IL-1ra Concentrations Research Articles

Influence of Interleukin-10 on the Interleukin-1 Receptor Antagonist/Interleukin-1β Ratio in the Colonic Mucosa of Ulcerative Colitis

A decrease in the ratio of IL-1ra/IL-1β produced regionally by the colonic mucosa of patients with ulcerative colitis (UC) is believed to play a role in the pathogenesis of UC. To investigate factors influencing intramucosal IL-1ra/IL-1β ratios, we evaluated polymorphism of the IL-1ra gene and the production of mucosal cytokines in Japanese patients with UC. Colonic biopsy specimens of mucosal tissue were placed in organ cultures for 24 h. Then, the supernatant concentrations of IL-1β, IL-1ra, IL-8, IL-4, IL-10, and TGF-β were assayed by ELISA. Genomic DNA was extracted from patient peripheral blood samples, then IL-1ra gene polymorphism was determined using PCR amplification. The mucosa from patients with active stage UC showed a tendency toward a decreased IL-1ra/IL-1β ratio. In the resolving stage, IL-1ra/IL-1β ratios increased with increasing IL-10 and TGF-β concentrations. The addition of human recombinant IL-10 to the culture supernatants produced concentration-dependent inhibition of IL-1β. In Japanese patients with UC, the IL-1ra allele gene 2 phenotype had no effect on the IL-1ra/IL-1β ratio. Our findings suggest that a relative deficiency of IL-10 in patients with UC may contribute to persistent inflammatory changes.

A randomized controlled trial of interleukin-1 receptor antagonist in a rabbit model of ascending infection in pregnancy.

Objective: To determinewhether treatment with interleukin-1 receptor antagonist (IL1-ra) would affect amniotic fluid concentrations of tumor necrosis factor alpha (TNF-α) and prostaglandins or clinical or microbiological outcomes in a model of ascending bacterial infection in pregnancy. Methods: Timed pregnant New Zealand white rabbits at 70% of gestation underwent endoscopic inoculation of the cervices with 106–106 cfu Escherichia coli . Animals were randomly assigned in a blinded manner to a 5-h intravenous infusion of human IL1-ra (10 mg/kg) or placebo beginning 1 – 2 h after inoculation. Blood was drawn fromthe does for assay of serum IL1-ra concentration before inoculation, at mid-infusion, after the infusion ended and at necropsy. At necropsy, temperature and cultures were taken, and aspirated amniotic fluid was pooled for assays of TNF-α, prostaglandin E2 (PGE2) and IL1-ra. Results: Serum IL1-ra concentrations rose to a mean of 2 mg/ml at mid-infusion and fell markedly after the infusion to concentrations barely detectable at necropsy. Between the two groups, there were no significant differences in the rates of fever or positive cultures or in amniotic fluid concentrations of PGE2 or TNF-α.One unique finding was the demonstration that administration of human IL1-ra to the does resulted inmeasurable concentrationsof human IL1-ra in the amniotic fluid. Conclusions: Treatment with an intravenous infusion of human IL1-ra after cervical inoculation with E. coli did not affect clinical or microbiological outcomes or amniotic fluid concentrations of TNF-α or PGE2. This experiment provides the first demonstration of passageof human IL1-ra from the maternal bloodstreamto the amniotic fluid.

Physical activity and plasma interleukin-6 in humans--effect of intensity of exercise.

The present study included data from three marathon races to investigate the hypothesis that a relationship exists between running intensity and elevated concentrations of interleukin (IL)-6 in plasma. The study included a total of 53 subjects whose mean age was 30.6 [95% confidence interval (CI) 1.4] years, mean body mass 77.7 (95% CI 2.0) kg, mean maximal oxygen uptake (VO2max) 59.3 (95% CI 1.4) ml x min(-1) x kg(-1), and who had participated in the Copenhagen Marathons of 1996, 1997 or 1998, achieving a mean running time of 206 (95% CI 7) min. Running intensity was calculated as running speed divided by VO2 max. The concentration of IL-6 in plasma peaked immediately after the run. There was a negative correlation between peak IL-6 concentration and running time (r = -0.30, P<0.05) and a positive correlation between peak IL-6 concentration and running intensity (r = 0.32, P<0.05). The IL-1 receptor antagonist (IL-1ra) plasma concentration peaked 1.5 h after the run and there was a positive correlation between the peak plasma concentrations of IL-6 and IL-1ra (r = 0.39, P<0.01). Creatine kinase (CK) plasma concentration peaked on the 1st day after the run, but no association was found between peak concentrations of IL-6 and CK. In conclusion, the results confirmed the hypothesized association between plasma IL-6 concentration and running intensity, but did not confirm the previous finding of a connection between IL-6 plasma concentration and muscle damage.

Interleukin-1 receptor antagonist in ascites indicates acute graft rejection after pediatric liver transplantation.

Acute graft rejection is one of the most frequent complications after pediatric liver transplantation (LTx). In clinical practice, it is sometimes difficult to differentiate acute cellular graft rejection from other complications because clinical and chemical findings are often nonspecific. We therefore investigated the value of cytokine quantification in drained ascites, in addition to quantification of cytokine concentrations of serum, in 30 children in the first 2 weeks after orthotopic liver transplantation (OLT). Six of 30 patients showed acute graft rejection, with rising levels of alanine aminotransferase (ALT) and alpha-glutathione-S-transferase (alpha-GST) in serum up to 24 h prior to biopsy-proven rejection. There were no significant elevations of interleukin-2 receptor (IL-2r) and interleukin-6 (IL-6) in serum and ascites. In contrast to these findings, the concentration in ascites of the interleukin-1 receptor antagonist (IL-1ra) increased 48 h before rejection was proven by liver biopsy (p < 0.01, in comparison with the non-rejecting group, n = 24). The IL-1ra concentration in ascites was up to 11-fold higher than in serum during rejection (15.43 vs. 1.38 ng/mL). Two children with early infectious complication showed no significant increase in ascitic IL-1ra concentration. We conclude from these data that quantification of IL-1ra in ascites indicates the start of graft rejection after LTx. As long as abdominal drainage is performed, this non-invasive procedure may be of additional value in differential diagnoses and early diagnosis of rejection.

Do Proinflammatory Cytokines Play a Role in Renal Dysfunction after Bypass?

Do Proinflammatory Cytokines Play a Role in Renal Dysfunction after Bypass? Gormley et al.(page 1210)Gormley et al. recruited 20 patients scheduled to undergo coronary artery bypass grafting with use of cardiopulmonary bypass to measure changes in proinflammatory and antiinflammatory cytokines during surgery. Their aim was to determine whether there was a correlation between the magnitude of the plasma proinflammatory response and perioperative proximal tubular damage as measured by urinary N -acetyl-β-[scap]d-glucosaminidase (NAG)/creatinine and α1-microglobulin/creatinine ratios.Baseline blood samples were obtained before induction of anesthesia, after aortic cross-clamp release, and 2 and 24 h after termination of cardiopulmonary bypass. Urine samples were obtained at baseline, after aortic cross-clamp release, and 2, 6, 24, 48, and 72 h after termination of cardiopulmonary bypass. Plasma and urinary samples were assayed for the proinflammatory cytokines interleukin (IL)-1β, tumor necrosis factor (TNF) α, and IL-8 and for the antiinflammatory cytokines IL-10, IL-1 receptor antagonist (IL-1ra), and TNF soluble receptor 2 (TNFsr2). Urine also was assayed for NAG, creatinine, and α1-microglobulin.After cardiopulmonary bypass, concentrations of plasma IL-8, IL-10, IL-1ra, and TNFsr2 were increased significantly compared with concentrations measured at baseline. Urinary IL-1ra, TNFsr2, NAG/creatinine and α1-microglobulin also were increased. The study showed a positive correlation between plasma TNFα concentrations at 2 h postoperatively and urinary NAG/creatinine ratios at 2 and 6 h postoperatively. Simultaneous with the increase in urinary IL-1ra and TNFsr2, there was a significant increase in proximal tubular dysfunction as indicated by increased urinary NAG/creatinine and α1-microglobulin/creatinine ratios. Although a direct causal relation is unlikely, what is likely is that a common mechanism may contribute both to the antiinflammatory cytokines in the urine and to the evidence of renal dysfunction. The authors suggest that the plasma proinflammatory cytokines, once filtered by the glomerulus, not only induce a degree of proximal tubular injury, but also trigger an intense intrarenal antiinflammatory response to allow the safe disposal of the proinflammatory cytokines. Thus, the kidney may be damaged by the inflammatory response it seeks to control.

Detection of cytokines in bovine colostrum

Colostrum contains factors that are protective for the neonate and may be a source of immunomodulary molecules that positively influence the immune status of the neonate. To confirm that colostrum contains a variety of cytokines with immunomodulatory properties, we established a bovine cytokine specific ELISA and five cytokines (IL-1β, IL-6, TNF-α, INF-γ or IL-1 receptor antagonist, IL-1ra) in the whey samples from cows at different stages of lactation were monitored. The expression of cytokine mRNAs (IL-1β, IL-6, TNF-α and INF-γ) in the colostral cells was detected by RT-PCR. The concentrations of cytokines in colostrum were significantly higher concentrations than those in the mature milk. A positive correlation was observed between the concentrations of IL-1ra and IL-1β in the colostrum samples. In conclusion, colostrum contains high levels of cytokines that could be produced and secreted in the mammary gland and that may have an immunomodulatory activity and influence neonatal immunity.

Changes in plasma concentrations of interleukin-6 and interleukin-1 receptor antagonists in response to adrenaline infusion in humans.

To investigate the possible role of adrenaline in the response of interleukin (IL)-6 and IL-1 receptor antagonists (ra) to extreme physiological conditions such as trauma and exercise, we examined the concentrations in the plasma of these cytokines during an adrenaline infusion. Given the fact that HIV infected patients have elevated levels of IL-6 in plasma, 12 HIV seropositive subjects and 6 HIV seronegative control subjects received a 1-h adrenaline infusion. Baseline concentrations of IL-6 and IL-1ra were higher in the HIV patients compared with the controls (P<0.05 and P<0.01, respectively), being most pronounced in the untreated subgroup of HIV infected patients (n = 6). The plasma concentration of adrenaline had increased 24-fold after 15 min of adrenaline infusion. The plasma concentration of IL-6 had increased by two- to threefold after 45 min of adrenaline infusion (P<0.01) and was still elevated 1 h after the infusion had ended (P<0.001 and P<0.05 in controls and HIV infected patients, respectively). The plasma concentration of IL-1ra had increased two- to threefold 1 h after ceasing the adrenaline infusion (P<0.05 and P<0.01 in controls and HIV infected patients, respectively). The relative increase in the cytokine levels was similar in controls and HIV infected patients. Thus, HIV infection did not influence the effect of adrenaline on IL-6 and IL-1ra. The present study supports the existence of a relationship between the plasma concentration of adrenaline and IL-6. It is possible that an increased adrenaline concentration in plasma induces a continued de novo synthesis of IL-6, thereby increasing plasma IL-6 in a time-dose dependent manner.

Experimental study on the possibility of treatment of some hemorrhagic fevers

After intracerebral challenge with 100 PFU of Lassa virus (strain Josiah), all infected mice (CBA/calac) died (control group). Production of pro-inflammatory cytokines (IL-1β, TNF-α) significantly increased in the blood of these mice during the infection. For neutralization of increasing concentrations of these cytokines recombinant IL-1RA was used intraperitonealy at a dose 100 μg kg −1, everyday, within 5 days from the third day after the challenge. Injections of IL-1RA decreased the concentration of IL-1β and TNF-α and resulted in survival of all infected mice (treatment group). Marburg fever (strain Popp) caused in guinea pigs by 5 LD 50 of virus lead to the significant increase of TNF-α in the animal’s blood and caused a lethal outcome (control group). Treatment of infected guinea pigs by IL-1RA or anti-TNF serum decreased the concentration of TNF-α and resulted in survival of half of the animals (treatment group). For the treatment recombinant IL-1RA was used at a dose 100 μg kg −1, intramuscularly, everyday, within 6 days from the third day after the challenge or anti-TNF serum, intramuscularly 0.5 ml (2000 U ml −1; 1 U of the antiserum neutralises 0.03 ng of TNF-α), everyday, within 6 days from the third day after the challenge.

Increased Soluble Tumor Necrosis Factor Receptor Levels in the Serum of Elderly People

Background: Soluble (s) forms of tumor necrosis factor (TNF) receptors are the only natural molecules known to interfere with TNF activity by competing for TNF binding with receptors on target cells. In a variety of pathologic situations, the concentrations of sTNF receptors (R) increase. Objective: To discuss possible causes of increased risks for infectious disease and cancer seen in the elderly. Methods: The participants were healthy subjects (n = 48) of three age groups (young, middle-aged, and elderly). Patients with senile dementia of Alzheimer type (n = 25) were also studied. For detection of cytokines, interleukin (IL) 1α, IL-1β, IL-6, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor, and TNF-α were measured in serum by enzyme-linked immunosorbent assays, as were soluble (s) IL-1 receptor antagonist (IL-1ra), sIL-6R, p55sTNF-R, and p75sTNF-R. Results: IL-1α, IL-1β, IL-6, and TNF-α were not detected, and sIL-6R and IL-1ra concentrations were not significantly different between the three age groups. However, sTNF-R and M-CSF were increased in sera from the elderly, both healthy and demented. A significant correlation was seen between sTNF-R and M-CSF concentrations. Conclusions: Increased sTNF-R levels may oppose the physiologic and protective effects of TNF by interference with its receptor binding. This interaction may contribute to the susceptibility of the elderly to infectious and neoplastic diseases.

DIFFERENCES IN THE GENOTYPES AND PLASMA CONCENTRATIONS OF THE INTERLEUKIN-1 RECEPTOR ANTAGONIST IN BLACK AND WHITE SOUTH AFRICAN ASTHMATICS AND CONTROL SUBJECTS

The allelic frequency of a variable tandem repeat (VNTR) polymorphism in intron 2 of the IL-1 Ra gene was studied in black and white patients with asthma as well as control individuals. The plasma IL-1 Ra concentration was also determined in asthmatics and compared to control individuals. The 410-bp allele of the IL-1 Ra was significantly increased in all black subjects (90%) as compared to all white subjects (74%, P<0.0001), while the 240-bp allele was significantly reduced in all black subjects (11%) as compared to all white subjects (27%, P<0.0001). There was no difference in the frequency of the VNTR of the IL-1 Ra between black asthmatics and black controls and between white asthmatics and white controls. The IL-1 Ra levels were significantly increased in black and white patients with severe or moderate asthma as compared to patients with mild asthma. Increased plasma concentrations of the IL-1 Ra was found to be associated with disease severity in all asthmatic patients.

Elevated serum concentration of interleukin-1 receptor antagonist (IL-1ra) is correlated to interleukin-6 and to hypoalbuminemia in cachectic patients with colorectal cancer

Background. The mechanisms leading to the development of cancer cachexia are still not well understood. Some important factors, including cytokines and growth factors, are involved, and recently, cytokines such as interleukin-1 and interleukin-6 have been reported to be involved as mediators of this disorder. Methods. In patients with colorectal cancer, serum concentrations of interleukin-1 receptor antagonist (IL-1ra) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA) and analyzed in relation to the patient's nutrition (in terms of albumin concentration [percentage of total protein] in the serum) and the tumor load. Results. The concentration of IL-1ra was significantly increased in cachectic patients compared with that in healthy volunteers and in the non-cachectic patients, and the concentration was correlated to the serum concentration of IL-6 and inversely correlated to the concentration of albumin (%). These concentrations, however, did not correlate to levels of tumor markers tested, ie, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9. Conclusion. It was shown that the serum concentration of IL-1ra was a useful indicator for cancer cachexia and hypoalbuminemia; IL-1ra seems to be produced by immune-regulating host cells rather than by neoplastic cells.

Human Endometrial Stromal Interleukin-1 Beta: Autocrine Secretion and Inhibition by Interleukin-1 Receptor Antagonist

Decidualization of human endometrial stromal cells is suppressed by endometrial IL-1 in an autocrine or paracrine manner, indicating that constant suppression of stromal decidualization by IL-1 requires a neutralizing mechanism for IL-1 action to accept embryo implantation. Since production of IL-1ra in human endometrium is reported to be 10- to 30-fold higher than that of IL-1α/β, we investigated whether endogenous IL-1β secreted from human endometrial stromal cells can be inhibited by IL-1ra by using an in vitro decidualization culture. Human stromal cells were cultured with 8-Br-cAMP to induce decidualization, and concentrations of IL-1β, IL-8, and prolactin in the culture supernatants were assayed before and after decidualization. There was no significant difference in mean IL-1β concentrations measured before and after decidualization. Addition of IL-1ra to endometrial stromal cell cultures strongly inhibited endogenous IL-8 secretion from the cells. Although IL-1β showed a biphasic effect on cell proliferation and a suppressive effect on decidualization of stromal cells, these effects were completely inhibited by IL-1ra. The results imply that a high in vivo concentration of IL-1ra in human endometrial tissues may regulate IL-1 effects on decidualization and cell proliferation of human endometrial stromal cells.

Circulating inflammatory cytokine levels in hemolytic uremic syndrome.

Experimental data suggest that the host's inflammatory response is involved in the pathophysiology of verotoxin-producing Escherichia coli (VTEC)-associated hemolytic uremic syndrome (HUS). We compared the circulating levels of pro- [interleukin (IL)-6, IL-8] and anti-inflammatory [IL-10 and IL-1 receptor antagonist (Ra)] mediators on enrollment among children with HUS due to E. coli O157:H7, according to the severity of renal dysfunction. The latter was evaluated by the occurrence of oligoanuria, the requirement for dialysis, and a glomerular filtration rate (GFR) </=80 ml/min per 1. 73 m(2) measured 1 year later. Increased levels of IL-6 (P<0.0001), IL-10 (P<0.0001), and IL-1Ra (P<0.07) were found among patients with HUS compared with normal controls. Children with severe renal dysfunction also had tenfold increased levels of IL-6 and higher concentrations of IL-10 and IL-1Ra. Both the IL-6/IL-10 (4.9+/-8.3 vs. 0.5+/-0.4, P=0.01) and the IL-6/IL-1Ra ratios (0.10+/-0.20 vs. 0. 01+/-0.01, P=0.04) were significantly increased. GFR correlated well with IL-6 levels, IL-6/IL-10 and IL-6/IL-1Ra ratios. Our data demonstrate that the inflammatory response of the host is associated with the severity of renal dysfunction during classic HUS. An imbalance between the pro- and the anti-inflammatory responses may be involved in the pathophysiology of VTEC-associated HUS.

Whole blood production of monocytic cytokines (IL-1beta, IL-6, TNF-alpha, sIL-6R, IL-1Ra) in haemodialysed patients.

The production of monocytic cytokines by isolated mononuclear cells after stimulation by phytohaemagglutinin (PHA) and lipopolysaccharide (LPS) is generally increased in haemodialysed (HD) patients. We performed whole blood (WB) cultures to evaluate cytokine production by blood cells inside their complex cellular and humoral network. Diluted whole blood from HD patients (collected before dialysis) and controls was cultured alone with PHA (2.5 microg/ml) or LPS (1 and 3 microg/ml). Supernatants were collected after 24 and 48 h of culture, and concentrations of IL-1 beta, IL-6, TNF-alpha, sIL-6R and IL-1Ra were determined by ELISA. The low spontaneous production of IL-1beta, IL-6 and TNF-alpha in both patients and controls was not significantly modified by PHA. The lower dose of LPS (1 microg/ml) induced a significant but lower increase in production of IL-1beta, IL-6 and TNF-alpha in patients than in controls. In contrast, while it did not further increase their production in controls, the higher concentration of LPS (3 microg/ml) still increased their production in patients to the same level than in controls. The plasma concentrations of sIL-6R were higher in patients than in controls. In both groups, the sIL-6R concentration did not vary during the culture period whether the cells were stimulated or not with LPS or PHA. This suggests that the increased plasma levels of sIL-6R were not produced by blood cells. Despite a similar significant LPS and PHA induced production of IL-1Ra, the IL-1Ra/IL-1beta ratio was always higher in patients than in controls. Monocytes from HD patients in WB cultures are hyporesponsive to PHA and LPS for their IL-1beta, TNFalpha and IL-6 production in contrast to isolated monocytes that demonstrate signs of activation. If it reflects the in vivo situation it could partly explain the immune defect in uraemic and haemodialysed patients. Higher sIL-6R/IL-6 and IL-1Ra/IL-1beta ratios could also participate to the complex immune disturbances of HD patients by reducing the biological activity of two cytokines playing a major role in the immune and inflammatory network.

Determination of interleukin-1 receptor antagonist, interleukin-10, and transforming growth factor-β1 in synovial fluid aspirates of patients with temporomandibular disorders

Purpose: This study was undertaken to examine the presence of interleukin-1 receptor antagonist (IL-1ra), IL-10, and transforming growth factor-β1 (TGF-βl) in the synovial fluid (SF) lavage specimens of patients with temporomandibular disorders (TMDs). Patients and Methods: Synovial fluid lavage specimens were obtained from 14 temporomandibular joints (TMJs) of 12 patients with TMJ internal derangement (ID) and 17 TMJs of 15 patients with TMJ osteoarthritis (OA). Seven synovial fluid lavage samples of TMJs of four asymptomatic donors served as normal controls. The concentrations of IL-1ra, IL-10, and TGF-β1 were detected with sensitive and specific sandwich enzyme-linked immunosorbent assay (sandwich-ELISA). Results: IL-1ra, IL-10, and TGF-β1 in all the normal controls were undetectable. IL-lra concentrations were 175.78 ± 52.43 pg/mL in the patients with TMJ ID and 187.85 ± 59.51 pg/mL in those with TMJ OA. IL-10 was undetectable in all the TMJ ID and OA samples. The concentration of TGF-βl in TMJ ID patients (47.93 ± 88.25 pg/mL) was significantly less than in patients with TMJ OA (143.61 ± 108.00 pg/mL) ( P < .01). Conclusion: The results suggest that deficiencies of IL-1ra, IL-10, and TGF-β1 probably play an important role in the cause and pathogenesis of TMJ ID and OA.

Interleukin 1 receptor antagonist and E-selectin concentrations: A comparison in patients with severe acute pancreatitis and severe sepsis

Purpose: This prospective clinical study was designed to compare interleukin 1 receptor antagonist (IL-1ra) and E-selectin concentrations in patients with severe acute pancreatitis to those with severe sepsis. Materials and Methods: Nine consecutive patients with severe acute pancreatitis and 11 consecutive patients with severe sepsis admitted to a medical/surgical intensive care unit were included in the study. Plasma concentrations of IL-1ra and E-selectin were serially measured daily for 7 days or throughout their stay in the intensive care unit if shorter. Results: The concentrations of IL-1ra were significantly higher on admission in patients with severe sepsis compared with the patients with severe pancreatitis (median levels 10,500 and 2,600 pg/mL, respectively, P = .007). When the data from the first 3 days were analyzed using analysis of variance (ANOVA), the levels of IL-1ra and E-selectin were similar in both groups. The concentrations of IL-1ra and E-selectin correlated to the development of multiorgan dysfunction as assessed by sequential organ failure assessment (SOFA) score ( P = .032 and .043, respectively). Conclusion: This study shows that IL-1ra and E-selectin are released in acute severe pancreatitis, and the levels seem to be comparable to those in patients with severe sepsis. Concentrations of IL-1ra and E-selectin correlate to the development of multiorgan failure as indicated by high SOFA scores during the first week of disease.

Circulating Pro- and Counterinflammatory Cytokine Levels and Severity in Necrotizing Enterocolitis

To evaluate the relationship between the severity of necrotizing enterocolitis (NEC) and circulating concentrations of proinflammatory cytokines interleukin (IL)-1beta and IL-8 and counterinflammatory cytokines IL-1 receptor antagonist (IL-1ra) and IL-10. These cytokines have been associated with bowel injury or inflammation and may be released more slowly or later than previously examined cytokines. Also, to determine if any one of these cytokines will predict the eventual severity of NEC when measured at symptom onset. Serial blood samples at onset, 8, 24, 48, and 72 hours were obtained from newborn infants with predefined signs and symptoms of NEC. Normal levels were defined from weight-, gestation-, and age-matched controls. Concentrations of the four cytokines were determined by enzyme-linked immunosorbent assay and compared throughout the time period by stage of NEC, using sepsis as a co-factor. Mean concentrations of each cytokine at onset were compared with the controls. Threshold values were obtained with the best combination of high sensitivity and high specificity for defining stage 1 NEC or for diagnosing stage 3 NEC at onset. There were 12 cases of stage 1, 18 cases of stage 2, and 6 cases of stage 3 NEC included in the study, as well as 20 control infants. Concentrations of IL-8 and IL-10 were significantly higher in infants with stage 3 NEC from onset through 24 hours compared with infants with less severe NEC. At onset, concentrations of all four cytokines were significantly higher in stage 3 NEC. To identify, at onset, the infants with a final diagnosis of stage 3 NEC, an IL-1ra concentration of >130 000 pg/mL had a sensitivity of 100% and a specificity of 92%. At 8 hours, an IL-10 concentration of >250 pg/mL had a sensitivity of 100% and a specificity of 90% in identifying stage 3 NEC in infants with symptoms suggestive of NEC at onset. The severity of NEC and its systemic signs and symptoms are not due to a deficiency of counterregulatory cytokines. In fact, mean concentrations of IL-1ra in NEC are higher than what has been reported in other populations. The cytokines IL-8, IL-1ra, and IL-10 are released later or more slowly after a stimulus and may be more useful in identifying, within hours of symptom onset, which infant will develop significant NEC.

Influence of psychological stress on immune-inflammatory variables in normal humans. Part II. Altered serum concentrations of natural anti-inflammatory agents and soluble membrane antigens of monocytes and T lymphocytes

The effects of academic examination stress on serum concentrations of interleukin (IL)-1 receptor (R) antagonist (A), soluble(s) IL-2R, sIL-6R, soluble glycoprotein 130 (sgp130), Clara cell protein (CC16), sCD8 and sCD14 were evaluated in 38 university students. The relationships among changes in the above immune-inflammatory variables, levels of serum cortisol, and scores on the Perceived Stress Scale (PSS) or the State–Trait Anxiety Inventory (STAI) were examined. Academic examination stress was associated with significant increases in PSS and STAI scores, and in serum sgp130 and sCD8 values. Academic examination stress was associated with significantly decreased serum sCD14 concentrations in students with high, but not low, stress perception. There were stress-induced differences in serum IL-1RA, sIL-6R and CC16 concentrations between students with high vs. low stress-induced anxiety. The stress-induced increase in serum sCD8 was significantly more pronounced in male students, whereas the increase in serum sgp130 was more pronounced in female students taking contraceptive drugs. These results suggest that: (1) psychological stress induces immune-inflammatory changes pointing toward complex regulatory responses in IL-6 signalling, a decreased anti-inflammatory capacity of the serum, and interactions with T cell and monocytic activation; and that (2) sex hormones may modify stress-induced immune-inflammatory responses.

Balance between Proinflammatory Cytokines and Their Inhibitors in Bronchial Lavage from Patients with Status Asthmaticus

Status asthmaticus (SA) is an acute respiratory failure combining an acute bronchospastic reaction with a severe airway inflammation. We previously reported an important influx of neutrophils and an increased secretion of interleukin-8 (IL-8) in patients with SA. The aim of this prospective study was to evaluate in bronchial lavage (BL) of patients with SA (n = 9) under mechanical ventilation (MV) the concentrations of cytokines and related mediators which have the ability to modulate inflammation, either proinflammatory (interleukin-1beta [IL-1beta], IL-6, tumor necrosis factor-alpha [TNF-alpha]), or anti-inflammatory mediators (IL-10, transforming growth factor-beta1 [TGF-beta1]), interleukin-1 receptor antagonist [IL-1Ra], soluble TNF receptor I and II [sTNFRI and II]). To determine the relative importance of both pro- and anti-inflammatory mediators, the net inflammatory activity was analyzed by the capacity of BL fluids (BLF) to increase intercellular adhesion molecule-1 (ICAM-1) expression in the human lung A549 epithelial cell line. These data were compared with those obtained from patients who required MV without respiratory disease (V, n = 4), controlled asthma (A, n = 11), and nonsmoking healthy volunteers (C, n = 8). Levels of IL-1, IL-6, TNF-alpha, and of the active form of TGF-beta1 were significantly higher in SA compared with the other groups. The concentrations of IL-1Ra, IL-10, the latent form of TGF-beta1, and of the sTNFRI and II were not significantly different between SA and V, albeit higher in SA than in A and C. The ratio between IL-1Ra and IL-1beta was significantly higher in patients with SA compared with the other groups, whereas there was no difference for the ratio between both types of sTNFR and TNF-alpha. Despite a marked increase of anti-inflammatory mediators in BL from patients with SA, the net inflammatory activity was found to be proinflammatory and mainly due to the presence of bioactive IL-1beta (79% inhibition of ICAM-1 expression with anti-IL-1beta antibodies) and to a lesser extent TNF-alpha (32% inhibition with anti-TNF-alpha antibodies).

Profile of Circulating Levels of Interleukin-1 Receptor Antagonist and Interleukin-6 in Colorectal Cancer Patients

Background: Circulating levels of pro-inflammatory cytokines are associated with the disease status of cancer patients. We investigated the profile of circulating levels of interleukin (IL)-6 and its antagonist in colorectal cancer patients. Methods: Serum concentrations of interkeukin-1 receptor antagonist (IL-1ra) and IL-6 in 80 colorectal cancer patients and tissue concentrations of IL-1ra and IL-6 in 60 primary colorectal cancers and normal colonic mucosas were determined. The serum concentration of immunosuppressive acidic protein (IAP) was also determined. Results: The serum concentrations of IL-1ra and IL-6 in the patients were significantly higher than those in the controls. The serum concentration of IL-1ra in the patients was associated with clinicopathologic factors including tumor size, liver metastasis, lymph node metastasis, vessel involvement, or serum level of carcinoembryonic antigen. Although the serum IL-1ra level increased in keeping with the increase of serum IL-6, the net balance between IL-1ra and IL-6 was significantly lower than that in the controls. The serum IL-1ra to IL-6 ratio decreased in association with the patient's age, the rate of loss of body weight and the serum level of IAP. Although the serum level of IL-6 correlated with the IL-6 concentration in the cancer tissue, the serum level of IL-1ra did not correlate with the IL-1ra concentration in this tissue. Conclusions: Serum IL-1ra, induced systemically by a marked activation of the IL-6 network in cancer tissue, may be a potent index that evaluates disease progression of colorectal carcinoma. Decreased serum IL-1ra to IL-6 ratio may reflect the deterioration of the systemic anti-inflammatory response that is associated with aging, tumor-related malnutrition, or immunosuppression.