Significant Increase In IL-1beta Research Articles

Cytotoxicity and proinflammatory effects of titanium and zirconia particles

BackgroundTo assess the effects of differently sized titanium (Ti) and zirconia (Zr) particles on (1) the metabolic activity of osteosarcoma-derived osteoblasts (SaOs-2) and human gingival fibroblasts (HGF) and (2) the cytokine expression of monocytes (THP-1)MethodsTi (60–80 nm and 100 nm) and Zr (2 μm and 75 μm) particles were incubated with SaOs-2, HGF, and THP-1 cells. At days 0, 2, 4, and 7 and 0, 1, 2, and 4 (THP-1), the mitochondrial activity was assessed and enzyme-linked immunosorbent assays were used to determine interleukin (IL)-1 beta and IL-6 concentrations of stimulated THP-1 at day 1.ResultsTi60–80, Ti100, Zr2, and Zr75 particles were associated with gradual and significant within-group decreases in the viability of SaOs-2 and HGF cells. These effects were less pronounced in the Zr group. Similar to control cells, THP-1 did not reveal any significant increases in IL-1 beta and IL-6 concentrations. Viability of THP-1 was merely impaired in the presence of Ti100.ConclusionsTi and Zr particles had a detrimental effect on the viability of SaOs-2 and HGF, but no proinflammatory effect on THP-1.

Induction of cytokines, MMP9, TIMPs, RANKL and OPG during orthodontic tooth movement

This controlled longitudinal intervention study investigated changes in cytokines and biomarkers of bone and tissue metabolism within gingival crevicular fluid (GCF) from patients undergoing orthodontic treatment. GCF was collected on Periopaper™ strips (Oraflow Inc., USA) from 20 volunteers at baseline, before tooth extraction and appliance placement and then at intervals during orthodontic treatment. Samples were taken 10 weeks following first appliance placement: at four hours; 7 days; and 42 days after application of distalising forces to maxillary canine teeth. Cytokines (GM-CSF, interferon-gamma, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 and TNFalpha), tissue biomarkers (MMP-9, TIMP-1 & 2) and bone metabolism indicators (RANKL and OPG) were measured in GCF using multiplex assays. Tension sites adjacent to canines showed significant increases in IL-1beta, IL-8, TNFalpha, MMP-9 and TIMPs 1 and 2 across all time points following force application, while compression sites exhibited increases in IL-1beta and IL-8 after 4 hours, MMP-9 after 7 and 42 days and RANKL after 42 days. These data demonstrate that high levels of pro-inflammatory cytokines and biomarkers of tissue and bone metabolism in GCF are associated with orthodontic force application. Elevated levels were evident at 4 hours but continued for periods of up to 6 weeks. The data suggest that GCF biomarker analysis may help optimise orthodontic forces for individual patients.

Cramoll 1,4 lectin increases ROS production, calcium levels, and cytokine expression in treated spleen cells of rats

This study reports the in vivo stimulatory effects of Cramoll 1,4 on rat spleen lymphocytes as evidenced by an increase in intracellular reactive oxygen species (ROS) production, Ca(2+) levels, and interleukin (IL)-1beta expression. Cramoll 1,4 extracted from seeds of the Leguminosae Cratylia mollis Mart., is a lectin with antitumor and lymphocyte mitogenic activities. Animals (Nine-week-old male albino Wistar rats, Rattus norvegicus) were treated with intraperitoneal injection of Cramoll 1,4 (235 microg ml(-1) single dose) and, 7 days later, spleen lymphocytes were isolated and analyzed for intracellular ROS, cytosolic Ca(2+), and IL-6, IL-10, and IL-1 mRNAs. Cell viability was investigated by annexin V-FITC and 7-amino-actinomycin D staining. The data showed that in lymphocytes activated by Cramoll 1,4 the increase in cytosolic and mitochondrial ROS was related to higher cytosolic Ca(2+) levels. Apoptosis and necrosis were not detected in statistically significant values and thus the lectin effector activities did not induce lymphocyte death. In vivo Cramoll 1,4 treatment led to a significant increase in IL-1beta but IL-6 and -10 levels did not change. Cramoll 1,4 had modulator activities on spleen lymphocytes and stimulated the Th2 response.

Sputum biomarker profiles in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) and association between pulmonary function

Lung diseases like cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are associated with chronic airway inflammation. The aim of our study was to compare a complex biomarker profile in order to characterize specific inflammatory patterns in sputum of patients with CF and COPD. Induced sputum samples of 19 CF-, 26 COPD patients and 21 healthy controls were analyzed for concentrations of IL-1beta, IL-2, IL-6, IL-8, IL-13, IP-10, MCP-1, IFN-gamma and TNF-alpha using the new cytometric bead array (CBA) technology. Significant differences in airway biomarker profiles of CF and COPD were detected. Patients with CF showed a significant increase in IL-1beta, IL-6, IL-8, IL-13, TNF-alpha, IFN-gamma and MCP-1. COPD patients showed an increase in IL-6, IL-8, IL-13 and MCP-1 compared to healthy controls. CF and COPD compared to each other exhibited differences in IL-1beta, IL-2, IL-8, TNF-alpha, IFN-gamma and MCP-1 levels. Significant correlations between the parameters of lung function and sputum biomarker levels were found. Analyzing induced sputum allows characterization of specific airway biomarker profiles in CF and COPD and can be related to the clinical status of the patient. CBA of induced sputum seems to be a pivotal tool to characterize pulmonary inflammation.

TNF‐α TGF‐β2 and IL‐1β levels in gingival and peri‐implant crevicular fluid before and after de novo plaque accumulation

The aim of this split-mouth study was to investigate levels of tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta2) and interleukin-1 beta (IL-1beta) in gingival crevicular fluid (GCF) and peri-implant crevicular fluid (PICF) after a 21-day-period of de novo plaque accumulation in the same patient. In 25 patients, samples of GCF and PICF were collected in the sulcus of the tooth and of the implant after professional hygiene. After the no-hygiene phase (21 days), second samples of GCF and PICF were taken. Third samples were collected after 69 days of re-establishment oral hygiene techniques. The crevicular fluids were used to determine the volume and the levels of TNF-alpha, TGF-beta2 and IL-1beta. The volume of the crevicular fluids increased significantly after 21 days of plaque accumulation around teeth and implants and decreased significantly by 69 days. TNF-alpha and TGF-beta2 did not change significantly among the three different samples. A significant increase of IL-1beta was observed after plaque accumulation around the teeth GCF, whereas in the PICF the increase was not statistically significant. These data suggest that increased volumes of GCF and PICF could be useful markers of early inflammation in gingival and peri-implant tissues. In the presence of de novo plaque, implants showed lower, and nearly significant, levels of IL-1beta compared with teeth.

The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia

Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment. Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS), results in behavioral deficits in the adult offspring that are relevant to schizophrenia. It is however unknown whether these effects are due to the direct action of the inflammatory stimulus on the developing fetus, or due to secondary immune mediators (cytokines) activated at maternal/fetal sites. In this study we sought to elucidate the site of action of LPS, following a single intraperitoneal (i.p.) injection, in pregnant rats at gestation day 18. Animals received 5 muCi of iodinated LPS ((125)I-LPS) and its distribution was assessed in maternal/fetal tissues (1-8 h). In addition, induction of the inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, was measured in maternal/fetal tissues following maternal LPS challenge (0.05 mg/kg, i.p.) (2-8 h). (125)I-LPS was detected in maternal tissues and placenta, but not the fetus. This distribution was accompanied by significant increases in TNF-alpha, IL-1beta and IL-6 in maternal plasma and placenta, but not in fetal liver or brain. A significant increase in IL-1beta was however detected in fetal plasma, possibly due to transfer from the maternal circulation or placenta. Collectively, these data suggest that effects of maternal LPS exposure on the developing fetal brain are not mediated by the direct action of LPS, but via indirect actions at the level of the maternal circulation or placenta.

IL-1beta, IL-6 and IL-8 levels in gyneco-obstetric infections.

During pregnancy cytokines and inflammatory mediators stimulate the expression of prostaglandin, the levels of which determine the onset of labor. The aim of this work was to study interleukin IL-1beta, IL-6 and IL-8 levels in the vaginal discharge, serum and urine of pregnant women with genitourinary infection before and after specific treatment. One hundred and fifty-one patients were studied during the second or third trimester of their pregnancy. The selected patients were: healthy or control group (n = 52), those with bacterial vaginosis (n = 47), those with vaginitis (n = 37), those with asymptomatic urinary infection (n = 15) and post-treatment. The level of cytokines was assayed by ELISA test. The Mann-Whitney U-test was used for statistical analysis. The IL-1beta levels in vaginal discharge were: control 103.5 +/- 24.2 pg/ml, bacterial vaginosis 1030 +/- 59.5, vaginitis 749.14 +/- 66.7l ( p < 0.0001), post-treatment 101.4 +/- 28.7. IL-6 values were similar in both control and infected groups, and there were no patients with chorioamnionitis. In vaginal discharge IL-6: control 14.2 +/- 3.9 pg/ml, bacterial vaginosis 13.2 +/- 3.8, vaginitis 13 +/- 4.2. IL-8 levels were: control 1643 +/- 130.3 pg/ml, bacterial vaginosis 2612.7 +/- 257.7, vaginitis 3437 +/- 460 (p < 0.0001), post-treatment 1693 +/- 126.6. In urine the results were: control 40.2 +/- 17 pg/ml, asymptomatic urinary infection 1200.7 +/- 375 (p < 0.0001). In patients with therapeutic success both IL-1beta and IL-8 returned to normal levels. Genitourinary infections induce a significant increase in IL-1beta and IL-8 levels in vaginal secretions, and IL-8 in urine as well. Both cytokines could be useful as evolutive markers of infection.

IL-1beta, IL-6 and IL-8 levels in gyneco-obstetric infections.

OBJECTIVE: During pregnancy cytokines and inflammatory mediators stimulate the expression of prostaglandin, the levels of which determine the onset of labor. The aim of this work was to study interleukin IL-1beta, IL-6 and IL-8 levels in the vaginal discharge, serum and urine of pregnant women with genitourinary infection before and after specific treatment. One hundred and fifty-one patients were studied during the second or third trimester of their pregnancy. METHODS: The selected patients were: healthy or control group (n = 52), those with bacterial vaginosis (n = 47), those with vaginitis (n = 37), those with asymptomatic urinary infection (n = 15) and post-treatment. The level of cytokines was assayed by ELISA test. The Mann-Whitney U-test was used for statistical analysis. RESULTS: The IL-1beta levels in vaginal discharge were: control 103.5 +/- 24.2 pg/ml, bacterial vaginosis 1030 +/- 59.5, vaginitis 749.14 +/- 66.7l ( p < 0.0001), post-treatment 101.4 +/- 28.7. IL-6 values were similar in both control and infected groups, and there were no patients with chorioamnionitis. In vaginal discharge IL-6: control 14.2 +/- 3.9 pg/ml, bacterial vaginosis 13.2 +/- 3.8, vaginitis 13 +/- 4.2. IL-8 levels were: control 1643 +/- 130.3 pg/ml, bacterial vaginosis 2612.7 +/- 257.7, vaginitis 3437 +/- 460 (p < 0.0001), post-treatment 1693 +/- 126.6. In urine the results were: control 40.2 +/- 17 pg/ml, asymptomatic urinary infection 1200.7 +/- 375 (p < 0.0001). In patients with therapeutic success both IL-1beta and IL-8 returned to normal levels. CONCLUSIONS: Genitourinary infections induce a significant increase in IL-1beta and IL-8 levels in vaginal secretions, and IL-8 in urine as well. Both cytokines could be useful as evolutive markers of infection.

Pro-inflammatory responses of human bronchial epithelial cells to acute nitrogen dioxide exposure.

Nitrogen dioxide (NO2) is an environmental oxidant, known to be associated with lung epithelial injury. In the present study, cellular pro-inflammatory responses following exposure to a brief high concentration of NO2 (45 ppm) were assessed, using normal human bronchial epithelial (NHBE) cells as an in vitro model of inhalation injury. Generation and release of pro-inflammatory mediators such as nitric oxide (NO), IL-8, TNF-alpha, IFN-gamma and IL-1beta were assessed at different time intervals following NO2 exposure. Effects of a pre-existing inflammatory condition was tested by treating the NHBE cells with different inflammatory cytokines such as IFN-gamma, IL-8, TNF-alpha, IL-1beta, either alone or in combination, before exposing them to NO2. Immunofluorescence studies confirmed oxidant-induced formation of 3-nitrotyrosine in the NO2-exposed cells. A marked increase in the levels of nitrite (as an index of NO) and IL-8 were observed in the NO2-exposed cells, which were further enhanced in the presence of the cytokines. Effects of various NO inhibitors combined, with immunofluorescence and Western blotting data, indicated partial contribution of the nitric oxide synthases (NOSs) toward the observed increase in nitrite levels. Furthermore, a significant increase in IL-1beta and TNF-alpha generation was observed in the NO2-exposed cells. Although NO2 exposure alone did induce slight cytotoxicity (<12%), but presence of inflammatory cytokines such as TNF-alpha and IFN-gamma resulted in an increased cell death (28-36%). These results suggest a synergistic role of inflammatory mediators, particularly of NO and IL-8, in NO2-mediated early cellular changes. Our results also demonstrate an increased sensitivity of the cytokine-treated NHBE cells toward NO2, which may have significant functional implications in vivo.

Lactobacillus plantarum 299: beneficial in vitro immunomodulation in cells extracted from inflamed human colon.

The present study determined the pattern of cytokine secretion (interleukin [IL]-1beta, tumor necrosis factor [TNF]-alpha, interferon [IFN]-gamma and IL-10) and their cellular sources in mononuclear cells isolated from colonic mucosa from normal and ulcerative colitis (UC) in response to probiotic and pathogenic bacteria. Mononuclear cells were extracted from normal and active UC colonic mucosa and incubated with pure sonicates of probiotic, commensal, and pathogenic bacteria. Cytokine secretion was measured in culture supernatant and intracellular cytokine staining measured using fluorescent-activated cytometry. In mononuclear cells isolated from normal mucosa, significant increases in mean IL-1beta were observed with enteropathogenic Escherichia coli (286.3 +/- 138.7 pg/mL P < 0.05) and E. coli (440.5 +/- 194.0 pg/mL P < 0.01) compared with unstimulated control cells (16.7 +/- 4.8 pg/mL). In contrast, mononuclear cells isolated from active UC mucosa produced significant increases in mean IL-1beta in response to stimulation with Salmonella dublin (230.5 +/- 38.8 pg/mL P < 0.05), enteropathogenic E. coli (231.7 +/- 45.3 pg/mL P < 0.05) and E. coli (465.4 +/- 60.2 pg/mL P < 0.001) compared with unstimulated control cells (60.7 +/- 17.1 pg/mL). Escherichia coli also produced significant mean increases of TNF-alpha and IFN-gamma compared with unstimulated control cells. No significant increases in IL-1beta, TNF-alpha or IFN-gamma were observed with Lactobacillus plantarum in cells derived from normal or inflamed mucosa. Strikingly, incubation of L. plantarum with mononuclear cells isolated from active UC mucosa resulted in significant increases of mean IL-10 (327 +/- 53.5 pg/mL, P < 0.05) compared with unstimulated control cells (29.7 +/- 13.2 pg/mL). Intracellular cytokine staining confirmed T-cell and macrophage IL-10 production after L. plantarum stimulation. Lactobacillus plantarum demonstrates beneficial immunomodulatory activity by increasing IL-10 synthesis and secretion in macrophages and T-cells derived from the inflamed colon. This may provide a mechanism through which probiotic bacteria ameliorate inappropriate inflammation and induce tolerance.

Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term.

Accumulating evidence suggests that human parturition represents an inflammatory process. Leukocytes are known to infiltrate uterine tissues but the exact timing, nature and quantity of these cells has not been formally characterized. We have previously demonstrated an apparent increase in pro-inflammatory cytokines within tissues of the labouring uterus. The aims of this study were to quantify and compare the leukocyte subpopulations before and during labour in fetal membranes, decidua and cervix and to quantify and compare mRNA expression of interleukin-1beta (IL-1beta), IL-6, IL-8 and tumour necrosis factor-alpha in myometrium, cervix, chorio-decidua and amnion. Biopsies of each of these tissues were obtained from pregnant women delivered by Caesarean section before and after the onset of spontaneous labour at term. Subpopulations of leukocytes were identified using immunohistochemistry and cytokine mRNA expression was quantified using Northern analysis. We found that parturition was associated with a significant increase in IL-1beta, IL-6 and IL-8 mRNA expression in cervix and myometrium, IL-6 and IL-8 mRNA expression in chorio-decidua and IL-1beta and IL-8 mRNA expression in amnion. Histological analysis demonstrated that leukocytes (predominantly neutrophils and macrophages) infiltrate the uterine cervix coincident with the onset of labour. These data lend further support to the hypothesis that labour is an inflammatory process.

Additive effects of amyloid β fragment and interleukin-1β on interleukin-6 secretion in rat primary glial cultures

The main constituent of the Alzheimer amyloid plaques is the amyloid beta (Abeta) peptide shown to activate glial cells in vitro. Activated glial cells are believed to contribute to neurotoxicity through production of inflammatory cytokines, such as interleukin-1 (IL-1), chemokines and neurotoxic substances. The IL-1 system has been proposed to play a role in neurodegenerative processes and can in turn induce expression of other cytokines such as IL-6. Recently, association of IL-1 and IL-6 gene polymorphism with Alzheimer's disease was reported, suggesting that these cytokines may play an important role in the development of the disease. In this study, rat primary mixed glial cells were treated with IL-1beta, Abeta(1-42) or Abeta(25-35). As expected the different treatments all resulted in activation of the transcription factor NFkappaB observed by electrophoretic mobility shift assay. Significant increases in IL-1beta and IL-6 mRNA levels, as analysed by reverse transcriptase-polymerase chain reaction (RT-PCR), were detected after the different treatments. In addition, increased secretion of IL-6 was detected by ELISA after 96 h exposure in response to IL-1beta, Abeta(1-42) or Abeta(25-35). When cells were exposed to both IL-1beta and Abeta(25-35) additive effects were observed. This supports that the effect of Abeta can be potentiated by concurrent exposure to inflammatory cytokines and that the IL-1 system is not necessary for Abeta effects on IL-6 expression in agreement with previous studies.

Improved recovery and delayed cytokine induction after closed head injury in mice with central overexpression of the secreted isoform of the interleukin-1 receptor antagonist.

The acute inflammatory response following traumatic brain injury (TBI) has been shown to play an important role in the development of secondary tissue damage. The proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNFalpha), are induced early after brain injury and have been implicated in the delayed damage. The IL-1 receptor antagonist (IL-1ra) has been shown to modulate the proinflammatory cytokine cascade by blocking the binding of IL-1 to its signaling receptor. In this study, we investigated the effect of transgenic overexpression of IL-1ra on the cytokine expression and neurological damage in a closed head injury (CHI) model of TBI. The neurological recovery, as analyzed by neurological severity score (NSS), was significantly higher in transgenic mice overexpressing the human secreted form of IL-1ra in astrocytes, directed by the murine glial fibrillary acidic protein promoter, as compared to wild-type mice. Analysis of tissue levels of cytokines by ELISA showed increased levels of TNFalpha in the cerebral cortex from the wild type mice 1 h after injury. After 4 h significant increases in the levels of IL-1beta and IL-6 were observed in the wild type mice. In the transgenic mice, on the other hand, no effect on TNFalpha levels was observed and no significant increases in IL-1beta and IL-6 levels could be detected until 6 h after injury. Thus, it can be concluded that blockage of IL-1 signaling by elevated levels of IL-1ra has a neuroprotective effect, in agreement with previous reports, and that central overexpression of IL-1ra results in delayed proinflammatory cytokine induction and improved neurological recovery after traumatic brain injury.

The immunomodulatory effects of prolonged intravenous infusion of propofol versus midazolam in critically ill surgical patients

Both propofol and midazolam are known to inhibit immune function. The aim of this study was to investigate cytokine production in critically ill surgical patients as early markers of immune response to prolonged infusion of propofol and midazolam. The study enrolled 40 elective patients who were to receive long-term sedation for more than 2 days. Patients were randomly allocated to one of two equally sized groups. Central venous blood samples for measurement of interleukin-1beta (IL-1beta), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were drawn prior to the start and after 48 h of infusion. After 48 h, propofol caused significant increases in IL-1beta (24%), IL-6 (23%) and TNF-alpha (4.8 times) levels, while midazolam caused significant decreases in IL-1beta (21%), IL-6 (21%) and TNF-alpha (19%). Both agents caused significant decreases in IL-8 levels (propofol: 30%, midazolam: 48%, p < 0.05). Propofol caused significant decreases in IL-2 levels (68%, p < 0.001) but increases in IFN-gamma (30%, p < 0.05), whereas there was no significant change with midazolam compared with the pre-infusion level. In conclusion, during 48 h of continuous infusion, propofol stimulated, while midazolam suppressed, the production of the pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha, and both caused suppression of IL-8 production. Propofol inhibited IL-2 production and stimulated IFN-gamma production, whereas midazolam failed to do so. Therefore, sedative agents may have clinical implications in high-risk and immunocompromised patients.

Storage of G-CSF-mobilized granulocyte concentrates.

Current standards limit granulocyte storage to 24 hours. Since G-CSF inhibits granulocyte apoptosis, it may be possible to store G-CSF-mobilized granulocytes for longer periods while maintaining cell viability and function. However, G-CSF mobilization increases the yield of granulocytes several times, and the resulting higher cell concentrations may diminish viability during storage and significant levels of pyrogenic cytokines may be produced. Ten granulocyte donors were given dexamethasone (8 mg PO), G-CSF (5 microg/kg SQ), or both and on the next day granulocyte concentrates were collected using a blood cell separator. Component cell counts, cell viablilities, pH, and IL-1beta, IL-6, IL-8 and TNF levels were measured at 2 to 4 (2), 20 to 28 (24), and 44 to 52 hours (48 hours). Significantly more granulocytes were collected when donors were given G-CSF (4.2 +/- 2.3 x 10(10)) or G-CSF plus dexamethasone (6.4 +/- 2.5 x 10(10)) compared with that collected with dexamethasone alone (2.2 +/- 1.2 x 10(10)); p = 0.03 and p = 0.002, respectively. Storage had little effect on WBC count. Slight but significant increases in IL-1beta and IL-8 occurred after 24 and 48 hours as compared to the levels at 2 hours' storage. Levels of IL-6 and TNF did not change. The pH dropped significantly with time in granulocytes mobilized with each regimen. Granulocytes mobilized with G-CSF plus dexamethasone were acidic immediately after collection, and pH was below 6.0 after 24 hours. To assess the effect of cell concentrations on pH, serial dilutions were performed on 13 granulocyte concentrates in autologous plasma prior to storage. The pH remained above 7.0 only when dexamethasone-mobilized granulocytes were diluted 1-in-8 and when the G-CSF plus dexamethasone-mobilized granulocytes were diluted 1-in-16. To optimize storage pH, mobilized granulocyte concentrates require a 1-in-8 to 1-in-16 dilution, which is operationally impractical. Clinical-grade granulocyte preservative solutions are needed to maintain pH during storage.

Induction of histidine decarboxylase in skeletal muscle in mice by electrical stimulation, prolonged walking and interleukin-1.

1. In normal non-exercised skeletal muscles in mice, the activity of histidine decarboxylase (HDC), the enzyme which forms histamine, was very low. 2. HDC activity in the quadriceps femoris muscle was markedly elevated following contractions evoked by even a few minutes of direct electrical stimulation, peaking at 8-12 h following contraction lasting 10 min, and gradually decreasing during the 24 h following contraction. The elevation in HDC activity depended on the duration and strength of stimulation. 3. Direct electrical stimulation induced a quantitatively similar elevation of HDC activity in the muscles of mast-cell-deficient mice (W/Wv mice). 4. Prolonged walking at a speed of 6 m min-1 for up to 6 h with a 30 min rest period at 3 h also elevated muscle HDC activity, the magnitude of the elevation being related to the duration of the walking. Repeated exercise (training) for several days diminished the elevation of muscle HDC activity induced by walking. In contrast, starvation augmented the elevation of muscle HDC activity induced by walking. 5. Intraperitoneal injection of interleukin-1beta (IL-1beta) also elevated muscle HDC activity in a dose-dependent manner, as little as 1 microg kg-1 of IL-1 producing a significant elevation of muscle HDC activity. 6. IL-1beta was immunohistochemically detected in normal non-exercised quadriceps femoris muscle. We could not detect a significant increase in IL-1beta after exercise in the muscle or in serum: it may be below the level of detection. 7. On the basis of these results, together with those reported previously and the known actions of histamine, we propose that an elevation of HDC activity and generation of histamine occur in skeletal muscle following muscle contraction possibly as a result of induction by IL-1beta and that the histamine may be involved in fatigue in skeletal muscle as part of a defence mechanism preventing damage to the muscle.

Regulatory effects of endogenous interleukin-1 receptor antagonist protein in immunoglobulin G immune complex-induced lung injury.

IL-1 receptor antagonist (IL-1Ra) has regulatory effects on IL-1 activity both in vitro and in vivo. In the IgG immune complex model of lung injury in rats, exogenously administered human IL-1Ra suppressed neutrophil recruitment and ensuing lung injury. In this study, we sought to determine if endogenous rat IL-1Ra might regulate this lung-inflammatory response. By Northern blot analysis of lung mRNA and Western analysis of bronchoalveolar lavage (BAL) fluids, rat IL-1Ra expression was found to increase during development of inflammation in IgG immune complex-mediated alveolitis. By immunostaining, alveolar macrophages and recruited neutrophils were the apparent sources of IL-1Ra. In vivo blocking of endogenous IL-1Ra resulted in a 53% increase in lung vascular permeability and a 180% increase in BAL fluid neutrophils. In companion studies, a significant increase in IL-1beta was found, whereas no significant change in TNF-alpha activity was observed. Whereas the in vivo regulatory effects of IL-1R appear to be limited to IL-1beta, IL-10 regulates both IL-1beta and TNF-alpha in this model, reflected by a 48% increase in BAL IL-1beta in rats treated with anti-IL-10. These findings suggest that IL-1Ra is an intrinsic regulator of inflammatory injury after deposition of IgG immune complexes and that it regulates production of IL-1beta.