Endogenous brain IL-1 mediates LPS-induced anorexia and hypothalamic cytokine expression

The present study was designed to determine the role of endogenous brain interleukin (IL)-1 in the anorexic response to lipopolysaccharide (LPS). Intraperitoneal administration of LPS (5-10 microgram/mouse) induced a dramatic, but transient, decrease in food intake, associated with an enhanced expression of proinflammatory cytokine mRNA (IL-1beta, IL-6, and tumor necrosis factor-alpha) in the hypothalamus. This dose of LPS also increased plasma levels of IL-1beta. Intracerebroventricular pretreatment with IL-1 receptor antagonist (4 microgram/mouse) attenuated LPS-induced depression of food intake and totally blocked the LPS-induced enhanced expression of proinflammatory cytokine mRNA measured in the hypothalamus 1 h after treatment. In contrast, LPS-induced increases in plasma levels of IL-1beta were not altered. These findings indicate that endogenous brain IL-1 plays a pivotal role in the development of the hypothalamic cytokine response to a systemic inflammatory stimulus.     

Expression of interleukin 1 alpha and beta, and interleukin 1 receptor antagonist mRNA in the rat central nervous system after peripheral administration of lipopolysaccharides

Interleukin 1alpha (IL-1alpha) and IL-1beta, and the endogenous IL-1 receptor antagonist (IL-1ra) are known members of the IL-1 family. Using in situ hybridization histochemistry we demonstrated that following endotoxin injection (lipopolysaccharides, LPS, 2.0 mg/kg, i.p.) a time dependent expression and partly different expression patterns of the cytokines occurred within the rat brain and pituitary gland. All cytokines were observed in the choroid plexus. In addition, IL-1ra mRNA expressing cells were observed scattered in the brain parenchyma, whereas scattered IL-1beta mRNA expressing cells were restricted to central thalamic nuclei, the dorsal hypothalamus, and cortical regions, such as the parietal and frontal cortex. A strong IL-1beta mRNA expression was found in the circumventricular organs. In the pituitary gland, a low IL-1alpha and a high IL-1beta mRNA expression was observed, with the highest density of cytokine-expressing cells seen in the posterior pituitary. The cell types expressing the mRNA's of IL-1alpha, IL-1beta and IL-1ra were identified as monocytes in the circumventricular organs and the pituitary gland, and as microglia in the brain parenchyma. In conclusion, the present findings revealed that cytokine production in response to a peripheral endotoxin challenge mainly occurs in peripherally derived monocytes in the circumventricular organs and the pituitary gland. IL-1beta is the predominant form expressed, whereas the expression of IL-1alpha mRNA and IL-1ra mRNA is lower. Our observations support the view that peripherally derived IL-1 may play a role in the induction of centrally mediated illness symptoms.     

Central injection of nicotine increases hepatic and splenic interleukin 6 (IL-6) mRNA expression and plasma IL-6 levels in mice: involvement of the peripheral sympathetic nervous system.

Accumulating evidence suggests that plasma levels of interleukin 6 (IL-6), a major cytokine stimulating the synthesis of acute-phase proteins, are intimately regulated by the central nervous system. Nicotine, one of the major drugs abused by humans, has been shown to affect immunological functions. In the present study, effects of intracerebroventricular (i.c.v.) injection of nicotine on plasma IL-6 levels were investigated in mice. Nicotine administered i.c.v. dose-dependently increased plasma IL-6 levels; the lowest effective dose was 0.3 ng/mouse and the maximal effect was attained with the dose of 105 ng/mouse. The nicotine (105 ng/mouse, i.c.v.)-induced plasma IL-6 levels peaked at 3 h and approached basal levels 6 h after injection. Mecamylamine, a nicotinic receptor antagonist, blocked nicotine-induced plasma IL-6 levels. Depletion of peripheral norepinephrine with 6-hydroxydopamine [100 mg/kg, intraperitoneal (i. p.)] inhibited the nicotine-induced plasma IL-6 levels by 57%, whereas central norepinephrine depletion with 6-hydroxydopamine (50 microgram/mouse, i.c.v.) had no effect. Pretreatment with prazosin (alpha1-adrenergic antagonist; 1 mg/kg, i.p.), yohimbine (alpha2-adrenergic antagonist; 1 mg/kg, i.p.), and ICI-118,551 (beta2-adrenergic antagonist; 2 mg/kg, i.p.), but not with betaxolol (beta1-adrenergic antagonist; 2 mg/kg, i.p.), inhibited nicotine-induced plasma IL-6 levels. Among the peripheral organs, including the pituitary, adrenals, heart, lung, liver, spleen, and lymph nodes, nicotine (105 ng/mouse, i.c.v.) increased IL-6 mRNA expression only in the liver and spleen, which was inhibited by peripheral norepinephrine depletion. These results suggest that stimulation of central nicotinic receptors induces plasma IL-6 levels and IL-6 mRNA expression in the liver and spleen via the peripheral sympathetic nervous system, alpha1-, alpha2-, and beta2-adrenoreceptors being involved.     

Central beta-amyloid peptide-induced peripheral interleukin-6 responses in mice

beta-Amyloid peptides (Abetas) share with lipopolysaccharide, a potent pro-inflammatory agent, the property of stimulating glial cells or macrophages to induce various inflammatory mediators. We recently reported that central administration of lipopolysaccharide induces peripheral interleukin-6 responses via both the central and peripheral norepinephrine system. In this study, the effect of intracerebroventricular injection of various synthetic Abetas on plasma interleukin-6 levels was examined in mice. Abeta(1-42) dose-dependently increased plasma interleukin-6 levels: 'aged' Abeta(1-42) was more effective than fresh, whereas Abeta(42-1) had no effect. 'Aged' Abeta(1-42) (205 pmol/mouse i.c.v.)-induced plasma interleukin-6 peaked at 2 h post injection, which is earlier than the peak time of the Abeta(1-42)-induced brain interleukin-6, tumor necrosis factor-alpha and interleukin-1beta levels, which was 4, 4 and 24 h, respectively. Among various peripheral organs, Abeta(1-42) (205 pmol/mouse i.c.v.) significantly increased interleukin-6 mRNA expression in lymph nodes and liver. Abeta(1-42) (205 pmol/mouse i.c.v.) significantly increased norepinephrine turnover in both hypothalamus and spleen. Either central or peripheral norepinephrine depletion effectively inhibited the Abeta(1-42)-induced peripheral interleukin-6 response. Pretreatment with prazosin (alpha(1)-adrenergic antagonist), yohimbine (alpha(2)-adrenergic antagonist), and ICI-118,551 (beta(2)-adrenergic antagonist), but not with betaxolol (beta(1)-adrenergic antagonist), inhibited Abeta(1-42)-induced plasma interleukin-6 levels. These results demonstrate that centrally administered Abeta(1-42) effectively induces the systemic interleukin-6 response which is mediated, in part, by central Abeta(1-42)-induced activation of the central and the peripheral norepinephrine systems.     

Site-specific modulation of LPS-induced fever and interleukin-1 beta expression in rats by interleukin-10

Bacterial lipopolysaccharide (LPS) induces fever that is mediated by pyrogenic cytokines such as interleukin (IL)-1 beta. We hypothesized that the anti-inflammatory cytokine IL-10 modulates the febrile response to LPS by suppressing the production of pyrogenic cytokines. In rats, intravenous but not intracerebroventricular infusion of IL-10 was found to attenuate fever induced by peripheral administration of LPS (10 microg/kg iv). IL-10 also suppressed LPS-induced IL-1 beta production in peripheral tissues and in the brain stem. In contrast, central administration of IL-10 attenuated the febrile response to central LPS (60 ng/rat icv) and decreased IL-1 beta production in the hypothalamus and brain stem but not in peripheral tissues and plasma. Furthermore, intravenous LPS upregulated expression of IL-10 receptor (IL-10R1) mRNA in the liver, whereas intracerebroventricular LPS enhanced IL-10R1 mRNA in the hypothalamus. We conclude that IL-10 modulates the febrile response by acting in the periphery or in the brain dependent on the primary site of inflammation and that its mechanism of action most likely involves inhibition of local IL-1 beta production.     

In vivo stimulation of sympathetic nervous system modulates osteoblastic activity in mouse calvaria

Previously, we demonstrated that epinephrine induced the expression of interleukin (IL)-6 mRNA via beta-adrenoceptors in cultured human osteoblastic cells. IL-6 is well known to modulate bone metabolism by regulating the development and function of osteoclasts and osteoblasts. Recently, restraint stress and intracerebroventricular injection of lipopolysaccharide (LPS) have been reported to induce the expression of IL-6 mRNA in peripheral organs in mice in which expression is mediated by the activation of the sympathetic nervous system. To prove the physiological role of sympathetic nerves in bone metabolism in vivo, we examined by RT-PCR analysis the effects of restraint stress and intracerebroventricular injection of LPS on IL-6 mRNA expression in mouse calvaria. The expression of IL-6 mRNA in mouse calvaria was stimulated by either restraint stress (30 min) or intracerebroventricular injection of LPS (50 ng/mouse, 60 min). The treatment of mice with the neurotoxin 6-hydroxydopamine (6-OHDA, 100 mg x kg-1 x day-1 ip for 3 days) inhibited LPS (icv)-induced expression of IL-6 mRNA in their calvaria. The expression of IL-6 mRNA induced by the restraint stress was not influenced by 6-OHDA, which destroys noradrenergic nerve terminals. Furthermore, pretreatment with a beta-blocker, propranolol (15 or 25 mg/kg ip), inhibited both stress- and LPS-induced increases in the level of IL-6 mRNA, but pretreatment with an alpha-blocker, phentolamine (5 mg/kg sc), did not inhibit them in mouse calvaria. In addition, treatment of calvaria with isoprenaline or norepinephrine increased IL-6 synthesis in the organ culture system. These results indicate that in vivo adrenergic stimulation modulates the osteoblastic activity in mouse calvaria via noradrenergic nerve terminals.     

The contribution of CNS MHPG to plasma MHPG in the rat

Two different experimental approaches were used to determine the central nervous system (CNS) contribution to plasma total 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in the rat. One experiment, using intracisternal injection of 6-hydroxydopamine (6-OHDA), depleted total forebrain norepinephrine (NE) and MHPG to 26 and 34% of control values, respectively. In spite of the substantial reduction in CNS MHPG, plasma MHPG was not significantly different from control values. The second experiment used clonidine and debrisoquine to differentially impair central and peripheral NE metabolism. The results of this experiment confirm those of the 6-OHDA experiment in suggesting that the CNS contribution to plasma MHPG in the rat is negligeable.     

Aspects of central and peripheral regulation of reproduction in mammals

To increase our knowledge concerning the central and peripheral regulation of reproduction in mammals a series of studies were performed. In the first experiment, we found that exogenous leptin altered the activity of the hypothalmo-pituitary-gonadotropic axis in sheep during insufficient feeding. The action of leptin appears to be mediated by changes in GnRH and LH secretion as well as NPY immunoreactivity. The aim of the second experiment was to investigate the role of the adipoinsular axis hormones during pregnancy in rats. The elevated levels of plasma leptin as wells as the increased mRNAs expression of the leptin receptors in placenta indicate the significant role of the hormone in fetal growth and development. On the other hand, a decrease in leptin receptors mRNA content within hypothalamus and pituitary together with unchanged plasma insulin level may suggest that during rat pregnancy leptin resistance was developed in the hypothalamus, pituitary and pancreatic islets. The third experiment was carried out to establish the role of opioids and glucocorticoids in the regulation of the hypothalmo-pituitary-gonadal axis in ewes during natural or synchronized estrous cycle. Prolonged treatment with progesterone resulted in significant changes in plasma levels of Met-enkephalin, cortisol and steroids and altered the expression of proenkephalin mRNA in the hypothalamus, pituitary, ovary and adrenals. Injections of Met-enkephalin or naltrexone (blocker of opioid receptors) modulated the progesterone influence in tested tissues. The data clearly suggest that opioids are involved in the regulation of the estrous cycle at the hypothalamo-pituitary-gonadal/adrenal axes.     

Differential Effects of Chemical Sympathectomy on Expression and Activity of Tyrosine Hydroxylase and Levels of Catecholamines and DOPA in Peripheral Tissues of Rats

Tyrosine hydroxylase (TH) mRNA and activity and concentrations of 3,4-dihydroxyphenylalanine (DOPA) and catecholamines were examined as markers of sympathetic innervation and catecholamine synthesis in peripheral tissues of sympathectomized and intact rats. Chemical sympathectomy with 6-hydroxydopamine (6-OHDA) markedly decreased norepinephrine and to a generally lesser extent TH activities and dopamine in most peripheral tissues (stomach, lung, testis, duodenum, pancreas, salivary gland, spleen, heart, kidney, thymus). Superior cervical ganglia, adrenals and descending aorta were unaffected and vas deferens showed a large 92% decrease in norepinephrine, but only a small 38% decrease in TH activity after 6-OHDA. Presence of chromaffin cells or neuronal cell bodies in these latter tissues, indicated by consistent expression of TH mRNA, explained the relative resistance of these tissues to 6-OHDA. Stomach also showed consistent expression of TH mRNA before, but not after 6-OHDA, suggesting that catecholamine synthesizing cells in gastric tissue are sensitive to the toxic effects of 6-OHDA. Tissue concentrations of DOPA were mainly unaffected by 6-OHDA, indicating that much of the DOPA in peripheral tissues is synthesized independently of local TH or sympathetic innervation. The differential effects of chemical sympathectomy on tissue catecholamines, DOPA, TH mRNA and TH activity demonstrate that these variables are not simple markers of sympathetic innervation or catecholamine synthesis. Other factors, including presence of neuronal cell bodies, parenchymal chromaffin cells, non-neuronal sites of catecholamine synthesis and alternative sources of tissue DOPA, must also be considered when tissue catecholamines, DOPA and TH are examined as markers of sympathetic innervation and local catecholamine synthesis.     

Distribution of transferrin synthesis in brain and other tissues in the rat

Levels of transferrin mRNA were measured by hybridization to transferrin cDNA in extracts from various areas of rat brain and other tissues. The highest concentrations of transferrin mRNA were found in the liver and the choroid plexus of the lateral and third ventricles. Lower concentrations were observed in the medulla and thalamus, choroid plexus of the fourth ventricle, cortex, hypothalamus, cerebellum, pituitary, testis, placenta, stomach, spleen, kidney, muscle, and heart. Yolk sac, small intestine, and adrenal glands did not contain detectable transferrin mRNA levels. The size of transferrin mRNA was the same in liver, brain, and testis. Upon incubation of choroid plexus pieces with [14C]leucine in vitro, about 4% of the radioactive protein secreted into the medium was found to be transferrin. Together with previous data (Dickson, P.W., Howlett, G.J., and Schreiber, G. (1985) J. Biol. Chem. 260, 8214-8219; Dickson, P.W., Aldred, A.R., Marley, P.D., Bannister, D., and Schreiber (1986) J. Biol. Chem. 261, 3475-3478) the obtained data suggest that the choroid plexus plays a role in maintenance of homeostasis in the microenvironment of the central nervous system by synthesizing and secreting plasma proteins.     

Desipramine administered chronically inhibits lipopolysaccharide-stimulated production of IL-1β in the brain and plasma of rats

Nowadays, it is assumed that therapeutic efficacy of antidepressants depends, at least partly, on their anti-inflammatory properties. The present study investigated for the first time the effect of 21-day oral administration of desipramine on the lipopolysaccharide (LPS)-stimulated IL-1β concentration in the olfactory bulb, hypothalamus, frontal cortex, hippocampus and plasma of rats, and on the LPS-induced IL-1β mRNA level in the olfactory bulb. Desipramine (15 mg/kg/day) reduced significantly the LPS (250 μg/kg i.p.)-induced IL-1β concentration in the olfactory bulb, hypothalamus and in plasma, and diminished the LPS effect on IL-1β mRNA in the olfactory bulb. Plasma concentration of desipramine was comparable to its therapeutic range. By using the α1/α2-adrenoceptor antagonist prazosin and the unspecific β-adrenoceptor antagonist propranolol given prior to LPS, we found that the effect of desipramine on LPS-induced IL-1β production was partially mediated by both adrenoceptors in the olfactory bulb and plasma, and that β-adrenoceptors contributed also to its effect on the stimulated IL-1β concentration in the hypothalamus. The effect of LPS on the cerebral IL-1β levels was, in part, mediated by β-adrenoceptors and, in a region-specific manner, by α1/α2-adrenoceptors. The findings provide evidence for central and peripheral anti-inflammatory activity of desipramine and confirm the impact of the noradrenergic system on IL-1β production induced by an immunostimulatory challenge.     

Dynamic changes in organ blood flow and oxygen consumption during acute asphyxia in fetal sheep

The effects of acute asphyxia on both the time course of blood flow changes in central and peripheral organs, including the skin, and the time course of changes in oxygen consumption were studied in 9 unanaesthetized fetal sheep in utero at 130 +/- 2 days of gestation during 4-min arrest of uterine blood flow. Blood flow distribution and total oxygen consumption were determined at 1-min intervals during asphyxia using isotope-labelled microspheres (15 micrograms diameter) and by calculating the decline of the arterial O2 content, respectively. During asphyxia peripheral blood flow including that to the skin, scalp, and choroid plexus decreased rapidly, whereas blood flow to the heart, brain stem and (in surviving fetuses only) adrenals increased slowly. Total oxygen consumption fell exponentially with time and was closely correlated with the fall in both arterial oxygen content and peripheral blood flow; the time courses of these changes were very similar to those of the decreasing blood flows to the skin and scalp. Blood flow within the brain was redistributed at the expense of the cerebrum and the choroid plexus; the total blood flow to the brain did not change. In the 5 fetuses that died during the recovery period adrenal blood flow failed to increase and, at the nadir of asphyxia, peripheral vessels dilated and central vessels constricted. We conclude that in fetal sheep near term during acute asphyxia the time course of changes in blood flow to central and peripheral organs is different; total oxygen consumption depends on arterial O2 content and peripheral blood flow; total blood flow to the brain does not change, but is redistributed towards the brain stem at the expense of the cerebrum and choroid plexus; fetal death is preceded by a failure of adrenal blood flow to increase, by peripheral vasodilatation, and by central vasoconstriction and skin blood flow validly indicates rapid changes in the distribution of blood flow and the changes in oxygen consumption that accompany it.     

Regional Distribution and Relative Abundance of Serotonin2c Receptors in Human Brain: Effect of Suicide

Abnormalities in serotonin receptor subtypes have been observed in the postmortem brain of suicide victims. We examined the regional distribution of serotonin (5HT)(2C) receptor mRNA in several areas of the human brain and also compared its protein and mRNA expression in the prefrontal cortex (PFC), hippocampus, and choroid plexus between suicide victims and normal control subjects. 5HT(2C) receptors were found to be distributed in several areas of the human brain (in order of abundance): highly concentrated and richest in choroid plexus; hypothalamus; nucleus accumbens; with the lowest abundance in PFC and cerebellum. Comparison of 5HT(2C) receptors between suicide victims and control subjects showed higher protein levels in the PFC but not the hippocampus or choroid plexus of suicide victims. However, there were no significant differences in mRNA levels between suicide victims and control subjects in these brain areas. These results suggest that 5HT(2C) receptors are richly distributed throughout the brain with the highest level in the choroid plexus and that abnormalities in protein expression of 5HT(2C) receptors in the PFC may be associated with suicide.     

Effect of L-threo-3,4-dihydroxyphenylserine (L-DOPS) on catecholamine levels in plasma and cerebrospinal fluid (CSF) in anesthetized rats

The effect of L-threo-3,4-dihydroxyphenylserine (L-DOPS) on norepinephrine (NE) levels in plasma and CSF was examined in urethane-anesthetized rats. Intravenous injection of L-DOPS (0.5, 1, and 10 mg/100 g body wt) raised plasma NE levels in a dose-related manner whereas CSF NE levels were significantly increased only by the largest dose of L-DOPS. Intracerebroventricular injection of L-DOPS (50 and 250 micrograms/rat) dose-relatedly raised CSF NE levels whereas plasma NE levels were slightly increased by a larger dose of L-DOPS. These findings may indicate that L-DOPS stimulates central noradrenergic mechanisms in the rat although a large dose of L-DOPS is required for peripheral administration.     

Changes in central and peripheral inflammatory responses to lipopolysaccharide in ovariectomized female rats

Obesity leads to increases in inflammatory responses in a site-specific manner. Ovariectomized animals, usually used as menopause models, exhibit obesity; however, their inflammatory responses have not been fully examined. In the present study, we investigated whether ovariectomy had site-specific effects on inflammatory responses. First, fever and anorectic responses to systemic injections of lipopolysaccharide (LPS) (500 μg/kg, i.p.) were compared between ovariectomized rats (OVX) and sham-operated female rats (Sham). Inflammatory cytokines at the central and peripheral levels were also compared under saline-injected and LPS-injected conditions. Body weight in OVX was significantly higher than in Sham. The anorectic responses (reduction of body weight and food intake) to LPS were higher in OVX than in Sham. In the hypothalamus, all of the examined cytokine (IL-1β, TNF-α and IL-6) mRNA levels in OVX were higher than in Sham under the LPS-injected condition. On the other hand, in serum and adipose tissue, only IL-6, not IL-1β and TNF-α, levels in OVX were significantly higher than those in Sham under the LPS-injected condition. Second, responses to central (intracerebroventricular) injections of LPS (500 ng) were compared between OVX and Sham. The result was that the fever response in OVX was more evident than in Sham. Finally, responses to systemic injections of LPS (500 μg/kg, i.p.) were compared between OVX (OVX-oil) and OVX with estradiol (E) and progesterone (P) supplementation (OVX-EP). The anorectic responses and hypothalamic cytokine mRNA levels under LPS-injected condition were not different between OVX-oil and OVX-EP. These results indicate that ovariectomy enhances inflammatory responses, especially at the central level compared with the peripheral level. As supplementation of E and P could not attenuate the anorectic and cytokine responses to LPS, the deficiency of gonadal steroids might not be directly involved in the increase of inflammatory responses in OVX.     

自发性高血压大鼠中枢血管紧张素Ⅱ的变化对中枢肾上腺素...

The content of norepinephrine (NE) and epinephrine (E) in the brain of spontaneously hypertensive rats has proved abnormal, but the cause remained unknown. It was shown in the recent work that NE content in pons, posterior hypothalamus, nucleus caudatus and E concentration in medulla oblongata, anterior and posterior hypothalamus of 12-week old stroke-prone spontaneously hypertensive rats (SHRSP) were much higher than those of age-matched Wister-Kyoto rats (WKY). SHRSP also showed higher levels of systolic blood pressure (SBP) and brain angiotensin II (A II) than WKY. Intracerebroventricular (icv) perfusion of angiotensin-converting enzyme inhibitor captopril (20 micrograms for each time and three times for each day for four weeks) inhibited the synthesis of brain A II and reduced SBP and NE, E contents in all examined brain areas in SHRSP and WKY. However, the effects of chronically perfused captopril on SBP and brain NE, E levels in SHRSP were much more significant than in WKY. The results indicate that the modulatory effects of central renin-angiotensin system (RAS) on central adrenergic and noradrenergic system might be overactivated in SHRSP, which might partially responsible for the abnormally high levels of NE, E in some of the brain areas of SHRSP.     

Rat choroid plexus specializes in the synthesis and the secretion of transthyretin (prealbumin). Regulation of transthyretin synthesis in choroid plexus is independent from that in liver

Synthesis of total protein and of transthyretin in rat choroid plexus was studied by measuring the incorporation of radioactive leucine into proteins in choroid plexus tissue incubated in vitro. About 20% of the protein newly synthesized in choroid plexus and about 50% of the newly synthesized protein secreted into the medium was transthyretin. Evidently, the choroid plexus is very active in the biosynthesis of this carrier protein for thyroid hormones and could be an important link in the chemical communication between the body and the central nervous system. Acute inflammation, which leads to a profound rearrangement of the pattern of plasma protein synthesis rates in the liver, produced distinct changes in the levels for plasma protein mRNAs in the liver. The levels of the mRNAs for alpha 1-acid glycoprotein and major acute phase alpha 1-protein increased more than 30-fold, those for transthyretin and albumin decreased to 27 and 57% of normal, respectively. The pattern of the observed changes in the levels of mRNAs for plasma proteins in the liver was independent of whether the acute inflammation was produced by subcutaneous injection of turpentine or intraperitoneal injection of a suspension of talcum. However, levels of transthyretin mRNA in choroid plexus were affected only very slightly, or not at all. Apparently, transthyretin synthesis in liver and choroid plexus is regulated independently during the acute phase response. No mRNA was detected in choroid plexus for albumin, alpha 1-acid glycoprotein, and major acute phase alpha 1-protein under any conditions.     

Roles of Prostaglandins D2 and E2 in Interleukin-1-Induced Activation of Norepinephrine Turnover in the Brain and Peripheral Organs of Rats

Abstract: Possible roles of prostaglandins (PGs) in interleukin-1 (IL-1)-induced activation of noradrenergic neurons were examined by assessing norepinephrine (NE) turnover in the brain and peripheral organs of rats. An intraperitoneal injection of human recombinant IL-1β accelerated NE turnover in the hypothalamus, spleen, lung, diaphragm, and pancreas. A similar increase in NE turnover was also observed after intracerebroventricular injection of corticotropin-releasing hormone (CRH). Pretreatment with indomethacin (cyclooxygenase inhibitor) abolished the IL-1-induced, but not the CRH-induced, increase in hypothalamic and splenic NE turnover. To elucidate which eicosanoid-cyclooxygenase product(s) is responsible for accelerating NE turnover, PGD₂, PGE₂, PGF_2α, U-46619 (stable thromboxane A₂ analogue), or carbacyclin (stable prostacyclin analogue) was administered intracerebroventricularly. Among them, PGE₂ was the only eicosanoid effective in increasing NE turnover in spleen, whereas PGD₂ was effective in the hypothalamus. The stimulative effect of PGD₂ was abolished by pretreatment with intracerebroventricular injection of a CRH antiserum. These results suggest that the action of IL-1 is mediated through PGD₂ production to activate the noradrenergic neurons in the hypothalamus, and through PGE₂ production to increase sympathetic nerve activity in spleen.     

Norepinephrine stimulates interleukin-6 mRNA expression in primary cultured rat hepatocytes

Non-invasive immobilization stress causes an increase in the plasma interleukin (IL)-6 level accompanied by increased IL-6 mRNA expression and IL-6 immunoactivity in the liver [Biochem. Biophys. Res. Commun. (1997) 238, 707-711]. In the present study, using rat primary cultured hepatocytes and non-parenchymal liver cells, the effect of norepinephrine (NE) on IL-6 mRNA expression was determined. IL-6 mRNA expression in hepatocytes, but not in non-parenchymal liver cells, increased when the cells were treated with NE. The stimulatory effect of NE was inhibited by the combined use of alpha- and beta-adrenergic antagonists. IL-6 mRNA expression in hepatocytes also increased on incubation with the culture medium of non-parenchymal liver cells treated with NE. The effect of the medium was blocked by an IL-1 receptor antagonist. Moreover, exogenous IL-1beta stimulated IL-6 mRNA expression in hepatocytes. IL-1beta was present in the medium of non-parenchymal liver cells and increased with NE-treatment. These results suggest that NE released from sympathetic nerve terminals during stress can directly increase IL-6 mRNA expression in hepatocytes and indirectly through IL-1beta production from non-parenchymal liver cells.