Indomethacin attenuates oxytocin and hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1 beta

Systemic administration of the cytokine IL-1 beta produces a significant release of ACTH into the plasma and activation of hypothalamic oxytocin (OT) and corticotropin releasing factor (CRF) cells. However, the mechanism(s) by which systemic IL-1 beta induces these responses is not clear. In the present study, we have investigated the proposal that catecholamine cells of the ventrolateral medulla (VLM) and nucleus of the solitary tract (NTS) can relay circulating IL-1 signals via a prostaglandin-dependent mechanism to effect the HPA axis responses in the rat. Intra-arterial administration of IL-1 beta (1 pg/kg) to otherwise untreated animals produced a prominent release of ACTH into the plasma, substantial c-fos expression in paraventricular medial parvocellular (mPVN) corticotropin releasing factor (CRF) cells, supraoptic (SON) and paraventricular nucleus (PVN) OT cells, area postrema cells, NTS and VLM catecholamine cells and cells of the central amygdala. Pretreatment with the prostaglandin synthesis inhibitor, indomethacin (10 mg/kg body weight ia) 15 min before IL-1 beta administration (1 pg/kg ia) significantly reduced plasma ACTH release and c-fos expression in PVN and SON OT cells and MPVN CRF cells, in addition, the area postrema, A1 and C1 catecholamine cell groups of the VLM and A2 and C2 catecholamine cell groups of the NTS, all exhibited concomitant reductions in c-fos expression. Conversely indomethacin administration did not alter the IL1 beta-induced expression of c-fos in the central amygdala. These data suggest that central pathways involved in the IL-1 beta-induced activation of the HPA axis and OT cells are, at least in part, dependent upon prostaglandin synthesis. It is proposed that neurons in the area postrema, NTS and VLM might mediate this IL-1 beta-induced activation of hypothalamic CRF and OT cells and release of ACTH into the plasma.     

Regulation of interleukin-1ra, interleukin-1 alpha, and interleukin-1 beta production by human alveolar macrophages with phorbol myristate acetate, lipopolysaccharide, and interleukin-4

An attempt was made to estimate the risk of severe cutaneous adverse reactions (SCARs) to Fansidar (sulfadoxine plus pyrimethamine). Cases were identified through a spontaneous reporting system. Persons exposed were estimated using sales data of 27 countries reporting one SCAR case for either Fansidar or a related product, Bactrim (cotrimoxazole; sulfamethoxazole plus trimethoprim). Between 1974 and 1989, 126 cases were notified for Fansidar: 87 cases of erythema multiforme or Stevens-Johnson syndrome, and 39 cases of toxic epidermic necrolysis. 86% of cases were reported in Europe or North America. In 116 cases with use known, prophylaxis was the reason in 103, and treatment in 13. Toxic epidermolysis and erythema multiforme/Stevens-Johnson syndrome had case fatalities of 36 (95% confidence intervals 21 to 53%) and 9% (4 to 18%), respectively. Fansidar users were estimated at 117 million, and the overall SCAR risk to be 1.1 (0.9 to 1.3) per million. For developing countries with mainly single dose use, the risk was estimated to 0.1 (0.0 to 0.1) per million. For Europe and North America with mainly prophylactic use, the risk was 10 (8 to 12) and 36 (23 to 48) per million, respectively. Prophylactic use had a 40 times higher risk than single dose therapeutic use. The aggregated risk peaked in 1984-1985, with global and North American SCAR frequencies of 3.4 (2.4 to 4.3) and 72 (41 to 102) per million, respectively. After 1985, North America reported only one further case despite continued use by an estimated 0.3 million persons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Volatile anesthetics do not alter bradykinin-induced release of nitric oxide or L-citrulline in crystalloid perfused guinea pig hearts

Trimethylamine N-oxide (TMAO) is an abundant compound of tissues of marine fish and invertebrates. During fish spoilage, certain marine bacteria can reduce TMAO to nauseous trimethylamine (TMA). One such bacterium has been isolated and identified as a new Shewanella species, and called Shewanella massilia. The anaerobic growth of S. massilia is greatly increased when TMAO is added, indicating that TMAO reduction involves a respiratory pathway. The TorA enzyme responsible for TMAO reduction is a molybdenum cofactor-containing protein of 90 kDa located in the periplasm. Whereas TorA is induced by both TMAO and dimethylsulfoxide (DMSO), this enzyme has a high substrate specificity and appears to only efficiently reduce TMAO as a natural compound. The structural torA gene encoding the TMAO reductase (TorA) and its flanking regions were amplified using PCR techniques. The torA gene is the third gene of a TMAO-inducible operon (torECAD) encoding the TMAO respiratory components. The torC gene, located upstream from torA encodes a pentahemic c-type cytochrome, likely to be involved in electron transfer to the TorA terminal reductase. TorC was shown to be anchored to the membrane and, like TorA, is induced by TMAO. Except for the TorE protein, which is encoded by the first gene of the torECAD operon, all the tor gene products are homologous to proteins found in the TMAO/DMSO reductase systems from Escherichia coli and Rhodobacter species. In addition, the genetic organization of these systems is similar. Although these bacteria are found in different ecological niches, their respiratory systems appear to be phylogenetically related, suggesting that they come from a common ancestor.     

Correlation of interleukin-1 beta, interleukin-6, and periodontitis

In order to understand the role of IL-1 beta and IL-6 in the periodontal tissue destruction coincident to periodontitis, we assessed the levels of these two mediators in both the gingival tissue and the serum of patients with periodontal disease and of periodontally healthy subjects. In addition, production of IL-6 by six healthy human gingival fibroblast (HGF) strains in response to IL-1 beta was also investigated. The levels of IL-1 beta and IL-6 in gingival tissues and in serum were examined by ELISA. Both mediators were observed to increase in diseased tissues of patients with adult periodontitis, and there was a positively significant relationship between both mediators and clinical assessments of periodontal destruction. Moreover, a significant correlation was also noted between levels of IL-1 beta and IL-6 in gingival tissues of periodontitis patients (r = 0.4334, p < 0.01). However, there was no significant difference in the serum levels of IL-1 beta and IL-6 between periodontitis patients and periodontally healthy controls. In fibroblast cultures, confluent monolayers of HGF were incubated with recombinant human IL-1 beta for 48 h at 37 degrees C in 5% CO2 and air. At the end of the culture period, supernatants were collected and assayed for IL-6 activity by inducing proliferation in the IL-6-dependent hybridoma cell line 7TD1. A dose-dependent stimulatory effect of IL-1 beta on IL-6 production by HGF was noted, wherein 3 strains exhibited higher IL-6 activity than the other 3. These data indicate that the levels of IL-1 beta and IL-6 in gingival tissues are closely related to the severity of periodontal disease and that the IL-1 beta and IL-6 produced in gingival tissues may not reflect these two mediators levels in serum. Moreover, IL-1 beta responsiveness of HGF in IL-6 production depends on both the concentration of IL-1 beta and cells of individual subjects. Since HGF are present in periodontal lesion, it is possible that IL-6 secretion stimulated by exposure to inflammatory cell products such as IL-1 beta may participate in the destruction of periodontal tissue in periodontitis.     

Influence of indapamide and chlorthalidone on reperfusion-induced ventricular fibrillation in isolated guinea pig hearts

The delayed rectifier potassium current (IK) is a major repolarizing current in guinea pig ventricular myocytes. Blockade of IK or other repolarizing currents is of increasing interest for development of antiarrhythmic drugs; however, these interventions may also be proarrhythmic. In the present study, we compared the potential antiarrhythmic properties of indapamide and chlorthalidone, two structurally related sulfonamide diuretics which differ in their ability to block the slow component of the delayed rectifier (IKs) in isolated, buffer-perfused guinea pig hearts. Hearts underwent 30-min global no-flow ischemia and 10-min reperfusion. Dose-response (10(-7)-10(-4) M) effects of indapamide or chlorthalidone on reperfusion-induced arrhythmias, coronary flow, and heart rate (HR) were evaluated in a randomized blinded fashion. There was no significant difference in the incidence of ventricular fibrillation (VF) for either compound as compared with untreated controls. However, VF duration was reduced to < 40 s in all hearts treated with indapamide 10(-4) M). Mean VF duration with indapamide 10(-4) M was 31 +/- 4 versus 70 +/- 40 s in controls (p < 0.05). Chlorthalidone did not protect against reperfusion-induced arrhythmias. HR was unchanged with either compound; coronary flow during the control perfusion period increased approximately 43% with indapamide 10(-4) M (p < 0.05 vs. all treatment groups). These results demonstrate that indapamide, but not chlorthalidone, confers significant protection against reperfusion-induced VF in this experimental preparation and suggest that selective block of IKs may be antiarrhythmic.     

Biological activity and brain actions of recombinant rat interleukin-1alpha and interleukin-1beta

An HMQC experiment is proposed, dubbed FHMQC, where water flip-back is achieved by a single water-selective pulse preceding the basic HMQC pulse sequence. The scheme is demonstrated with a 15N,1H-HMQC spectrum of uniformly 15N/2H-labelled S. aureus DNA gyrase B with a molecular weight of 45 kDa for the unlabelled protein. The sensitivity of the experiment is improved compared to that of an FHSQC spectrum. It is further shown that the original FHSQC experiment can be shortened by the use of bipolar gradients. Relaxation times of different 15N magnetizations and coherences were measured. The new FHMQC scheme is implemented in 3D NOESY-15N-HMQC and 3D 15N-HMQC-NOESY-15N-HMQC pulse sequences which are demonstrated with a 24 kDa fragment of uniformly 15N/13C/2H-labelled S. aureus DNA gyrase B.     

Induction of intracellular ceramide by interleukin-1 beta in oligodendrocytes

The sphingomyelin pathway has been implicated in mediating the effect of several extracellular agents leading to important biochemical and cellular changes. The aim of this investigation is to study interleukin-1 beta (IL-1 beta) signaling in oligodendrocytes. For this purpose, the CG4 oligodendrocyte cells were differentiated and incubated with IL-1 beta. This treatment induced a time- and dose-dependent increase of the endocellular ceramide. To mimic the effect of the elevation of endogenous ceramide, the CG4 cells were treated with the ceramide analogue C2-ceramide. Cell survival, measured with the MTT assay, showed that, by increasing the concentration of ceramide, up to 40% of CG4 cells were dying within 6 h, similar data were obtained with the primary differentiated oligodendrocytes. Condensation of chromatin, nuclear fragmentation, and formation of apoptotic bodies indicated that apoptosis was the cause of death. Surprisingly, long-term exposure (72 h) to increasing concentrations of IL-1 beta, which increases intracellular ceramide, did not induce oligodendroglial cell death. These results show that an increase of intracellular ceramide is not sufficient to induce apoptosis in oligodendrocytes and that IL-1 beta signaling through the ceramide pathway in these cells can mediate functions other than programmed cell death.     

Mouse peritoneal macrophages contain abundant omega-6 lipoxygenase activity that is independent of interleukin-4

The action of an omega-6 lipoxygenase (LO) has been implicated in the development of atherosclerosis through a mechanism involving oxidation of LDL, and its regulation in macrophages may have important implications for the disease process. Human monocyte-derived macrophages (HMDMs) showed no demonstrable LO protein or activity unless they were incubated with interleukin-4 (IL-4). In contrast, mouse peritoneal macrophages (MPMs) possessed significant basal levels of LO activity and protein that were augmented by IL-4 treatment. Interferon gamma prevented the induction of LO in both HMDMs and MPMs. Whereas interferon gamma could completely block the IL-4 induction of LO in human cells, it did not suppress basal LO activity in MPMs. Both HMDMs and MPMs exhibited similar concentration-response relationships for stimulation of LO activity and protein, with maximal induction at 1 ng/mL IL-4. The time course of IL-4 induction of LO activity was markedly different in human and murine cells. IL-4 induced LO activity and protein in human cells by 48 hours that were maximal by 72 hours; there was a decline to a new baseline by 96 hours. MPMs have a significant amount of LO activity at baseline, which declined with time by nearly 10-fold in the absence of IL-4, IL-4 blunted the decline of LO activity with time and restored activity to that found at baseline by 48 hours. IL-4 was not responsible for the LO activity present in freshly isolated MPMs since both activity and protein content were similar in cells harvested from IL-4+/+ and IL-/- mice. Therefore, whereas IL-4 may be an important modulator of LO production in vitro, it is not essential for the in vivo expression of this protein. Further, these studies demonstrate that significant differences exist between monocyte-derived macrophages matured in vitro and tissue macrophages that have matured in vivo.     

A neuromodulatory role of interleukin-1beta in the hippocampus

It is widely accepted that interleukin-1beta (IL-1beta), a cytokine produced not only by immune cells but also by glial cells and certain neurons influences brain functions during infectious and inflammatory processes. It is still unclear, however, whether IL-1 production is triggered under nonpathological conditions during activation of a discrete neuronal population and whether this production has functional implications. Here, we show in vivo and in vitro that IL-1beta gene expression is substantially increased during long-term potentiation of synaptic transmission, a process considered to underlie certain forms of learning and memory. The increase in gene expression was long lasting, specific to potentiation, and could be prevented by blockade of potentiation with the N-methyl-D-aspartate (NMDA) receptor antagonist, (+/-)-2-amino-5-phosphonopentanoic acid (AP-5). Furthermore, blockade of IL-1 receptors by the specific interleukin-1 receptor antagonist (IL-1ra) resulted in a reversible impairment of long-term potentiation maintenance without affecting its induction. These results show for the first time that the production of biologically significant amounts of IL-1beta in the brain can be induced by a sustained increase in the activity of a discrete population of neurons and suggest a physiological involvement of this cytokine in synaptic plasticity.     

Effect of prolactin on nitric oxide and interleukin-1 production of murine peritoneal macrophages: role of Ca2+ and protein kinase C

The Psychiatric Hospital at the Municipal (General) Hospital in G?rlitz, Germany, was the only Department of Psychiatry in a non-University (general) hospital in the newly integrated German provinces who were originally part of the so-called "German Democratic Republic" before the re-unification of Germany, to participate in the German collective study on "Psychiatric and Psychosomatic Consultation and Liaison Service in German General Hospitals-A Multicentre Empirical Study to Assess and Evaluate Existing Structures and Services". This study is an independent part project that includes specific questions forming part of the European collective study on "Effectiveness of Mental Health Consultation and Liaison Service Delivery in the General Hospital".     

Systemic liberation of interleukin-1 beta and interleukin-1 receptor antagonist in the perioperative phase of liver transplantation

We measured systemic serum levels of interleukin-1 receptor antagonist (IL-1ra), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) during the preoperative, anhepatic, and postreperfusional phases up to the 7th postoperative day in 60 patients undergoing orthotopic liver transplantation (LTx). In contrast to IL-1 beta, IL-1ra, TNF-alpha, and IL-6 showed a significant elevation in relation to the early phase after reperfusion, while TNF-alpha displayed a high grade of scatter. In addition, IL-1ra levels were significantly elevated during the anhepatic phase. Maximum serum levels were found at 15 min after reperfusion, 120 min after reperfusion, and on the 1st postoperative day, respectively. Serum levels decreased considerably at 24 h and 7 days after reperfusion. The comparative monitoring of systemic cytokine and cytokine antagonist levels, in particular the liberation of IL-1ra and IL-6 may provide useful parameters for the development of new liver preservation theories for LTx.     

Role of nitric oxide in responses to renin-angiotensin system inhibition in sodium-depleted guinea pig and rat

Previous reports have suggested that NO is an important mediator of the antihypertensive effects of renin-angiotensin system (RAS) inhibition. We examined the effects of the NO synthase inhibitor L-NNA on the hypotensive effects of captopril, the Ang II antagonist EXP 3174, or the renin inhibitor terlakiren. In sodium-depleted guinea pigs (GPs), L-NNA (3 mg/kg) increased MAP by 15-21% for at least 5 hours. L-NNA partially blocked the hypotensive effects of captopril (1 mg/kg, iv), but not those of EXP 3174 (1 mg/kg, iv) or terlakiren (3 mg/kg). In sodium-depleted rats, 10 mg/kg L-NNA (iv) increased MAP by 16-22%, and partially or fully blocked the hypotensive effect of EXP 3174 (1 mg/kg, iv) or captopril (3 mg/kg, iv), respectively. Thus, in contrast to the rat, NO in GPs appears to participate only in the hypotensive action of ACE inhibition and does not appear to be strongly involved in the hypotensive action of AII antagonism or renin inhibition. The involvement of NO in the hypotensive effects of RAS antagonists other than ACE inhibitors may be species-dependent.     

Histamine H2-receptor antagonism of T-593: studies on positive chronotropic responses in guinea pig atria

To assess the impact of changes in practice patterns, hospital charges (overall and component charges excluding professional fees) for 1992 were compared to 1985 data for three orthognathic surgical procedures: bilateral sagittal split osteotomy (BSSO), Le Fort I osteotomy (LFI), and a combination of both (BSSO/LFI). Data for 1992 were obtained for 59 patients (26 BSSO, 18 LFI, 15 BSSO/LFI). Secondary analysis of similar data for 1985 included 77 patients (27 BSSO, 16 LFI, 34 BSSO/LFI). Changes in clinical practice from 1985 to 1992 reduced mean length of stay (days): BSSO 3.2 to 1.2, LFI 3.7 to 1.4, BSSO/LFI 4.1 to 1.8. Mean total charges (dollars) increased: BSSO 3,086 to 5,023, LFI 3,538 to 6,784, BSSO/LFI 4,778 to 8,816. If 1992 charges are expressed in 1985 dollars, ancillary, pharmacy, and room charges all are reduced. Charges attendant to the surgical procedure (anesthesia, operating room, supply, and recovery) were just over half of total charges in 1985. By 1992, these components escalated to 80% of total charges. Most notable was the increase in supply charges. Charges for rigid fixation were a major component of increased supply charges in 1992. Surgeons minimally influence charges attendant to the operating room and postanesthesia recovery, the major components of total charges in 1992. Quality can be maintained with reduction in some charge categories, but these components total less than 25% of the patient's bill. Technology changes benefit patients, but a judgment must be made weighing benefits against increased health care costs.     

Immunopotentiation of bovine respiratory disease virus vaccines by interleukin-1 beta and interleukin-2

Three experiments, using 85 crossbred beef calves, were conducted to evaluate the adjuvanticity of single, multiple, and combined doses of recombinant bovine IL-1 beta (rBoIL-1 beta) and recombinant bovine IL-2 (rBoIL-2), with a modified-live bovine herpesvirus-1/parainfluenza-3 (BHV-1/PI-3) virus vaccine and a killed bovine viral diarrhea (BVD) virus vaccine. Cytokines were administered intramuscularly at vaccination but at different injection sites. All cytokine treatments increased non-major histocompatibility complex (MHC)-restricted cytolytic capability of peripheral blood mononuclear cells (PBMC) against virus-infected target cells and serum neutralizing (SN) antibody titers to BHV-1 and BVD virus. Multiple, consecutive injections of rBoIL-2 generally showed the greatest adjuvant effect, and no additive effect was observed when rBoIL-1 beta and rBoIL-2 were administered together. In a challenge experiment, calves were vaccinated with a modified-live BHV-1/PI-3 vaccine and infected with BHV-1 on Day 21. Cytokine-treated calves had higher SN antibody titers to BHV-1 than did the control calves at the time of challenge. Calves that were administered rBoIL-2 on 5 consecutive days shed less BHV-1 and had the highest SN antibody titer to BHV-1 (Day 28). These data suggest that rBoIL-1 beta and rBoIL-2 may be useful immunoadjuvants for bovine respiratory disease virus vaccines.