large molecules like IL-1 the opportunity to enter the brain ŽKatsuura et al., 1990; Banks et al., 1991.. Furthermore, Banks et al. Ž1991. demonstrated that small amounts Ž0.06% to 0.08% of the total intravenous dose. of radiolabelled IL-1 a and IL-1 b were able to access the brain in mouse via a saturable mechanism without disruption to the blood–brain barrier. It is uncertain, however, if this small an amount is sufficient to activate the HPA. The findings of Hashimoto et al. Ž1991., demonstrate that IL-1 b could be internalized by the BBB endothelial cells, suggesting that cytokines can transported across the BBB by endocytosis. In addition, in an inflammatory response, a secondary disruption of the BBB can occur allowing the production of IL-1 a , IL-1 b and TNFa which initiate further interactions with the brain ŽDantzer, 1994; Fabry et al., 1994.. Centrally, IL-1 induces astrocytes and microglia to release endogenous IL-1 ŽCoceani et al., 1988.. Peripheral effects of IL-1 include activation of the sympathetic system in the spleen, liver and diaphragm thus effecting increased NE release centrally and peripherally. Whether these cytokines of central or peripheral origin, act separately or in concert, is unclear but the consequent central effects are an increased release of CRH, prostaglandins ŽPGD 2 and PGE 2 . ŽStitt, 1986; Terao et al., 1995. and NE. One possibility suggested by Terao et al. Ž1995. is that prostaglandins PGD 2 and PGE 2 mediate the action of intraperitoneally administered IL-1 with PGD 2 acting directly on the hypothalamus and PGE 2 enhancing IL-1’s effects by increasing sympathetic activity in the spleen. Sakata et al. Ž1994. found that neither ICV injection of IL-1 b nor intra-hypothalamic injection of PGE 2 failed to produce an increase in plasma NE increase supporting the view that systemically delivered IL-1 b acts through peripherally induced prostaglandins to cause increased plasma catecholamine turnover. In the same experiments increased plasma NE and epinephrine induced by intravenous LPS were blocked by pre-treatment with indomethacin suggesting that prostaglandins were essential to increased catecholamine turnover. Furthermore ŽKomaki et al., 1992. found raised PGE 2 in some brain areas including the OVLT, in response to intravenous injection of IL-1 b . This again suggests that the central effects of IL-1 b are at least in part mediated through prostaglandin release. Evidence for IL- a and IL-1 b mediated prostaglandin release and subsequent noradrenergic activation also emerges from studies in culture systems. Katsuura et al. Ž1989. demonstrated that although the effect of IL-1 a was 100-fold less
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effective, both IL-1 b and IL-1 a caused an increased release prostaglandin PGE 2 in cultured rat astrocytes. In addition, CRH has also been implicated in the mediation of IL-1’s effects centrally ŽBerkenbosch et al., 1987; Sapolsky et al., 1987; Uehara et al., 1987; for review see Rivier, 1995.. Besides its role as mediator of ACTH release and subsequent corticosterone release, CRH also has been shown to activate the central noradrenergic neurons. Valentino et al. Ž1983. demonstrated that application of CRF to the locus corereus ŽLC. neurons increased firing rates of the LC neurons suggesting noradrenergic activation. Emoto et al. Ž1993. also found an increase in 3m ethoxy-4-hydoxy-phenylethyleneglycol sulphate ŽMHPG-SO4; a major metabolite of NA. in several brain regions Žhypothalamus, amygdala, LC, medulla obloggata q pons. on ICV injection of CRF, thereby supporting CRFs function as a noradrenergic activator. Interleukin-1 is also involved in increasing nociceptive threshold in rats and the effect is mediated by the noradrenergic neurons and CRF. It has been shown that this effect is blocked completely when the animals are pretreated with 6-OHDA Žto deplete the catecholaminergic neurons., prazosin Žan a 1-adrenorecptor antagonist. and CRF antagonist, a-helical CRH-41, suggesting that both IL-1 a and CRF are capable of activating the noradrenergic system in the rat brain ŽBianchi and Panerai, 1995.. Intraventricular injections of IL-1 have been shown to increase NE turnover in the hypothala-mus and spleen which has remained resistant to intraperitoneal indomethacin Ža cyclooxyengase inhibitor., suggesting that the NE release in these organs is CRHmediated ŽTerao et al., 1993.. Contemporary experiments also show that pretreatment with antiserum to CRH can attenuate the IL-1-stimulated hypothalamic NE release ŽTerao et al., 1993., thereby, strengthening the role of CRH in mediating HPA activation. The results described in our study do not support a theory of direct action of IL-1 on the HPA and contrast those of Shintani et al. Ž1993.. The differences in technique between Shintani’s study and ours include the location of infusion Žanterior hypothalamus compared to medial hypothalamus., type of IL-1 used ŽIL-1 b versus IL-1 a ., dosage of IL-1 Ž0.1 nM versus 0.2 ng w2 m l of IL-1 @100 ngrmlx. and mode of delivery microinjection vs. slow infusion. may account for the outcome. Terrazzino et al. Ž1995. found an increase in NE release in the paraventricular nucleus of the hypothalamus on intracerebroventricular ŽICV. injection of IL-1 b Ž10 ng in 5m l. paralleling an adrenocorticotrophin response with peaks at 20 min and again at 140 min. The time course for increased NE release in their experiments approximates NE increases in our experiments Žsee Fig. 1., but only for the intraperitoneally Žip. injected IL-in our case. We did not observe any NE increase on intracerebral delivery. We are unable to explain this discrepancy, but whether an ICV route as opposed to a direct injection into the hypothalamus allows for sufficient time for induction and interac-
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tions of other hypothalamic intermediates such as CRF, prostaglandins, and endogenous IL-1 ŽFontana et al., 1982. Žsubstances which appear to be intimately involved in HPA activation., has to be considered. The question whether our use of IL-1 a as opposed to the more potent IL-1 b could somehow have contributed to our failure to induce NE release has been addressed in the introduction. There are reports suggesting differences between the actions of IL-1 a and IL-1 b centrally in the induction of thermogenesis and fever and that IL-1 a does not act through CRF to mediate ACTH release ŽBusbridge et al., 1989. but there is evidence to the contrary, demonstrating that IL-1 a is capable of CRF release in vitro from incubated hypothalami although the required molar concentration for IL-1 a is higher than IL-1 b ŽTsagarakis et al., 1989.. Therefore, it appears that one of the many effects of IL-1 is the production of itself, and a cascade of other cytokines and hormones among which are PGD 2 , PGE 2 and CRF in the brain, particularly in the HPA. The consequent increase in catecholamine turnover is in part facilitated by these intermediate products. The fact that antagonism of both prostaglandins and CRH can decreaserattenuate the noradrenergic effects of interleukin-1 suggests that these intermediate products and pathways are important for IL-1 to effect central NE release. Peripherally delivered IL-1 or other challenges such as stress or infectious agents probably serve as messengers for the initiation of crosstalk between the peripheral and CNS immune systems and perhaps endogenous IL-1 is the first essential step in this chain of events. 5. Unlinked reference Paxinos and Watson, 1986, Dunn, 1992 References Banks, W.A., Kastin, A.J., Durham, D.A., 1989. Bidirectional transport of interleukin-1 alpha across the blood-brain barrier. Brain Res. Bull. 23 Ž6., 433–437. Banks, W.A., Ortiz, L., Plotkin, S.R., Kastin, A.J., 1991. Human interleukin ŽIL. 1 a , murine IL-1 a nd murine IL-1 b are transported from blood to brain in mouse by a shared saturable mechanism. J. Pharmacol. Exp. Ther. 259 Ž3., 988–996. Berkenbosch, F., van Oers, J., del Rey, A., Tilders, F., Besedovsky, H., 1987. Corticotrophin-releasing factor-producing neurons in rat activated by interleukin-1. Science 238, 524–526. Bianchi, M., Panerai, A.E., 1995. CRH and the noradrenergic system mediate nociceptive effect of central interleukin-1a in the rat. Brain Res. Bull. 36 Ž1., 113–117. Blatteis, C.M., 1988. Neural mechanisms in pyrogenic and acute-phase responses to interleukin-1. Intern. J. Neurosci. 38, 223–232. Busbridge, N.J., Dascombe, M.J., Tilders, F.J.H., van Oers, J.W.A.M., Linton, E.A., Rothwell, N.J., 1989. Central activation of thermogenesis and fever by interleukin-1 b and interleukin-1 a involves different mechanisms. Biochem. Biophys. Res. Commun. 162 Ž2., 591–596.
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