Plasma Levels Of IL-1beta Research Articles

A Role for Interleukin‐10 in Alcohol‐Induced Liver Sensitization to Bacterial Lipopolysaccharide

Proinflammatory cytokines play an important role in alcohol-induced liver injury. The role of anti-inflammatory cytokines in the initiation and progression of alcoholic liver disease has received little attention. This study tested the hypothesis that an imbalance exists between pro- and anti-inflammatory cytokines in the liver during chronic exposure to alcohol. Alcohol exposure results in predominantly proinflammatory cytokine secretion and liver injury. IL-10 knock-out and their C57BL/6J counterpart wild-type mice were fed alcohol in drinking water for 7 weeks. At the end of alcohol feeding, Gram-negative bacterial lipopolysaccharide (LPS) was administered, and the animals were killed after 3 and 8 hr. Liver histology, plasma alanine aminotransferase and aspartate aminotransferase activity, tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-10 levels, and liver cytokine messenger RNA levels were measured. Alcohol feeding and LPS treatment did not change plasma enzyme activity levels in wild-type mice. In the IL-10 knock-out mice, LPS alone increased aspartate aminotransferase and alanine aminotransferase enzyme activity, and this was potentiated by alcohol. Alcohol induced liver steatosis in both wild-type and knock-out mice. LPS markedly enhanced the histological effects further, especially in the knock-out mice, with the emergence of focal necrosis, polymorphonuclear infiltration, and microabscesses in the liver. Plasma tumor necrosis factor-alpha and IL-1beta levels were not affected by alcohol alone. Proinflammatory cytokine levels were increased by LPS and further enhanced by alcohol treatment, particularly in the IL-10 knock-out mice. IL-10 plasma levels in the wild-type animals were down-regulated by alcohol. Changes in liver cytokine messenger RNA paralleled those seen in plasma cytokine levels. Alcohol-induced liver sensitization to LPS in wild-type mice may involve down-regulation of IL-10. This anti-inflammatory cytokine, known for its hepatoprotective effects, is secreted simultaneously with proinflammatory cytokines. IL-10 may also limit alcohol-induced liver damage by counteracting the effects of proinflammatory cytokines.

Proinflammatory cytokines, prostaglandins and zinc in febrile convulsions.

Some changes in the levels of proinflammatory cytokines, prostaglandins and zinc (Zn) in peripheral blood and cerebrospinal fluid (CSF) have been suggested to occur for the pathogenesis of febrile convulsions (FC). In order to test this hypothesis, the levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha, IL-1 beta and prostaglandins (PGE(2), PGF(2 alpha), PGD(2)) in the CSF and plasma and the levels of Zn in serum and CSF were investigated in children during the acute and late phases of FC. Results were compared with control subjects with meningismus. During the acute phase of FC, children had significantly elevated plasma levels of IL-1 beta, CSF levels of TNF-alpha, plasma levels of PGE(2), PGF(2 alpha) and PGD(2) and CSF levels of PGD(2) (P<0.05). A positive correlation between the degree of fever and plasma IL-1 beta levels was observed in both patients and controls. Three months after the acute phase of FC, plasma levels of IL-1 beta had returned to levels seen in controls. Children with FC also had significantly decreased serum Zn levels during the acute phase (P<0.05). However, there was no significant difference between the groups with respect to CSF Zn levels (P>0.05). During the acute phase of FC, patients had significantly increased plasma IL-1 beta and prostaglandin levels and decreased serum Zn levels. These changes may be responsible for FC pathogenesis.

Classic NSAID and selective cyclooxygenase (COX)-1 and COX-2 inhibitors in healing of chronic gastric ulcers.

Prostaglandins (PG) derived from COX-1 are essential for the maintenance of mucosal integrity but COX-2 isoform synthesizes PG at a site of inflammation. Recently, COX-2 mRNA expression was demonstrated at the ulcer edge during healing of chronic gastric ulcers but the role for expression of COX-2 and its products such as PGE(2) and cytokines including interleukin (IL-1beta) and tumor necrosis factor alpha (TNFalpha) in ulcer healing remains unknown. In this study, Wistar rats with gastric ulcers produced by serosal application of acetic acid (ulcer area 28 mm(2)) received daily treatment either with: (1) vehicle (saline); (2) NS-398 (10 mg/kg-d i.g.) and Vioxx (5 mg/kg-d i.g.), both, highly specific COX-2 inhibitors; (3) meloxicam (5 mg/kg-d i.g.), a preferential inhibitor of COX-2; (4) resveratrol (10 mg/kg-d i.g.), a specific COX-1 inhibitor; (5) indomethacin (5 mg/kg-d i.g); and (6) aspirin (ASA; 50 mg/kg-d i.g.), non-selective inhibitors of both COX-1 and COX-2. At day 3, 7, and 14 after ulcer induction, the animals were sacrificed and the area of gastric ulcers was determined by planimetry and histology, gastric blood flow (GBF) at ulcer base and margin was measured by H(2) clearance technique, and blood was withdrawn for measurement of plasma IL-1beta and TNFalpha levels. The mucosal biopsy samples were taken for the determination of PGE(2) generation by RIA and expression of COX-1, COX-2, IL-1beta, and TNFalpha mRNA by RT-PCR. In vehicle-treated rats, gastric ulcers healed progressively and at day 14 the healing was completed, accompanied by a significant rise in the GBF at ulcer margin. The IL-1beta, TNFalpha, and COX-1 mRNA were detected in intact and ulcerated gastric mucosa, whereas COX-2 mRNA were upregulated only in ulcerated mucosa with peak observed at day 3 after ulcer induction. The plasma IL-1beta level was significantly increased at day 3 and 7 but then declined at day 14 to that measured in vehicle-controls. Indomethacin and ASA, which suppressed PGE(2) generation both in the non-ulcerated and ulcerated gastric mucosa, significantly delayed the rate of ulcer healing and this was accompanied by the fall in GBF at ulcer margin and further elevation of plasma IL-1beta and TNFalpha levels, which was sustained up to the end of the study. Treatment with NS-398 and Vioxx, which caused only a moderate decrease in the PGE(2) generation in the non-ulcerated gastric mucosa, delayed ulcer healing and attenuated significantly the GBF at ulcer margin and PGE(2) generation in the ulcerated tissue, while raising the plasma IL-1beta and TNFalpha similarly to those observed in indomethacin- and ASA-treated rats. Resveratrol, which suppressed the PGE(2) generation in both non-ulcerated and ulcerated gastric mucosa, prolonged ulcer healing and this was accompanied by the fall in the GBF at the ulcer margin and a significant increase in plasma IL-1beta and TNFalpha levels. We conclude that (1) classic NSAID delay ulcer healing due to suppression of endogenous PG, impairment in GBF at ulcer area, and excessive cytokine expression and release, and (2) this deleterious effect of classic NSAID on the healing of pre-existing ulcers can be reproduced by selective COX-1 and COX-2 inhibitors, suggesting that both COX isoforms are important sources of PG that appear to contribute to ulcer healing.

Bradykinin receptor antagonists type 2 attenuate the inflammatory changes in peptidoglycan-induced acute arthritis in the Lewis rat.

We studied the ability of bradykinin (BK) receptor antagonists type 1 and 2 (B1-RA, B2-RA) to prevent acute inflammation. A peptidoglycan-polysaccharide (PG-APS)-induced model of arthritis in the Lewis rat was analyzed. Four groups of animals were studied for 5 days. Treatment was administered subcutaneously (s.c.) 1 mg/kg every 12 h. Group I received PG-APS and was treated with the B2-RA, CP-0597 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-NChg-Arg). Group II received PG-APS and was treated with a combined B1 and B2-RA, B9430 (DArg-Arg-Pro-Hyp-Gly-Igl-Ser-Dlgl-Oic-Arg). Group III received PG-APS and albumin control. Group IV received albumin control. Joint diameter, liver weight, hematocrit, white blood count and plasma concentrations of prekallikrein, high molecular weight kininogen, HK and IL-beta were measured. Groups were compared by ANOVA. Acute arthritis and hepatomegaly were attenuated in the B2-RA-treated animals (p<0.05). Weight loss was more pronounced in the B1/B2-RA-treated animals. Anemia induced by PG-APS was prevented by B2-RA and B1/B2-RA treatment (p<0.001). A marked decrease in plasma HK to 64% of normal was found in the disease-untreated animals, which was completely normalized by B2-RA treatment and partially attenuated by the B1/B2-RA (78%). The decrease in plasma prekallikrein levels was prevented by combined B1/B2-RA treatment (p<0.05). Finally, elevated plasma IL-1beta levels were lowered by B1/B2-RA treatment and were below detection limits with the B2-RA treatment. These results indicate that the systemic inflammation is due in part to BK generation which can be blocked by B2-RA, while inhibiting the B1 receptor prevents an anti-inflammatory response.

Raised levels of plasma interleukin‐1β in major and postviral depression

Interleukin-1beta (IL-1beta) is released as part of the acute phase immune response and can directly stimulate the release of corticotrophin-releasing hormone and thus induce hypothalamic pituitary adrenal axis hyperactivity. Major depression has been shown to be accompanied by both an acute phase immune response, including raised IL-1beta production and hypothalamic pituitary adrenal axis hyperactivity. In this study the possible role of IL-1beta in major depression and postviral depression was investigated. Plasma IL-1beta levels were measured in four groups; patients suffering from postviral depression (n= 17), patients with major depression (n = 20), subjects who were postviral and euthymic (n= 12) and normal controls (n = 20). IL-1beta serum concentrations were significantly elevated in both groups of depressed patients compared to controls. The serum concentrations of IL-1beta were higher in the postviral group than in the major depression group; this difference was not significant. These data confirm previous suggestions of elevated IL-1beta levels in major depression and postviral depression. IL-1beta is known to induce depressive symptoms as well as sickness behaviour and may contribute to the hypothalamic pituitary adrenal axis hyperactivity found in mood disorders.

Serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment.

Activation of the inflammatory response system and varied levels of cytokines in acute schizophrenia have been suggested by recent studies. Psychopharmacologic agents can differentially effect cytokine production, which suggests that therapeutic function of neuroleptics may involve immunomodulation. The present study was carried out to examine: (i) serum concentrations of interleukin (IL)-1beta, soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8 and tumour necrosis factor (TNF)-alpha in schizophrenic patients; (ii) their relation with psychopathological assessment; and (iii) the relation of the initial cytokine levels with responsiveness to risperidone therapy. Thirty-four drug-free schizophrenic patients with acute exacerbation and 23 age- and gender-matched healthy controls were recruited for this study. Psychopathological assessments at admission and throughout risperidone treatment for 60 days were recorded. Serum cytokine concentrations were determined with chemilumunescence assays. According to our results, serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha concentrations adjusted for age, gender, body mass index and smoking were no different in patients with schizophrenia and controls and among subtypes of schizophrenia. However, the initial TNF-alpha concentrations had a significant effect on Brief Psychiatric Rating Scale and Scale Assessment of Positive Symptoms scores. The initial cytokine concentrations of the patients responsive to risperidone were not significantly different from those of non-responsive patients. The present study demonstrates that plasma levels of IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha adjusted for confounding factors are not altered in drug-free schizophrenic patients at acute exacerbation. We suggest that, if cytokine production is altered in schizophrenia, these alterations may not be detectable in systemic circulation. According to our results, the therapeutic effect of risperidone is not related to basal levels of the aforementioned cytokines. However, serum TNF-alpha may contribute to symptomatology in schizophrenia

IL-4 VNTR gene polymorphism in chronic polyarthritis. The rare allele is associated with protection against destruction.

To evaluate the occurrence of variants of the interleukin 4 (IL-4) and IL-4 receptor (IL-4R) genes in patients with rheumatoid arthritis (RA) and their possible contribution to joint destruction. Allelic frequencies for polymorphisms in the IL-4 [variable number of tandem repeat (VNTR) polymorphism in intron 3] and IL-4 receptor alpha chain (transition at nucleotide 1902) genes were assessed in 335 RA patients and 104 controls. Clinical indices of disease activity, disability and joint destruction and plasma levels of IL-1beta, IL-1Ra and sCD23 were assessed to evaluate a possible functional effect. Carriage of the rare IL-4(2) allele was higher in patients with non-destructive RA (40%) than in those with destructive RA (22.3%; odds ratio = 1.9, 95% confidence interval 1. 1-3.5, P = 0.0006) and in controls (26%, P = 0.002). Patients positive for this rare allele had significantly less joint destruction, assessed by the Larsen wrist index (P = 0.004) and a lower erythrocyte sedimentation rate (P = 0.04). A significantly higher carriage rate of IL-4(2) was seen in HLA-DR4/DR1(-) patients with non-destructive RA than in those with destructive RA. The IL-4 receptor polymorphism was not over-represented. Plasma levels of IL-1beta, IL-1Ra and sCD23, known to be modified by IL-4, were not different in individuals having different alleles. This IL-4 VNTR gene polymorphism may be a protective factor for severe joint destruction in RA that could be used as a prognostic marker early in the course of the disease.

Interleukins 1-beta, -8, and histamine increases in highly trained, exercising athletes.

Exercise-induced hypoxemia (EIH) in highly trained athletes is associated with an increase in histamine release (%H) during exercise. Certain cytokines, known as histamine-releasing factors, are capable of interacting with basophils and/or mast cells to cause the release of histamine. The aim of this study was to determine whether the increased histamine release in highly trained athletes is related to a high plasma level in interleukin-1 beta (IL-1beta), IL-3, or IL-8 in arterial blood. These parameters were measured in 11 endurance athletes (23.2 +/- 1.2 yr (mean +/- SEM)) known to develop exercise-induced hypoxemia and 11 control subjects (25.0 +/- 1.1 yr) at rest, during an incremental exhaustive exercise test, and at the fifth minute of recovery. Histamine release increased between rest and maximal exercise in the athletes (P < 0.01), showing a strong correlation with EIH (r = 0.76, P < 0.01) and was unchanged in the controls. IL-3 plasma concentration was not altered with training and/or with exercise. Circulating IL-8 levels were not different between trained and untrained subjects at any testing level and increased at maximal exercise in both groups (P < 0.01). IL-1beta plasma levels were higher in athletes than in controls (P < 0.05) at each testing level and increased during exercise only in the athletes (P < 0.05). An elevated concentration of IL-1beta in plasma and its association with increased IL-8 levels during exercise may partly explain the increase in %H associated with EIH in highly trained athletes. Histamine, IL-8, and IL-1beta releases during exercise reflect an inflammatory reaction, which is probably involved in EIH.

Activation of Genes for Superoxide Dismutase, Interleukin-1ß, Tumor Necrosis Factor-a, and Intercellular Adhesion Molecule-1 during Healing of Ischemia-Reperfusion-Induced Gastric Injury

Ischemia followed by reperfusion (I/R) induces gastric lesions, probably due to excessive formation of free radicals, but the role of the scavenger of these radicals, proinflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), in the healing of these lesions has not been extensively studied. It is also unknown whether expression of intercellular adhesion molecule-1 (ICAM-1), which mediates neutrophil-induced injury and neutrophil infiltration, is involved in the recovery from I/R lesions. I/R lesions were induced in Wistar rats by applying a small clamp to the celiac artery for 30 min (ischemia phase), followed by the removal of the clamp for 60 min (reperfusion phase). The influence of I/R on gastric secretion was also tested in rats equipped with a gastric fistula (GF) without or with the exposure to a standard period of I/R. Two series of rats (A and B) were used to determine the effects of exogenous and endogenous superoxide dismutase SOD (series A) and allopurinol, a xanthine oxidase inhibitor (series B), on the mucosal recovery from the gastric lesions induced by I/R. The animals were killed immediately after the exposure to I/R (0 h) and at 3 h, 24 h, or 3, 5, or 10 days after this I/R, the area of gastric lesions being measured by planimetry, and the gastric blood flow (GBF) determined by the H2 gas clearance method. Blood was withdrawn for measurement of plasma IL-1beta and TNF-alpha levels with enzyme-linked immunosorbent assay, and plasma gastrin with radioimmunoassay. Biopsy samples of oxyntic mucosa were taken for the assessment of SOD, IL-1beta, TNF-alpha, and ICAM-1 mRNAs by reverse-transcription polymerase chain reaction and Southern blot. Exposure to I/R resulted in acute gastric erosions, with the maximal increase of the area of these lesions observed 3 h after the end of I/R. This effect was accompanied by a decrease in the GBF, a significant increase in blood free radicals and plasma gastrin increments, and almost complete suppression of gastric secretion. Starting 24 h after I/R, the gastric superficial lesions progressed into deeper ulcers that healed progressively within 10 days, and this was accompanied by gradual restoration of the gastric secretion and the GBF. Treatment with SOD and allopurinol accelerated significantly the healing of I/R erosions, and this effect was accompanied by a significant increase in the GBF and the attenuation of blood free radicals. At 0, 3, and 12 h after I/R a significant decrease in SOD mRNA was observed, whereas expression of TNF-alpha, IL-1beta, and ICAM-1 showed a progressive increase starting immediately after I/R, reaching a maximum on day 3. The plasma level of TNF-alpha and IL-1beta started to increase on day 3 and peaked on day 5 after I/R, being still significantly higher at day 10 than that measured in the vehicle-treated control gastric mucosa. On day 10 the gastric ulcers were almost completely healed, and a decrease in the expression for TNF-alpha, IL-1beta, and ICAM-1 mRNA and an increase in the expression of SOD mRNA were observed. 1) exposure to I/R produces gastric lesions mediated by the excessive formation of free radicals, resulting in suppression of both gastric microcirculation and secretory activity of the stomach; 2) SOD and allopurinol accelerate the healing of I/R lesions, probably due to suppression of oxygen free radicals and improvement of gastric microcirculation; and 3) the upregulation of SOD mRNA, with subsequent increase in the SOD production and local release of IL-1beta and TNF-alpha, may activate ICAM-1 expression and neutrophil infiltration, which appear to play an important role in the progression of I/R-induced acute gastric erosions into chronic ulcers.

Interleukin‐1β (IL‐1β) inhibition: a possible mechanism for the anti‐inflammatory potency of liposomally conjugated methotrexate formulations in arthritis

1. Liposomes with conventional and long-circulation times were employed as carriers for the methotrexate derivative MTX-gamma-DMPE (MTX-EPC and MTX-PEG respectively), their mechanism of action was investigated in vitro and in vivo and their therapeutic efficacy assessed using the rat collagen-induced arthritis (CIA) model. 2. At non-toxic dose, both MTX-EPC and MTX-PEG inhibited the lipopolysaccharide (LPS) induced release of IL-1beta from activated rat peritoneal macrophages (rPMPhi) in a dose and time dependent manner. Free methotrexate (MTX) was not active in this respect. After a single intravenous injection (i.v.), and at equivalent doses, both free MTX (500 microg) and MTX-EPC inhibited the LPS induced rise in plasma IL-1beta levels observed in MTX-PEG and saline treated rats. 3. When used to treat established CIA, MTX-EPC resulted in significantly lower clinical score (CS) (1.0+/-0.42 (P<0.001)) and hind paw diameter (HPD) (6.5+/-0.34 mm (P<0.001)) measurements than controls (3.0+/-0.26; 7.33+/-0.41 mm), after only two i.v. doses, and remained significantly lower for the entire experimental period. By day 24 both CS (2+/-0.61 (P<0.001)) and HPD (6.97+/-0.25 mm (P<0.002)) measurements had also become significantly lower in MTX-PEG treated rats than in saline treated controls (3.62+/-0.17, 7. 92+/-0.38 mm) and remained lower until day 30. Joint inflammation in MTX treated rats was completely ameliorated by day 20 but the health and well being of the animals was compromised and the experiment terminated at this time-point. 4. Our results clearly demonstrate that both MTX-EPC and MTX-PEG liposomes have potential for development into therapeutic modalities for the treatment of inflammatory joint disease in man.

Plasmatic levels of interleukin-1beta and interleukin-6 in newborn infants with fever

OBJECTIVE: To study plasma levels of IL-1beta and IL-6 in order to distinguish the presence of bacterial infection in newborn infants with fever. METHODS: A cohort of 117 newborn infants with postnatal age equal to or less than 5 days, with no previous use of antibiotic therapy, and with clinical suspicion of bacterial infection was studied from July 1995 through August 1996. Those with definite criteria for sepsis were considered infected. Fever was defined as axillar temperature > 37.5 degrees C in three independent measurements. The patients were classified in four different groups: Group 1: infected with fever; Group 2: infected without fever; Group 3: not infected with fever; Group 4: not infected without fever. Complete blood count, platelet count, blood or other fluid cultures, and plasmatic levels of IL-1beta and IL-6 were collected before the beginning of antibiotic therapy. RESULTS: Of the 117 newborn infants studied were 66 infected and 51 not infected. Fever was present in 45 (38.46%). The median values of IL-1beta and IL-6 were significantly higher in newborn infants with fever than in those with no fever. There were significant differences between groups 1 and 2, 1 and 4, and 2 and 3 for IL-1beta. There were no significant differences between groups 2 and 4, and 1 and 3 for IL-1beta. Eight (72%) newborn infants with no infection and no fever had environment heating, and 3 had dehydration. There were no differences in median IL-6 levels between groups 1 and 2, and 3 and 4. There were significant differences in the median IL-6 levels between groups 1 and 3, and 1 and 4. CONCLUSIONS: IL- 6 is a marker of early neonatal sepsis. IL-1beta is related to neonatal fever response independently of the presence of bacterial infection.

Thermoregulation during exercise in women who are taking oral contraceptives.

Thermoregulation during exercise was studied in seven women who were taking oral contraceptive pills for 3 weeks of each month. The subjects were studied once in the 3rd week of taking the pill (P) and once during the following week when they took no pil (N). Rectal temperature (Tre), heart rate (fc) and evaporative water loss (EWL, ventilated capsule technique) were measured while they walked on a treadmill for 60 min at 4.8 km.h-1 at a 10% gradient. Ambient temperature was 22 degrees C. A venous blood sample was drawn 30 min before each experiment for measurement of hematocrit (packed cell volume, PCV), plasma osmolality (Osmpl), and plasma levels of the endogenous pyrogens interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6). Resting Tre was 0.31 degree C higher in P than in N (P < 0.01) and Tre remained higher in P throughout the entire exercise period (P < 0.01). Threshold Tre for the onset of EWL was 0.32 degree C higher in P than in N (P < 0.01). Exercise fc was 6.5 beats.min-1 higher in P than in N (P < 0.01). There was no significant difference in PCV, Osmpl, IL-1 beta or IL-6 between P and N. It was concluded that the administration of synthetic progestins in oral contraceptives causes an upward shift in the threshold for heat loss responses, resulting in higher body core temperatures both at rest and during exercise. There was no evidence that these alterations in thermoregulation were mediated by changes in body fluid balance or in plasma levels of IL-1 beta or IL-6.

Blood cytokine levels rise even after minor surgical trauma.

The exact changes in cytokine production and clinical implications of the increased cytokine levels following operative trauma remain unclear. In this study, systemic production of a spectrum of cytokines, including IL1 alpha, IL1 beta, IL6, IL8, IL10, and IFN gamma, was examined in patients undergoing minor elective operative trauma. The levels of IL1 receptor antagonist (ra) and IL6 soluble receptor (sR) were also determined. Although there were no changes in IL1 alpha and IL1 beta plasma levels during the entire observation period, there was a significant rise in IL1 ra level in all patients between postoperative day 1 and postoperative day 14. A significant increase in the IL6 plasma level was seen on days 1, 3, and 7 after surgery and an increase in the IL6 sR level was observed on postoperative days 10 and 14. Interestingly, the IL8 plasma values had risen significantly on days 1 and 3 following the operation. In some patients, an elevation in IL10 plasma level was noted on days 1 and 3 postsurgery. Results demonstrated that even a minor surgical procedure such as cholecystectomy with uneventful wound healing was followed by an appearance in the blood circulation of significant levels of cytokines between day 1 and day 14 after surgery. These observations point to the necessity of searching for methods of down-regulating the systemic cytokine effects after surgical trauma for the routine postoperative management.

Cytokine levels in the seminal plasma of infertile males.

Cytokines released by various cell subsets in the male urogenital tract are capable of markedly influencing sperm function and fertility. We determined the cytokine content in the seminal plasma of patients with unexplained infertility and correlated the results with urogenital infections and sperm parameters. Routine sperm parameters, bacterial culture of seminal plasma and blood follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were obtained from 14 infertile males and 8 healthy control subjects. Interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF alpha) levels in the seminal plasma were measured by enzyme-linked immunosorbent assay (ELISA). IL-1 beta, IL-6, and TNF alpha levels in the seminal plasma were negatively correlated with the number of progressively motile sperm, but there was no correlation with total sperm counts, viability, pH, morphological alterations, type of abnormality, and hormone parameters. Cytokine levels were significantly elevated in seminal plasma exhibiting bacterial or mycoplasmal infections of the urogenital tract. Urogenital infections lead to an release of inflammatory cytokines, most probably by immunocompetent cells of the lymphocyte/macrophage origin. Cytokines such as IL-1, IL-6, and/or TNF alpha might influence sperm motility via direct or indirect effects, resulting in reduced mucosa penetration properties. Therefore, our data suggest that cytokines may be involved in reduced male fertility.

Effects of Granulocyte Colony-Stimulating Factor on Plasma Cytokine and Cytokine Receptor Levels and on the In Vivo Host Response to Endotoxin in Healthy Men

We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on cytokine and cytokine receptor plasma levels and on the in vivo host response to Salmonella abortus equi endotoxin in healthy males. Twenty volunteers received 0.8 ng/kg endotoxin and saline intravenously 1 week apart in randomized order. Twelve hours before both experiments, 10 of these subjects were pretreated with 300 micrograms G-CSF subcutaneously. G-CSF itself increased granulocyte and monocyte counts and the plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R) p55, and p75 and interleukin-1 receptor antagonist (IL-1ra). G-CSF did not influence plasma IL-1 beta and IL-6 levels. In the G-CSF-pretreated subjects endotoxin-induced surges in rectal temperature and in the plasma levels of TNF-alpha plasma levels were about 50% increased, and surges in the plasma levels of both sTNF-Rs and IL-1ra were about twice as high as in the control group. Endotoxin-induced increases in IL-6, cortisol, and heart rate were not modified by G-CSF pretreatment. Endotoxin administration induced a transient 50% reduction in leukocyte counts in the G-CSF-pretreated subjects that was not seen in the control group. We conclude that a single stand dose of G-CSF increases the plasma levels of cytokines and cytokine receptors and considerably modifies the host response of healthy humans to a low dose of endotoxin.

Influence of Hemodialysis Membranes on Gene Expression and Plasma Levels of Interleukin‐iβ

Plasma levels of interleukin-1 beta (IL-1 beta) were measured in 10 normal subjects, in 11 nondialyzed end-stage renal failure (ESRD) patients, and in 22 hemodialysis (HD) patients. Of the HD patients, 7 were dialyzed with Cuprophan (CU), 7 with polymethylmethacrylate (PMMA), and 8 with polysulphone (PS) dialyzers. In normal controls, nondialyzed ESRD patients, and HD equipped with CU, PAMM, and PS dialyzers, plasma levels of IL-1 beta were 10.73 +/- 5.24 pg/ml, 9.97 +/- 3.61 pg/ml, 13.17 +/- 4.04 pg/ml, 15.16 +/- 6.16 pg/ml, and 13.96 +/- 5.47 pg/ml, respectively. There were no statistically significant differences among the groups (p > or = 0.05). In contrast, the gene expression of IL-1 beta for peripheral blood mononuclear cells (PBMC) by in situ hybridization showed differences among the groups. The gene for IL-1 beta for PBMC appears in HD equipped with different membranes, but not in cases of nondialyzed uremic patients and normal subjects. With computer imaging analysis, we carried out quantitative analysis of cells in in situ hybridization with an area of positive spots to an area of total cells. In HD with CU, PMMA, and PS, the results were 10.64 +/- 1.07, 3.34 +/- 0.74, and 3.27 +/- 0.64%, respectively. The levels of IL-1 beta gene expression in CU were higher than that in PMMA or PS. There were statistically significant differences (p < or = 0.001) between CU and PMMA or PS and no significant difference between the PMMA and PS (p > or = 0.05). We suggest measuring the gene expression of cytokines for PBMC and which may be better than measuring cytokine levels only for investigating the blood compatibility of dialyzers, which may help in understanding chronic complications of the dialysis procedure.

Subdiaphragmatic vagotomy blocks induction of IL-1 beta mRNA in mice brain in response to peripheral LPS

To test the possibility that the vagus nerve is involved in the communication between the immune system and the brain, we injected sham-operated and vagotomized mice with physiological saline or lipopolysaccharide (LPS; 400 micrograms/kg ip). Vagotomy attenuated LPS-induced depression of general activity measured 2 h after treatment but did not alter the increase in plasma levels of IL-1 beta in response to LPS. In addition, vagotomy abrogated the LPS-induced increase in the levels of transcripts for IL-1 beta, as determined by semiquantitative polymerase chain reaction after reverse transcription, in the hypothalamus and hippocampus, but not in the pituitary of vagotomized mice. This relationship between the effects of vagotomy on the behavioral effects of LPS and the LPS-induced brain expression of IL-1 beta mRNA indicates that vagal afferent fibers play a prominent role in the pathways of communication between the immune system and the brain.

Persistent Elevation of Inflammatory Cytokines Predicts a Poor Outcome in ARDS: Plasma IL-1β and IL-6 Levels Are Consistent and Efficient Predictors of Outcome Over Time

Inflammatory cytokines have been related to the development of adult respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction syndrome (MODS). We tested the hypothesis that unfavorable outcome in patients with ARDS is related to the presence of a persistent inflammatory response. For this purpose, we evaluated the behavior of inflammatory cytokines during progression of ARDS and the relationship of plasma inflammatory cytokines with clinical variables and outcome.We prospectively studied 27 consecutive patients with severe medical ARDS. Plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukins (ILs) 1 beta, 2, 4, 6, and 8 were measured (enzyme-linked immunosorbent assay [ELISA] method) on days 1, 2, 3, 5, 7, 10, and 12 of ARDS and every third day thereafter while patients were receiving mechanical ventilation. Subgroups of patients were identified based on outcome, cause of ARDS, presence or absence of sepsis, shock, and MODS at the time ARDS developed. Subgroups were compared for levels of plasma inflammatory cytokines on day 1 of ARDS and over time.Of the 27 patients, 13 survived ICU admission and 14 died (a mortality rate of 52%). Overall mortality was higher in patients with sepsis (86 vs 38%, p < 0.02). The mean initial plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 were significantly higher in nonsurvivors (p < 0.0001) and in those patients with sepsis (p < 0.0001). Plasma levels of IL-1 beta (p < 0.01) and IL-6 (p = 0.03) were more strongly associated with patient outcome than cause of ARDS (p = 0.8), lung injury score (LIS), APACHE II score, sepsis (p = 0.16), shock, or MODS score. Plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 remained significantly elevated over time (p < 0.0001) in those who died. Although it was the best early predictor of death (p < 0.001), plasma IL-2 > 200 pg/mL lost its usefulness after the first 48 h. A plasma IL-1 beta or IL-6 level > 400 pg/mL on any day in the first week of ARDS was associated with a low likelihood of survival.Our findings indicate that unfavorable outcome in acute lung injury is related to the degree of inflammatory response at the onset and during the course of ARDS. Patients with higher plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 on day 1 of ARDS had persistent elevation of these inflammatory cytokines over time and died. Survivors had lesser elevations of plasma inflammatory cytokines on day 1 of ARDS and a rapid reduction over time. Plasma IL-1 beta and IL-6 levels were consistent and efficient predictors of outcome.

Release of Cytokines, Soluble Cytokine Receptors, and Interleukin-1 Receptor Antagonist After Intravenous Immunoglobulin Administration In Vivo

We investigated the in vivo effects of one bolus injection (400 mg/kg) of intravenous immunoglobulin (IVIG) on a number of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist (IL-1Ra) in plasma in 12 patients with primary hypogammaglobulinemia. A significant and rapid increase in plasma levels of IL-6, IL-8, and tumor necrosis factor alpha (TNF alpha) was seen within 1 hour after IVIG infusion. This increase was accompanied by a more prolonged elevation in levels of both types of soluble TNF receptors (sTNFRs), which remained elevated throughout the study period (44 hours) although they reached peak levels within 1 hour. After an initial increase in the ratio between TNF alpha and sTNFRs, this ratio decreased to values significantly lower than baseline values 20 and 44 hours postinfusion with approximately 600-fold molar excess of sTNFRs to TNF alpha (trimer). Although only a modest but statistically significant increase in plasma levels of IL-1 beta was seen, IVIG infusion was followed by a marked increase in plasma levels of IL-1Ra with 1,000-fold molar excess of IL-1Ra to IL-1 beta in some patients. The demonstrated effects of IVIG infusion on the cytokine network, particularly the induction of IL-1Ra and sTNFRs release, might be important for the therapeutic effects of IVIG in several immune-mediated disorders.

Release of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist after intravenous immunoglobulin administration in vivo

We investigated the in vivo effects of one bolus injection (400 mg/kg) of intravenous immunoglobulin (IVIG) on a number of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist (IL-1Ra) in plasma in 12 patients with primary hypogammaglobulinemia. A significant and rapid increase in plasma levels of IL-6, IL-8, and tumor necrosis factor alpha (TNF alpha) was seen within 1 hour after IVIG infusion. This increase was accompanied by a more prolonged elevation in levels of both types of soluble TNF receptors (sTNFRs), which remained elevated throughout the study period (44 hours) although they reached peak levels within 1 hour. After an initial increase in the ratio between TNF alpha and sTNFRs, this ratio decreased to values significantly lower than baseline values 20 and 44 hours postinfusion with approximately 600-fold molar excess of sTNFRs to TNF alpha (trimer). Although only a modest but statistically significant increase in plasma levels of IL-1 beta was seen, IVIG infusion was followed by a marked increase in plasma levels of IL-1Ra with 1,000-fold molar excess of IL-1Ra to IL-1 beta in some patients. The demonstrated effects of IVIG infusion on the cytokine network, particularly the induction of IL- 1Ra and sTNFRs release, might be important for the therapeutic effects of IVIG in several immune-mediated disorders.