Brain endothelial cell production of a neuroprotective cytokine, interleukin-6, in response to noxious stimuli

Brain endothelial cells (BECs), specialized cells of the blood–brain barrier (BBB), are ideally positioned to monitor and respond to events in the periphery. The present study examined their potential role in transducing immune signals to the brain and in responding to noxious stimuli. BECs were isolated from rhesus monkeys at 3 age points (fetal/neonatal, adult, and very old animals). Cells were then challenged in vitro with either an immune stimulus (interleukin-1β (IL-1β), or lipopolysaccharide (LPS)) or an oxidative challenge (hypoxia). BECs released interleukin-6 (IL-6), which is known to have neurotrophic and neuroprotective functions. Furthermore, higher amounts of IL-6 were released in both baseline and stimulated conditions by BECs derived from aged animals. This research indicates a pathway whereby immune signals may be communicated to the CNS and has revealed one way that the BBB may protect neuronal survival under challenge conditions.     

Different receptor mechanisms mediate the effects of endotoxin and interleukin-1 on female sexual behavior

Activation of the immune system by lipopolysaccharide (LPS) produces physiological, neuroendocrine and behavioral effects, some of which are mediated by cytokine production. We have previously shown that the cytokine interleukin-1 (IL-1) inhibits sexual behavior in female, but not male rats, while producing a comparable suppression of locomotion in both sexes. The present study examined the effects of LPS on sexual behavior and locomotion of male and female rats, and the involvement of IL-1 receptors in mediating the effects of IL-1 and LPS on females' behavior. Peripheral (i.p.) administration of LPS (50 or 250 μg/kg) significantly decreased sexual behavior in females, up to 6 h after administration, while it had no effect on male sexual behavior. However, locomotor activity, measured in the open-field test, was similarly reduced by LPS in both males and females. Pretreatment with the IL-1 receptor antagonist (IL-1ra) either i.p. (10 mg/kg) or intracerebroventricularly (i.c.v.) (50 μg/rat) did not prevent the inhibition of female sexual behavior and locomotion induced by either i.p. (50 μg/kg) or i.c.v. (200 or 400 ng/rat) administration of LPS, respectively. However, identical doses of IL-1ra significantly reversed the effects of IL-1β, administered either i.p. (5 μg/kg) or i.c.v. (50 ng/rat), respectively. These results demonstrate that both LPS and IL-1β produce marked inhibition of sexual behavior in female, but not in male rats. However, IL-1 receptors are not required for the effects of LPS on sexual behavior in female rats.     

Catecholamines and lipopolysaccharide synergistically induce the release of interleukin-6 from thymic epithelial cells

The thymus as the major site of T-cell development is exposed to circulating hormones as well as to neurotransmitters released from peripheral nerves. We investigated the influence of catecholamines on the synthesis of interleukin-1 (IL-1) and IL-6 by cultured rat thymic epithelial cells. Basal or lipopolysaccharide (LPS)-stimulated production of IL-1 was not affected by catecholamines. Release of IL-6 was stimulated only scarcely by catecholamines or tumor necrosis factor-α (TNF-α) and moderately by LPS alone. However, co-stimulation with adrenaline, noradrenaline, or the β-adrenoceptor agonist isoproterenol (isoprenaline) had an additive (TNF-α) or synergistic (LPS) effect on IL-6 release. The synergistic effect was dose-dependent on catecholamine or LPS concentrations. It was mediated by β-adrenoceptors that are linked to elevation of intracellular cAMP levels, since it was promoted by β-adrenoceptor agonists and could be blocked by β-adrenoceptor antagonists. Co-incubation of LPS with agents directly raising cAMP-levels like forskolin or dibutyryl cAMP yielded even stronger IL-6 induction. After co-stimulation IL-6 mRNA was first detected after 3–4 h and a constant increase of IL-6 bioactivity in the culture supernatant was measured for up to 48 h. Since IL-6 is an important factor for thymocyte differentiation and proliferation, the findings demonstrate an influence of neuronal or hormonal catecholamines on the thymic microenvironment that is created by thymic epithelial cells.     

Soluble interleukin-1 receptor type II levels are elevated in cerebrospinal fluid in Alzheimer's disease patients

Evidence from epidemiological, clinical and experimental studies favour the hypothesis that inflammatory events are part of the neuropathology in Alzheimer's disease. Proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) have been found in activated microglia in the vicinity of amyloid plaques in Alzheimer's disease brain. In the present study, the levels of soluble IL-1 receptor type II (sIL-1R type II), IL-1 receptor antagonist (IL-1ra), IL-1beta, IL-6 and TNF-alpha were analyzed in cerebrospinal fluid (CSF) samples from Alzheimer's disease patients and control subjects. The levels of sIL-1R type II were significantly higher in CSF from Alzheimer's disease patients than in CSF samples from control subjects (38.5+/-8 pg/ml (mean+/-S.E.M.) vs. 7.9+/-4 pg/ml, p<0.05). Measurements of the proinflammatory cytokines IL-6 and TNF-alpha showed no significant difference between the two groups, and the levels of IL-1beta and IL-1ra in the present material were too low to permit detection. The increased levels of sIL-1R type II may reflect a compensatory mechanism to balance an increased release of IL-1 receptor agonists in the Alzheimer's disease brain.     

The role of interleukin-6 in the activation of the hypothalamo-pituitary-adrenocortical axis and brain indoleamines by endotoxin and interleukin-1β

Interleukin-6 (IL-6) is one of several cytokines that can stimulate the hypothalamo-pituitary-adrenocortical (HPA) axis. Because IL-6 is produced in response to the administration of endotoxin (LPS) and interleukin-1 (IL-1), it is possible that IL-6 contributes to the neuroendocrine and neurochemical changes induced by them. In this study, intraperitoneal (i.p.) injection of LPS elevated plasma concentrations of IL-6 while activating the HPA axis in a dose-dependent manner. Both responses reached a peak at around 2–3 h. Mouse IL-1β administration (100 ng, i.p.) induced large increases in plasma corticosterone and a substantial, but short-lived increase in plasma IL-6 with a peak at 2 h. Pretreatment of mice intraperitoneally with a monoclonal antibody to mouse IL-6 significantly attenuated the plasma ACTH and corticosterone responses to LPS at 3 h, but not at 1 h. Anti-IL-6 treatment also attenuated the LPS-induced increases of tryptophan and the serotonin catabolite, 5-hydroxyindoleacetic acid (5-HIAA), but not that of the norepinephrine catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG). Pretreatment of mice with anti-IL-6 significantly attenuated the IL-1-induced increases of plasma ACTH and corticosterone at 2 h, but not at 4 h. The IL-1-induced increases of MHPG, tryptophan and 5-HIAA in hypothalamus and brain stem were not significantly altered. These results suggest that IL-6 contributes to the later phases of the LPS- and IL-1-induced stimulations of the HPA axis and to the indoleaminergic responses to LPS, but not to IL-1.     

Intracerebroventricular injection of interleukin-6 induces thermal hyperalgesia in rats

We assessed the effect of interleukin-6 (IL-6) in the brain on nociception by using the hot-plate test in rats. Recombinant human IL-6 (rhIL-6, 30 pg-300 ng) was microinjected into the lateral cerebroventricle (LCV) and the paw-withdrawal latency was then measured for 60 min after injection. RhIL-6 at 300 pg reduced the paw-withdrawal latency at 15 min after injection. Further increase of rhIL-6 doses to 3, 30 and 300 ng resulted in the decreased paw-withdrawal latency at 15 and 30 min. Although the peak responses observed at 3–300 ng did not differ significantly, the time taken for recovery tended to be longer with increasing doses. The rhIL-6 (30 ng)-induced reduction of the paw-withdrawal latency was completely blocked by the co-injection of either Na salicylate (30 ng, LCV) or α-melanocyte stimulating hormone (30 ng, LCV), an anti-cytokine substance. However, it was not affected by the co-injection of IL-1 receptor antagonist (30 ng, LCV) which had been previously shown to be able to block IL-1β-induced hyperalgesia. These findings indicate that IL-6 in the brain induces hyperalgesia by its prostanoids-dependent action in rats. The hyperalgesic action of central IL-6 thus does not appear to depend on the action of IL-1.     

Cerebrospinal fluid levels of interleukin-6 and interleukin-12 in children with meningitis

Purpose  Certain cytokines play important roles in the pathophysiology of meningitis. The main purpose of this study was to investigate if the levels of interleukin-6 (IL-6) and interleukin-12 (IL-12) in cerebrospinal fluid (CSF) could be diagnostic predictors of bacterial meningitis in children. Methods  CSF was obtained from 95 patients suspected with meningitis. These cases were classified to the bacterial meningitis (n = 12), aseptic meningitis (n = 41), and nonmeningitis (n = 42) groups. The levels of IL-6 and IL-12 in CSF were measured using the enzyme-linked immmunosorbent assays test. Results  The CSF IL-6 levels in the bacterial meningitis group (45.2 ± 50.0 pg/ml) were significantly higher than those in the aseptic meningitis group (12.9 ± 10.2 pg/ml) and the nonmeningitis group (6.5 ± 7.8 pg/ml; p < 0.05). The CSF IL-12 levels in the bacterial meningitis group (69.8 ± 67.1 pg/ml) were significantly higher than those in the aseptic meningitis group (22.9 ± 10.8 pg/ml) and the nonmeningitis group (15.3 ± 11.2 pg/ml; p < 0.05). With regard to diagnosis, the measurement of CSF IL-6 and IL-12 levels showed sensitivities of 96% and 96%, respectively, and specificities of 51% and 75%, respectively. Conclusion  It is suggested that the CSF IL-6 and IL-12 levels are useful markers for distinguishing bacterial meningitis from aseptic meningitis.     

精神分裂症偏执型患者血浆及脑脊液白细胞介素2,6及免疫球蛋白G水平的研究

目的　探讨首发精神分裂症偏执型患者血浆及脑脊液中白细胞介素 2 (IL 2 )、IL 6、免疫球蛋白G (IgG)水平的变化 ,及其与精神病理之间的关系。方法　患者组为 30例未用过抗精神病药治疗的精神分裂症偏执型患者 ,对照组为 2 0例无精神疾患的轻微脑外伤患者 ,以阳性和阴性症状量表 (PANSS)评定精神分裂症患者的精神症状 ,用酶联免疫吸附法检测IL 2、IL 6 ,用速率散射比浊法检测IgG。 结果　 (1)患者组血浆及脑脊液IL 2、IL 6和IgG均高于对照组 (P <0 0 1和P <0 0 5 )。(2 )在患者组中 ,血浆IL 6与血浆IgG(r =0 6 90 )和脑脊液IL 6 (r =0 4 2 5 )呈正相关 (P <0 0 1和P <0 0 5 ) ,血浆IgG与脑脊液IgG呈正相关 (r =0 4 0 9,P <0 0 5 ) ;脑脊液IL 6与脑脊液IgG呈正相关 (r =0 5 10 ,P <0 0 5 )。在对照组中 ,血浆IL 2与血浆IL 6 (r =0 5 0 4 ,P <0 0 5 )和IgG (r =0 74 0 ,P <0 0 1)呈正相关 ,血浆IL 6与血浆IgG(r=0 6 75 ,P <0 0 1)和脑脊液IL 6 (r =0 6 33,P <0 0 1)呈正相关 ,血浆IgG与脑脊液IgG(r =0 6 19,P <0 0 5 )呈正相关。 (3)血浆IL 2与P因子分呈正相关 (r =0 6 4 5 ,P =0 0 0 )。结论　首发精神分裂症偏执型患者处于免疫激活状态 ,IL 2、IL 6、IgG与精神病理之间存在一定的     

Timecourse and corticosterone sensitivity of the brain, pituitary, and serum interleukin-1β protein response to acute stress

Activation of peripheral immune cells leads to increases of interleukin-1β (IL-1β) mRNA, immunoreactivity, and protein levels in brain and pituitary. Furthermore, IL-1β in brain plays a role in mediating many of the behavioral, physiological, and endocrine adjustments induced by immune activation. A similarity between the consequences of immune activation and exposure to stressors has often been noted, but the potential relationship between stress and brain IL-1β has received very little attention. A prior report indicated that exposure to inescapable tailshocks (IS) raised levels of brain IL-1β protein 2 h after IS, but only in adrenalectomized (and basal corticosterone replaced) subjects. The studies reported here explore this issue in more detail. A more careful examination revealed that IL-1β protein levels in hypothalamus were elevated by IS in intact subjects, although adrenalectomy, ADX (with basal corticosterone replacement) exaggerated this effect. IL-1β protein increases were already present immediately after the stress session, both in the hypothalamus and in other brain regions in adrenalectomized subjects, and no longer present 24 h later. Furthermore, IS elevated levels of IL-1β protein in the pituitary, and did so in both intact and adrenalectomized subjects. IS also produced increased blood levels of IL-1β, but only in adrenalectomized subjects. Finally, the administration of corticosterone in an amount that led to blood levels in adrenalectomized subjects that match those produced by IS, inhibited the IS-induced rise in IL-1β in hypothalamus and pituitary, but not in other brain regions or blood.     

Overexpression of interleukin-6 in the central nervous system of transgenic mice increases central but not systemic proinflammatory cytokine production

Production of inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6), in the brain is increased in various diseases. To investigate the relationships between the effect of overproduction of IL-6 in the brain on central and peripheral production of TNF, IL-1β and IL-6 itself, we used transgenic mice (NSE-hlL-6) where neuronal human IL-6 expression under the control of the neuronal specific enolase promoter results in astrocytosis and gliosis. These mice had higher cerebral endogenous IL-6 (12-fold). 11.-I β (12-fold) and TNF (4-fold) production measured in brain homogenates after intracerebroventricular (i.c.v.) injection of 2.5 μg LPS, lipopolysaccharide (LPS) than wild-type mice (no TNF or IL- I were detectable in saline-injected NSE or control mice). Cerebral cytokines production was also increased in NSE-hIL-6 mice treated i.p. with LPS doses that do not normally induce cytokines in the brain. The induction of peripheral (serum or spleen) TNF, IL-1β or IL-6 was the same in all these experiments in NSE-hIL-6 and wild-type mice. Furthermore, using microglial cell clone pretreated in vitro with IL-6 we noted an increase in LPS-induced TNF and IL-6 production and proliferation of pretreated cells than control. This study indicates that overproduction of IL-6 in the central nervous system (CNS) may ultimately result in increased central production of inflammatory cytokines, probably due to increased proliferation and activation of the cells which produce cytokine in the CNS.     

Formation of interleukin-6 in the brain of the febrile cat: relationship to interleukin-1

Previous investigations have shown that interleukin-6 (IL-6), unlike other cytokines, is produced in larger amounts in the brain of the febrile animal regardless of the route, peripheral vs. central, of pyrogen administration. In addition, depending on the experimental condition IL-6 production may or may not require the prior induction of interleukin-1 (IL-1). The present study was carried out in the conscious cat to assess the importance of brain-derived IL-6 in the pathogenesis of fever and the interaction at that site between this cytokine and IL-1. IL-6 was detected in cerebrospinal fluid (CSF) collected at rest and its levels increased during the fever to intravenous (i.v.) endotoxin. The IL-6 elevation, but not the fever, was reversed by pretreatment with intracerebroventricular (i.c.v.) IL-1 receptor antagonist (hIL-1ra). Conversely, when pyrogens (endotoxin, IL-1) were given i.c.v., i.c.v. hIL-1ra reduced the fever without altering significantly the associated rise in CSF IL-6. We conclude that IL-6 is formed in brain in response to both i.v. and i.c.v. pyrogens; however, its formation, whether requiring the prior induction of IL-1 or not, does not appear to be critical for the development of the fever. Blood-borne IL-6, unlike brain-derived IL-6, may still play a role in fever as a trigger of signal-transducing mechanisms operating across the blood–brain barrier.     

Higher CSF interleukin-6 and CSF interleukin-8 in current depression in older women. Results from a population-based sample

ObjectiveThe literature regarding cerebrospinal fluid (CSF) cytokines in geriatric depression is sparse. The aim of this study was to examine associations between CSF interleukin-6 (IL-6), interleukin-8 (IL-8) and depression in a population-based sample of older women who were followed for 17 years.Methods86 dementia-free women aged 70–84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992–3. CSF IL-6 and CSF IL-8 were measured. Psychiatric symptoms were rated with the Comprehensive Psychopathological Rating Scale at baseline and at three subsequent face-to-face examinations. Depression (major or minor) was diagnosed in accordance with DSM-IV/DSM-IV research criteria.ResultsAt baseline, women with ongoing major (n = 10) or minor depression (n = 9) had higher levels of CSF IL-6 (p = 0.008) and CSF IL-8 (p = 0.007) compared with those without depression (n = 67). Higher CSF IL-8 was related to higher MADRS score (p = 0.003). New cases of depression were observed in 9 women during follow-ups. No associations between CSF cytokine levels and future depression could be shown in women without depression at baseline.ConclusionHigher levels of CSF IL-6 and IL-8 were associated with current depression in this population-based sample. CSF IL-6 and CSF IL-8 may play a role in depression in late life.     

Cytokine-induced change in hypothalamic norepinephrine turnover: involvement of corticotropin-releasing hormone and prostaglandins

Changes in norepinephrine (NE) turnover in restricted brain regions were examined in rats after administration of the major mediators of the acute phase response, interleukin-1β (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF). An increase in NE turnover was observed after intraperitoneal injection of IL-1 (1 μg/rat) in the whole hypothalamus and several specific hypothalamic nuclei, but not in the medulla oblongata and cerebral cortex. The stimulatory effect of IL-1 was mimicked by an intracerebroventricular injection of much lower doses of IL-1 (10–100 ng/rat). This IL-1-induced increase in hypothalamic NE turnover was blocked by the pretreatment with either indomethacin (cyclooxygenase inhibitor) or anti-corticotropin releasing hormone (CRH) antibody but not by naloxone. Intracerebroventricular injection of CRH increased NE turnover not only in the hypothalamus but also in the medulla oblongata and cerebral cortex. However, prostaglandin (PG) E₂ and PGF_2α did not show such effect. It was therefore suggested that IL-1 activates noradrenergic neurons projecting to the hypothalamus by its direct action to the brain, and that CRH and eicosanoid-cyclooxygenase product(s) within the brain are involved in this process. In contrast, neither IL-6 nor TNF influenced brain NE turnover regardless of whether they were given intraperitoneally or intracerebroventricularly. Thus, although IL-6 and TNF, as well as IL-1, show common central effects such as fever and pituitary-adrenal activation, these effects may be independent of the activation of NE metabolism in the hypothalamus.     

Antibodies to interleukin-1 inhibit cytokine-induced proliferation of neonatal rat Schwann cells in vitro

Unfractionated cytokines have been shown to induce in vitro proliferation of neonatal rat Schwann cells but the nature of the mitogen(s) is not known. A mixture of rabbit antibodies specific for recombinant interleukin-1α (IL-1α) and interleukin-1β (IL-1β) inhibited Schwann cell proliferation induced by unfractionated human cytokines whereas antibodies to interleukin-2 (IL-2) and control IgG did not. However, purified human IL-1 and recombinant human IL-1α or β did not induce Schwann cell proliferation on their own.     

Evidence for a different sensitivity to various central effects of interleukin-1 β in mice

Interleukin 1 (IL-1) induces a series of metabolic and endocrine effects. Activation of the hypothalamus-pituitary-adrenal axis, inhibition of food and water intake, elevation of serum interleukin-6 (IL-6) concentration and hypoglycemia are some of the effects induced by IL-1. The purpose of this study was to compare the sensitivity of these effects following central and peripheral administration of IL-1β. Different doses of IL-1β (0.1–1000 ng/mouse) were centrally (ICV) or peripherally (IP) injected to male mice two hours prior to sacrifice. The ICV administration was more efficacious than the IP injection in elevating serum corticosterone and IL-6 concentrations, whereas no difference was evident in the IL-1β-induced hypoglycemia. Central IL-1β administration was also more potent than IP injection in inhibiting overnight food and water intake. A dose-dependent effect was evident in all these cases. In summary, our data compare effects elicited by central or peripheral administration of different doses of IL-1β. This comparison suggests that the IL-1β stimulation of serum corticosterone and IL-6 and inhibition of food and water intake are events more centrally mediated than the IL-1β-induced hypoglycemia.     

Actinomycin D blocks interleukin-1α-induced pial arteriolar dilation and increased prostanoid production in newborn pigs

Effects of protein synthesis and cyclooxygenase inhibitors on interleukin-1α (IL-1α)- and histamine-induced pial arteriolar dilation and cerebrospinal fluid (CSF) prostanoid increases were examined in anesthetized piglets using closed cranial windows. Topical IL-la (10.8 μg) increased pial arteriolar diameter from 15 to 30 min after its infusion, and enhanced CSF prostanoids. Topical protein synthesis inhibitor, actinomycin D, at a concentration of 10⁻⁸ M attenuated and 10⁻⁸ M completely blocked both IL-1α-induced vasodilation and CSF prostanoid increase. Inhibition of prostaglandin H synthases with indomethacin blocked both vasodilation and CSF prostanoid increase by IL-1α. Topical histamine (10⁻⁶ M) also increased pial arteriolar diameter and CSF prostanoids but without the delay seen between IL-1α infusion and responses. These histamine effects were not modified by coinfusion of actinomycin D but blocked by indomethacin. These results suggest that, although IL-1α and histamine do share the same mechanism insofar as activation of prostaglandin synthesis is concerned, an additional step appears to be involved for IL-1α, likely involving de novo protein synthesis.     

Association of plasma IL-6 and soluble IL-6 receptor levels with the Asp358Ala polymorphism of the IL-6 receptor gene in schizophrenic patients

Recent studies indicate a role of excessive interleukin-6 (IL-6) signaling in the pathogenesis of schizophrenia. A previous study reported a significant association of schizophrenia with the IL-6 receptor (IL-6R) gene Asp358Ala polymorphism, which is known to regulate circulating IL-6 and soluble IL-6R (sIL-6R) levels in healthy subjects. To further examine the influence of the polymorphism in schizophrenic patients, we compared the plasma levels of IL-6 and sIL-6R between schizophrenic patients and healthy controls for each genotype of the Asp358Ala polymorphism. Asp358Ala genotyping and plasma IL-6 level measurements were performed in 104 patients with schizophrenia and 112 healthy controls. Of these participants, 53 schizophrenic patients and 49 controls were selected for the measurement of plasma sIL-6R levels. A two-way factorial analysis of covariance was performed with the transformed plasma levels as the dependent variable, diagnosis and genotype as independent variables, and sex and age as covariates. No significant diagnosis × genotype interaction was observed for IL-6 and sIL-6R levels. The Ala allele of Asp358Ala was significantly associated with higher levels of both IL-6 and sIL-6R. IL-6 levels were significantly elevated in schizophrenic patients compared to those in controls, whereas no significant difference in sIL-6R levels was observed between schizophrenic patients and controls. Our findings suggest that the presence of schizophrenia is associated with elevated IL-6 levels, whereas sIL-6R levels are mainly predetermined by the Asp358Ala genotype and are not associated with the disease status. Increased IL-6 levels without alterations in sIL-6R levels may result in excessive IL-6 signaling in schizophrenia.     

Discriminant power of combined cerebrospinal fluid τ protein and of the soluble interleukin-6 receptor complex in the diagnosis of Alzheimer's disease

Alzheimer's disease (AD) still can only be definitively diagnosed with certainty by examination of brain tissue. There is a great need for a noninvasive, sensitive and specific in vivo test for AD. We combined cerebrospinal fluid analyses of τ protein (levels were significantly increased in AD patients [p=0.0001]), a putative marker of neuronal degeneration, with components of the soluble interleukin-6 receptor complex (sIL-6RC: IL-6, soluble IL-6 receptor and soluble gp130), putative markers of neuroregulatory and inflammatory processes in the brain. A stepwise multivariate discriminant analysis revealed that τ protein and soluble gp130 (levels were significantly reduced in AD subjects [p=0.007]), the affinity converting and signal-transducing receptor of neuropoietic cytokines, maximized separation between the investigated groups. The discriminant function predicted 23 of 25 clinically diagnosed AD patients (sensitivity 92%) with mild to moderate dementia correctly as having AD. Furthermore, 17 of 19 physically and cognitively healthy age-matched control subjects (specificity 90%) were accurately distinguished by this test. Later predicting with the jackknife procedure each case in turn through the remaining patient group, the discriminant function remained stable. Our data suggest that multivariate discriminant analysis of combined CSF τ protein and sIL-6RC components may add more certainty to the diagnosis of AD, however, the method will need to be extended to an independent group of patients, comparisons and control subjects to assess the true applicability.     

Behavioral effects of peripheral interleukin-1 administration in adult CD-1 mice: specific inhibition of the offensive components of intermale agonistic behavior

Peripheral administration of interleukin-1β (IL-1β) in rodents reduces exploratory behavior in a novel environment while decreasing social investigation of a juvenile conspecific. In this study we wanted to test the effects of peripherally administered IL-1β on another aspect of the mouse social repertoire, namely intraspecific fighting towards an adult male intruder. In the first experiment, sickness behavior induced by IL-1β (1 μg/mouse) in adult CD-1 mice was assessed by direct observation of behavioral changes following placement into a novel environment. Three hours after injection, subjects were individually introduced for 20 min in a cage with clean sawdust and a number of behavioral items recorded. Blood samples were collected at the end of the testing session. Body temperature was measured right before, 1 h and 3.5 h following injection. In IL-1β treated mice, exploration (assessed by measuring duration and frequency of Wall Rearing and Rearing behaviors) was nearly totally suppressed, while duration and frequency of behaviors such as Grooming, Bar Holding, and Digging were also markedly reduced. Administration of IL-1β significantly elevated CORT secretion above basal levels and, as previously reported for mice, induced hypothermia (about 2°C). In the second experiment, we assessed mice receiving IL-1β (0.25; 0.5 or 1 μg/mouse or saline solution) in a social context. Three hours after injection, subjects were placed into a neutral cage for 20 min with a non-injected adult male conspecific and aggressive behavior scored. Overall, IL-1β administration affected the social repertoire of treated mice in a dose-dependent fashion. Specifically, agonistic components of aggressive behavior were nearly totally suppressed, while the defensive elements, such as Upright Defensive posture, Upright Submissive posture, Crouching, or Flee were not affected by IL-1β. Overall these data support the notion that sickness behavior induced by IL-1β administration represents an organized behavioral strategy and is not an aspecific response to an illness-type of condition.