Serotoninergic and Suprachiasmatic Nucleus Involvement in the Corticotropic Response to Systemic Endotoxin Challenge in Rats

We have investigated whether the serotonin system participates in the mechanisms underlying the corticotropic response in experimentally infected rats. Intra-arterial injection of lipopolysaccharide (LPS; 25 microg/kg b.w.) resulted in a slight but significant increase in serotonin (5-HT) metabolism, detectable 60 min after the stimulus and lasting more than 480 min. Adrenocorticotropin (ACTH) and corticosterone (CORT) responses in intact rats conformed to earlier reports, increasing as early as 30 min after LPS injection and reaching maximal concentrations in the circulation 60 min after the bacterial endotoxin injection. Plasma concentrations of interleukin-1beta (IL-1beta) increased only after 60 min, reaching maximal levels 120 min after LPS. Depletion of hypothalamic 5-HT (-93%) by pretreatment of the animals with para-chlorophenylalanine (p-CPA), resulted in a halved ACTH response to LPS, despite an overall unchanged secretory pattern. Neither CORT nor IL-1beta secretory patterns were affected in these rats pretreated with p-CPA. Complete bilateral electrochemical lesions of the suprachiasmatic nucleus (SCN), which is innervated by mesencephalic 5-HT, impaired the early phase of the ACTH (-75% at 30 min) and CORT (-40% at 30 min) responses but did not affect the later increases of the corticotropic and the plasma IL-1beta responses following the LPS injection. These results indicate that serotonin pathways and SCN are involved in the earlier mechanisms of corticotropic axis recruitment following systemic LPS endotoxemia.     

Interleukin-1β and lnterleukin-6 Stimulate Neurohypophysial Hormone Release in vitro

Interleukin-1 (IL-1) and interleukin-6 (IL-6) have been reported to stimulate the release of corticotrophin-releasing hormone (CRN) in vitro, the response being antagonized by the cyclo-oxygenase inhibitor, indomethacin. The effects of cytokines on the other major ACTH-releasing hormone, vasopressin (AVP), and the other neurohypophysial hormone, oxytocin, have been little studied, and the published data are conflicting. We have therefore used a previously validated rat hypothalamic expiant model to evaluate whether IL-1β and IL-6 can directly activate the AVP and oxytocin neurosecretory system. In addition, we have also investigated the effects of inhibition of cyclo-oxygenase (CO) and lipoxygenase (LO) activities on the stimulated release of AVP and oxytocin by means of a series of antagonists, including a specific LO pathway inhibitor. The static rat hypothalamic incubation system used involves fresh hypothalamic expiants with consecutive 20-min incubations, and estimation of AVP and oxytocin concentrations in the medium by specific and sensitive radioimmuno-assays. It was found that IL-1β produced a dose-dependent increase in the release of AVP and oxytocin at doses of 10 and 100 U/ml (P<0.005). Only at the higher dose of 100 U/ml was IL-6 able to increase significantly AVP and oxytocin release (P<0.05). These stimulatory effects of IL-1β and IL-6 were blocked by cyclo-oxygenase inhibitors, indomethacin (28 μM) and ibuprofen (100 nM), but not by the lipooxygenase inhibitor, BW A4C (10 μg/ml), suggesting that prostaglandins are involved in this process. Thus, cytokines are clearly able to modulate the neurohypophysial system in vitro, the effects probably being mediated by cyclo-oxygenase products.     

Effect of interleukin 1beta on the HPA axis in H1-receptor knockout mice

OBJECTIVES AND METHODS: Circulating cytokines such as interleukin-1 (IL-1), and tumor necrosis factor-alpha as well as lipopolysaccharide (LPS) are potent ACTH secretagogues, acting via stimulation of corticotropin-releasing hormone (CRH) and vasopressinergic neurons in the paraventricular nucleus of the hypothalamus (PVN). Histamine (HA) has been shown to stimulate ACTH secretion in rats, an effect in part mediated by CRH and arginine vasopressin (AVP). We have previously shown that inhibition of neuronal HA synthesis or central blockade of H(1) receptors (H(1)R) decreased the ACTH response to LPS in male rats. To further elucidate the role of neuronal HA in cytokine-induced activation of the HPA axis, we compared the effect of H(1)R knockout on IL-1beta-induced ACTH secretion in adult male mice. RESULTS: In H(1)R knockout mice, ACTH secretion increased from basal levels of 261 to 492 pmol/l in response to IL-1beta whereas the cytokine-induced ACTH secretion increased from 140 to 406 pmol/l in wild-type mice. Plasma corticosterone (CORT) rose from basal levels of 99 to 831 nmol/l in knockout mice upon IL-1beta stimulation, whereas in wild-type mice CORT levels rose from 112 to 841 nmol/l. There was no significant difference in IL-1beta-stimulated plasma ACTH or CORT levels between wild-type and knockout mice. Furthermore, there was no significant difference in basal or IL-1beta-stimulated hypothalamic levels of histamine and tele-methyl-histamine between wild-type and knockout mice. HDC gene expression was significantly lower in knockout mice than in wild-type mice both under basal and IL-1beta-stimulated conditions, while there were no significant differences in CRH gene expression in the PVN in knockout mice under basal and IL-1beta-stimulated conditions. Increased basal expression of AVP in the PVN of knockout mice was observed in this study compared to wild-type mice. CONCLUSION: We conclude that the lack of the gene for histamine H(1)R does not seem to be crucial for the ACTH and CORT response to IL-1beta, either due to possible functional compensation in the H(1)R knockout mouse or due to activation of pathways other than the neuronal histaminergic system.     

The role of monoaminergic systems in central IL-1β-induced changes in intestinal motility

Abstract Intracerebroventricular (i.c.v.) injection of interleukin-1β (IL-1β) in fed rats induces stimulation of caecocolonic contractions, involving corticotropin-releasing factor (CRF) and the reappearance of the fasted motor pattern (presence of migrating myoelectric complexes, MMCs) at the small intestinal level, which is mediated by prostaglandins (PGs). The mechanisms of these effects were further investigated by focusing on the possible involvement of central monoaminergic systems. Motility was appraised in conscious rats chronically implanted with electrodes in the jejunum and caecum, and a catheter in a lateral ventricle of the brain. IL-1β (15 ng, i.c.v.) was administered in fed rats that were untreated, or after previous administration of either antagonists of α₁ and α₂ adrenergic (prazocin and yohimbine), D₁ and D₂ dopaminergic (SCH 23390 and sulpiride) and 5HT₃ serotonergic (granisetron) receptors. Only prazocin and yohimbine (1 mg kg⁻¹ i.p.) significantly reduced the duration of the MMC pattern induced by IL-1β at the jejunal level (78 ± 35 min and 40 ± 12 min, respectively, vs 223 ± 48 min in control studies). In contrast, the caecal stimulation triggered by IL-1β was not only blocked by prazocin and yohimbine (1 mg kg⁻¹ i.p.), but also by sulpiride (1 mg kg⁻¹ i.p.) and granisetron (1 mg kg⁻¹ i.p.). This study confirms that IL-1-induced changes in small and large intestinal motility are expressed through two separate pathways. We can suggest that mediators acting to modulate CRF release, such as catecholamines through α₁ and α₂ receptors, dopamine through D₂ receptors, and serotonin through 5HT₃ receptors, could be involved in the caecal stimulation. PG-dependent changes in the jejunal motility pattern seem to be linked to activation of α adrenoceptors.     

Prior exposure to glucocorticoids potentiates lipopolysaccharide induced mechanical allodynia and spinal neuroinflammation

While stress and stress-induced glucocorticoids are classically considered immunosuppressive, they can also enhance proinflammatory responses to subsequent challenges. Corticosterone (CORT) primes rat immune cells, exacerbating pro-inflammatory responses to subsequent immune challenges. Stress can also sensitize pain. One possibility is that stress primes spinal immune cells, predominantly glia, which are key mediators in pain enhancement through their release of proinflammatory cytokines. Therefore, we aimed to identify whether prior CORT sensitizes spinal cord glia such that a potentiated pro-inflammatory response occurs to later intrathecal (IT) lipopolysaccharide (LPS), thereby enhancing pain. Rats received subcutaneous CORT/vehicle 24 h before IT LPS/vehicle. Hind paw pain thresholds were measured before CORT/vehicle, before and up to 48 h after IT LPS/vehicle. In separate rats treated as above, lumbar spinal cord tissue was collected and processed for proinflammatory mediators. CORT alone had no effect on pain responses, nor on any pro-inflammatory cytokines measured. LPS induced allodynia (decreased pain threshold) lasting <4 h and elevated spinal IL-1β and IL-6 protein. Prior CORT potentiated allodynia, lasting >24 h following LPS and potentiated spinal IL-1 and IL-6 protein. Coadministration of IL-1 receptor antagonist with LPS IT completely blocked the allodynia irrespective of whether the system was primed by CORT or not. At 24 h, TLR2, TLR4, MD2, and CD14 mRNAs were significantly elevated within the spinal cord in the CORT + LPS group compared to all other groups. Prior CORT before a direct spinal immune challenge is able to potentiate pain responses and pro-inflammatory cytokine production.     

Effects of the IL-1 receptor antagonist on the IL-1- and endotoxin-induced activation of the HPA axis and cerebral biogenic amines in mice

Endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) are known to activate the hypothalamo-pituitary- adrenocortical (HPA) axis, as well as brain norepinephrine (NE) and indoleamine metabolism. Because LPS administration is known to induce the synthesis and secretion of IL-1, it has been proposed that IL-1 is the endogenous mediator of the response to LPS. This proposal has been tested using various antagonists of IL-1 with varied results. Therefore we have re-examined this question using a wide range of doses of the interleukin-1- receptor antagonist protein (IL-1ra) at various times after intraperitoneal LPS. The results indicate that IL-1ra at doses more than adequate to prevent responses to exogenously administered IL-1beta, failed to significantly attenuate the increases in plasma ACTH and corticosterone and the cerebral catecholamine and indoleamine responses induced by intraperitoneal LPS in mice. IL-1ra was also ineffective when plasma ACTH and corticosterone were measured at longer times after LPS, although some trends towards attenuations were occasionally observed at 4 or 6 h. The latter is consistent with the time course of IL-1 induction by LPS. Intracerebroventricular administration of IL-1ra attenuated the endocrine and neurochemical responses to intraperitoneal IL-1beta. However, intracerebroventricular IL-1ra failed to antagonize the HPA and neurochemical responses to intraperitoneal administration of LPS or to intravenous IL-1beta. In all of these experiments, there were very close parallels between the HPA and the neurochemical responses, especially that of NE. We conclude that IL-1 does not mediate the HPA or the neurochemical responses to intraperitoneal LPS, although it may contribute in a minor way to the late HPA responses. However, IL-1 within the CNS may contribute to the responses to intraperitoneal IL-1, but not to intraperitoneal LPS or intravenous IL-1.     

Interleukin-1β is increased in the cerebrospinal fluid of patients with small infarcts

Background and purpose:  Interleukin-1beta (IL-1β) and interleukin-6 (IL-6) are involved in inflammatory responses during large vessel occlusion in animal models. The aim of this study was to investigate the intrathecal levels of cytokines in patients with acute small infarcts.
Methods:  Forty patients with acute minor stroke and 32 non-stroke patients (including 29 age- and gender-matched subjects) who received operations with spinal anesthesia were studied prospectively and underwent measurements of cerebrospinal fluid (CSF) IL-1β and IL-6 levels.
Results:  After an age- and gender-matched analysis of 58 patients (29 pairs), the mean intrathecal levels of IL-1β were 0.80 pg/ml in patients with small infarcts and 0.59 pg/ml in non-stroke patients ( P  <   0.0001). In addition, the mean CSF levels of IL-6 were 21.54 pg/ml and 7.52 pg/ml in the stroke and control groups, respectively ( P  =   0.38). These results were consistent with the data without matching. The CSF levels of IL-1β in the 40 stroke patients were significantly higher than in the 32 non-stroke controls ( P  <   0.0001).
Conclusions:  The proinflammatory cytokine IL-1β, but not IL-6, remained elevated in the CSF of patients in the acute stage of small infarcts.     

T-cell interleukin-6 receptor binding in interferon-β-1b-treated multiple sclerosis patients

Multiple sclerosis (MS) is a T-cell-mediated autoimmune demyelinating disease of the central nervous system, associated with an altered cytokine network. We previously assayed peripheral blood T-lymphocyte binding for two prototypic cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and found that T cells from MS patients had significantly more TNF-alpha and IL-6 receptors than those from healthy controls. In the present work, paralleling a previous one on T-cell TNF-alpha binding, we studied the effect of interferon (IFN)-beta-1b treatment on T-lymphocyte IL-6 binding in patients with relapsing-remitting MS. T cells from MS patients had significantly (P < 0.001) higher amounts of IL-6 receptors than those from controls [292 +/- 6 vs. 228 +/- 8 (mean +/- SEM) receptors per cell, respectively], whereas the ligand-receptor affinity values were similar in the two groups [26.2 +/- 0.7 and 25.7 +/- 0.4 (mean +/- SEM) pmoles/l, respectively]. After a 3-month IFN-beta-1b treatment, they showed a significant decrease in IL-6 binding [266 +/- 7 (mean +/- SEM) receptors per cell]. After 6 and 9 months, T-cell IL-6 B(max) values were even lower [258 +/- 8 and 251 +/- 8 (mean +/- SEM) receptors per cell]. Since an increased IL-6 binding might be linked to a lymphocyte activation, our data give further support for an enhanced immune response in patients with MS. Our data seem to demonstrate that the major effects of IFN-beta-1b treatment result in a decrease of T-cell activation.     

Activation of the hypothalamic-pituitary-adrenal axis in IL-1 beta-converting enzyme-deficient mice

Interleukin-1beta (IL-1beta) plays a key role in immune, behavioral and neuroendocrine responses to inflammation or infection. IL-1beta could also be involved in the response of the hypothalamic-pituitary-adrenal (HPA) axis during stress. Mature IL-1beta derives from a 31-kD precursor (pro-IL-1beta) that is processed by IL-1beta-converting enzyme (ICE). Mice in which the ICE gene has been nullated by homologous recombination were used to investigate the role of IL-1beta in the HPA axis response. Plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) in response to an intraperitoneal injection of 5 microg lipopolysaccharide (LPS) were similar in ICE-deficient mice and wild-type (WT) controls. In contrast, plasma ACTH response to restraint or to 200 ng of rat recombinant IL-1beta (rrIL-1beta) was higher in ICE-deficient mice as compared to WT animals. This hyperreactivity of the HPA axis in ICE knockout mice appears not to be related to the production of plasma IL-1beta or IL-6, which was similar to that of WT mice after rrIL-1beta injection. After lipopolysaccharide, ICE-deficient mice exhibited a smaller increase in plasma-immunoreactive IL-1beta and IL-6 as compared to WT controls. After restraint stress neither increase in plasma IL-1beta nor IL-6 was observed. The mechanisms responsible for the increased reactivity of the HPA axis in ICE-deficient mice may result from a higher sensitivity of the HPA axis to inflammatory cytokines or to cleavage products of pro-IL-1beta processed by non-ICE proteases.     

Polymorphism in CRHR1 gene affects the IL-1β levels in suicidal attempters

Approximately one million people commit suicide every year, being suicide attempts and ideation even more common. Changes in stress response and activation of the immune system have been associated with suicide risk. Here we investigated the interaction between immune system and HPA axis alterations in the suicide risk, looking for the influence of rs110402 CRHR1 SNP in the IL-1β levels according to suicide ideation and attempt. This study evaluated 171 subjects of which 15 had suicidal ideation, 20 had suicide attempt and 136 were controls. Genotyping was performed by real-time PCR and IL-1β levels were measured by ELISA. Our data showed that for each point increase in IL-1β levels the risk of suicide attempt increased 5% [relative risk = 1.05 (95% CI: 1.0–1.10)]. After sample stratification by rs110402 SNP genotypes, we observed that in subjects carrying the A allele the risk raised to 15% [relative risk = 1.15 (95% CI: 1.03–1.28)], suggesting an apparent effect modification. Thus, this study showed that alterations in CRHR1 gene were associated with higher levels of IL-1β, and increased risk for suicide, reinforcing the importance of multifactorial interactions of biological markers for psychiatric disorders.     

癫痫发作间期血清中IL-1β和IL-6水平分析研究

目的癫痫发作间期外周血清中白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)的含量分析及意义。方法 ELISA法分别测定53例癫痫患者发作间期及30例正常人外周血清中IL-1β和IL-6含量,对癫痫组和正常组之间,同时对癫痫患者组内进行性别、年龄、病程、发作频度、间期脑电的正异常、起源区域局限性(局限和广泛)进行比较,实验数据(含量)结果用x±s表示,两样本采用秩和检验。结果癫痫组与正常组之间IL-1β和IL-6外周血液血清中含量的差异均有统计学意义;癫痫组不同发作频度之间IL-6血清中含量的差异有统计学意义,不同发作频度对于IL-1β含量无统计学意义;癫痫组不同性别、年龄、病程、间期脑电(正常和异常)、起源区域(局限和广泛)血清中IL-1β和IL-6含量的差异均无统计学意义。结论发作间期IL-1β和IL-6在外周血清中的含量因癫痫而发生变化,癫痫患者的免疫系统处于活化状态,证明两种细胞因子参与癫痫活动,血清中IL-6含量与发作频度有关。     

Interleukin-1 interaction with neuroregulatory systems: selective enhancement by recombinant human and mouse interleukin-1 of in vitro opioid peptide receptor binding in rat brain

Interleukin-1 (IL-1) exerts a wide variety of biological effects on various cell types and may be regarded as a pleiotropic peptide hormone. Biological evidence suggests that IL-1 participates in the modulation of central nervous system physiology and behaviour in a fashion characteristic of neuroendocrine hormones. In this investigation, recombinant (r) human (h) IL-1 and r mouse (m) IL-1 were examined for their modulation of opioid peptide receptor binding in vitro. Experiments were performed on frozen sections of rat brain. Receptor binding of radiolabeled substance P and of radiolabeled neurotensin were not significantly affected by the presence of rIL-1s. Recombinant IL-1s, however, significantly enhanced specific binding of 125I-beta-endorphin (125I-beta-END) and of D-ala2-(tyrosyl-3,5-3H)enkephalin-(5-D-leucine) (3H-D-ALA), equipotently and in a concentration-dependent manner with maximal activity occurring at a concentration of 10 LAF units/ml. The increased binding of 125I-beta-END and 3H-D-ALA was blocked steroselectively by (-)-naloxone and by etorphine, suggesting detection of opiate receptors. In addition, brain distribution patterns of receptors labeled in the presence of rIL-1s corresponded to patterns previously published for opiate receptors. Autoradiographic visualization of receptors revealed that rIL-1s in the different areas of the brain exert their effect on opioid binding with comparable potencies. The data suggest that certain central nervous system effects of IL-1s may be mediated by their selective interaction with opiatergic systems at the receptor level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypophysiotropic Role and Hypothalamic Gene Expression of Corticotropin-Releasing Factor and Vasopressin in Rats Injected with Interleukin-1β Systemically or into the Brain Ventricles

Intact adult male rats were injected intravenously (i.v., 400 ng/kg), intraperitoneally (i.p., 400 ng/kg) or intracerebroventricularly (i.c.v., 100 ng/kg) with interleukin-1β (IL-1β) or its vehicle. In comparison with vehicle-treated animals, IL-1β induced significant (P<0.01) increases in plasma ACTH levels measured 30 min later regardless of the route of cytokine administration. These changes were markedly blunted in rats administered specific antibodies directed against corticotropin-releasing factor (CRF). In contrast, vasopressin (VP) antibodies significantly blunted ACTH released by the i.c.v. injection of IL-1β, but only modestly altered the effect of the systemic injection of the cytokine. We then used semi-quantitative in situ hybridization analysis to measure changes in steady-state mRNA levels, as they might occur in response to these same doses of IL-1β. Following administration of the vehicle, measurement of gene expression in the paraventricular (PVN) portion of the hypothalamus indicated a measurable amount of hybridization signals for both CRF and VP. No detectable changes in either CRF or VP gene expression were observed in rats injected with IL-1β i.v. or i.p. 5 h earlier. In contrast, the i.c.v. administration of the cytokine significantly (P<0.01) increased both CRF and VP mRNA levels measured 5 h later. These results suggest that while endogenous CRF modulates the response of the corticotrophs to this cytokine regardless of the route of administration, the role of VP is more important in rats injected centrally than in those injected peripherally. The observation that at the dose tested and over the time-course studied, systemic injection of IL-1β failed to alter CRF or VP gene expression, supports our earlier hypothesis that blood-born IL-1β acts primarily at the level of nerve terminals in the median eminence.     

Effects of chronic stress on in vivo pituitary-adrenocortical responses to corticotropin releasing hormone

Experimental evidence indicates that animals exposed to chronic stress demonstrate increased adrenocorticotropin (ACTH) and corticosterone (CORT) responses to novel stimuli (facilitation) but attenuated ACTH and CORT responses to the chronic stressor (adaptation). The mechanisms responsible for facilitation and adaptation of ACTH and CORT responses are not known. In the present experiments, we chronically exposed male Fischer-344 rats to sessions of a two-way shock-escape stress procedure following a schedule which we had previously shown to elicit adaptation of ACTH and CORT responses. To determine if pituitary-adrenocortical adaptation to stress was mediated by alterations in pituitary responsiveness to corticotropin-releasing hormone (CRH), control and chronically stressed rats received intra-arterial injections of a low and a high dose of CRH and blood samples from each animal were assayed for ACTH and CORT levels. The results showed that ACTH responses to the low (but not the high) dose of CRH were attenuated by chronic stress. In addition we confirmed previous reports which showed that chronic stress increased adrenocortical sensitivity to ACTH. Thus, we concluded that adaptation of ACTH responses to chronic stress may be in part mediated by a reduction of the CRH-induced ACTH secretory response.     

Attenuated stress response to acute lipopolysaccharide challenge and ethanol administration in vasopressin V1b receptor knockout mice

The arginine vasopressin (Avp) 1b receptor (Avpr1b) present on anterior pituitary corticotrophs is involved in the stimulation of adrenocorticotrophic hormone (ACTH) secretion, especially during times of stress. Corticotrophin-releasing hormone (CRH) is considered the major ACTH secretagogue during acute stress whereas Avp appears to be the more dominant mediator of the hypothalamic-pituitary-adrenal (HPA) axis response during chronic stress situations. To investigate the role of the Avpr1b in the HPA axis response to acute stress, we measured ACTH and corticosterone (CORT) plasma levels in Avpr1b knockout (KO) mice and wild-type controls in response to bacterial lipopolysaccharide (LPS) challenge and ethanol (EtOH) administration. Mice deficient in Avpr1b had markedly compromised plasma ACTH and CORT responses to acute (30 min) LPS, but normal ACTH and CORT response to more extended exposure (4 h) to the immune system activator. The plasma ACTH and CORT levels stimulated by intoxicating, sedative doses of EtOH (3.2 and 4 g/kg) were significantly decreased in the Avpr1b KO mice compared to wild-type littermates. Significantly higher EtOH-induced plasma ACTH and CORT secretion was measured in female than in male Avpr1b wild-type mice. There were no differences in the blood alcohol levels following acute EtOH administration in Avpr1b KO or wild-type mice of either gender. Our results clearly suggest that Avpr1b plays a significant role in the HPA axis response to acute immune stress and EtOH intoxication.     

Neural activities of IL-6-type cytokines often depend on soluble cytokine receptors

Cytokines of the interleukin-6 (IL-6) family participate in regulatory and inflammatory processes within the nervous system. IL-6, ciliary neurotrophic factor (CNTF) and IL-11 act via specific membrane receptors which, together with their ligands, associate with signal-transducing receptor subunits thereby initiating cytoplasmic signalling. Cells which only express signal-transducing receptor subunits but no ligand binding subunits for IL-6, CNTF and IL-11 are refractory to these cytokines. An unusual feature of the IL-6 cytokine family is that the soluble forms of the ligand binding receptor subunits generated by one cell type in complex with their ligands can directly stimulate the signal-transducing receptor subunits on different cell types which lack ligand binding receptor subunits. This process has been named transsignalling. This article focuses on the importance of transsignalling events in neuronal differentiation and survival responses.     

IL-1β and IL-6 excite neurones and suppress cholinergic neurotransmission in the myenteric plexus of the guinea pig

The effects of the inflammatory mediators interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) on myenteric neurones were investigated by intracellular recordings in a conventional myenteric plexus preparation of guinea pig ileum. Micropressure ejection of IL-1beta and IL-6 (10-7 mol L-1) both caused an excitatory effect in, respectively, 19% (13/70) and 7% (5/70) of the myenteric neurones. The IL-1beta-induced depolarizations were inhibited by superfusion of the IL-1beta receptor antagonist. The responses seen were tetrodotoxin-resistant, indicating a direct neuronal effect. Responses to both cytokines were seen in nitric oxide synthase-immunoreactive as well as choline acetyltransferase-immunoreactive neurones. In addition, both IL-1beta and IL-6 reversibly caused a presynaptic inhibition of acetylcholine release from cholinergic nerve terminals. Both cytokines had no effect on the slow excitatory postsynaptic potentials. Therefore, we can conclude that the inflammatory mediators IL-1beta and IL-6 can act as excitatory neuromodulators of gastrointestinal motility through direct excitatory actions on a subset of myenteric neurones and through the presynaptic inhibition of acetylcholine release.     

白细胞介素-6与脑胶质瘤关系的研究

目的:通过观察人脑胶质瘤细胞是否可以自发分泌白细胞介素-6(interleukin-6,IL-6),为进一步探讨IL-6在脑胶质瘤发生、发展中的可能作用提供线索。方法:对4例脑胶质瘤病人的手术标本进行原代细胞培养,分不同时相收获上清,并对其上清进行IL-6活性检测。结果:各组上清中均有IL-6活性,IL-6生物活性以D_(0～6)上清活性最高(1.131U/L),D_(0～6)上清活性最低(0.18U/L)。人脑胶质瘤细胞受细菌脂多糖刺激后,分泌IL-6的能力略有增强。IL-6单克隆抗体可中和脑胶质瘤上清对B9.9细胞的增殖作用。结论:原代培养的人脑胶质瘤细胞可自发分泌IL-6。     

安宫牛黄注射液对脑外伤后脑内IL-1β和ICAM-1表达研究

目的探讨安宫牛黄注射液对脑外伤后炎性反应因子白细胞介素-1β（IL-1β）和细胞间粘附分子-1（ICAM-1）表达的影响。方法将72只SD大鼠随机分为3组，采Feeney法造成鼠脑挫裂伤模型，对照组和治疗组大鼠分别在伤后6、24、48、72h时间点完整取出脑组织，匀浆后离心，取上清液0．5ml，用酶联免疫吸附实验法（ELISA）做IL-1β因子和ICAM．1水平检测。结果治疗组脑组织IL-1β和ICAM-1水平在伤后6h、24h、48h时间点显著低于对照组（P〈0．05）。结论安宫牛黄注射液可抑制脑外伤后脑内IL-1β和ICAM-1的表达，减轻炎性反应，对脑组织起保护作用。