Interleukin-1 Receptor Antagonist Concentrations Research Articles

Clinical Correlates of Elevated Serum Concentrations of Cytokines and Autoantibodies in Patients With Spinal Cord Injury

Davies AL, Hayes KC, Dekaban GA. Clinical correlates of elevated serum concentrations of cytokines and autoantibodies in patients with spinal cord injury. Objective To determine the serum cytokine profiles of patients with spinal cord injury (SCI) and varying clinical presentations relative to healthy, able-bodied, age-matched control subjects. Design Cross-sectional study. Setting Clinical research unit. Participants People with SCI (N=56) and different clinical presentations, and healthy, able-bodied, age-matched control subjects (N=35). Interventions Not applicable. Main Outcome Measures Serum levels of the proinflammatory cytokines interleukin (IL) 1β, IL-6, tumor necrosis factor alpha (TNF-α), the anti-inflammatory cytokines IL-4 and IL-10, the regulatory cytokine IL-2, the IL-1 receptor antagonist (IL-1RA), and autoantibodies against myelin-associated glycoprotein and GM 1 ganglioside (anti-GM 1) immunoglobulin (IgG and IgM), as determined by enzyme-linked immunosorbent assay. The relationship between elevated serum cytokine levels and clinical variables was also studied. Results SCI subjects exhibited serum concentrations of IL-6, TNF-α, IL-1RA, and anti-GM 1 (IgG) that were greater ( P<.05) than control group values. Elevated cytokine concentrations were not associated with high white blood cell counts, level of injury, or American Spinal Injury Association classification; they were evident in SCI subjects who were asymptomatic for medical complications, but were further elevated in subjects with pain, urinary tract infection (UTI), and pressure ulcers. Conclusions Elevated levels of circulating proinflammatory cytokines and autoantibodies are present in the serum of SCI subjects without medical complications, and are further elevated in SCI subjects with neuropathic pain, UTI, or pressure ulcers, relative to healthy, able-bodied control subjects. These findings may be indicative of a protective autoimmunity, simply a consequence of occult or evident infection, or evidence of cytokine dysregulation that may contribute to an immune-mediated impairment of axonal conduction.

Clinical, biochemical, and histologic effects of intra-articular administration of autologous conditioned serum in horses with experimentally induced osteoarthritis

To assess the clinical, biochemical, and histologic effects of intra-articular administration of autologous conditioned serum (ACS) in the treatment of experimentally induced osteoarthritis in horses. 16 horses. Osteoarthritis was induced arthroscopically in 1 middle carpal joint of all horses. In 8 placebo- and 8 ACS-treated horses, 6 mL of PBS solution or 6 mL of ACS was injected into the osteoarthritis-affected joint on days 14, 21, 28, and 35, respectively; PBS solution was administered in the other sham-operated joints. Evaluations included clinical assessment of lameness and synovial fluid analysis (performed biweekly); gross pathologic and histologic examinations of cartilage and synovial membrane samples were performed at necropsy. No adverse treatment-related events were detected. Horses that were treated with ACS had significant clinical improvement in lameness, unlike the placebo-treated horses. Among the osteoarthritis-affected joints, ACS treatment significantly decreased synovial membrane hyperplasia, compared with placebo-treated joints; although not significant, the ACS-treated joints also appeared to have less gross cartilage fibrillation and synovial membrane hemorrhage. The synovial fluid concentration of interleukin-1 receptor antagonist (assessed by use of mouse anti-interleukin-1 receptor antagonist antibody) was increased following treatment with ACS. Results of this controlled study indicated that there was significant clinical and histologic improvement in osteoarthritis-affected joints of horses following treatment with ACS, compared with placebo treatment. On the basis of these findings, further controlled clinical trials to assess this treatment are warranted, and investigation of the mechanisms of action of ACS should be pursued concurrently.

Interleukin-1 (IL-1) receptor antagonist gene polymorphism in normal weight obese syndrome: Relationship to body composition and IL-1 α and β plasma levels

Interleukin-1 receptor antagonist concentration is upregulated in the plasma of patients with obese related disease, and its synthesis is under genetic control. We tested the hypothesis that the polymorphism in the interleukin-1 receptor antagonist gene second intron might be associated with normal weight obese syndrome. The polymorphism of intron 2 in the interleukin-1 receptor antagonist gene, containing a variable numbers of a tandem repeat (VNTR), and interleukin-1α and β plasma levels were evaluated in 110 Caucasian Italian women, divided in three groups: non-obese, normal weight obese and preobese-obese. The allele 1 frequency was not significantly different in the three groups. The alleles 3 and 4 were not observed in any group. The allele 2 frequency in normal weight obese woman (12.5%) and preobese-obese (17.5%) groups were significantly different in comparison with the non-obese group (6.7%). The allele 5 was observed exclusively in non-obese and normal weight obese subjects (13.3 and 7.5%, respectively). In normal weight obese women, plasma concentrations of interleukin-1 α and interleukin-1 β were significantly higher than in non-obese. The allele 2 was observed in normal weight obese as well as a significant association between the increase of interleukin-1 β plasma amount and the allele 2 carrier. Our findings suggest that the allele 2 might be an important high-risk genetic marker for normal weight obese syndrome and obesity related diseases.

Clinical Response Is Associated with Elevated Plasma Interleukin-1 Receptor Antagonist During Selective Granulocyte and Monocyte Apheresis in Patients with Ulcerative Colitis

Depletion of granulocytes and monocytes (GM) by selective apheresis (GMA) with an Adacolumn exerts an anti-inflammatory effect in patients with ulcerative colitis (UC) or rheumatoid arthritis. However, the mechanism of the anti-inflammatory effect of GMA is not fully understood yet. We investigated the effect of GMA on the plasma concentration of interleukin-1 receptor antagonist (IL-1ra), a potent anti-inflammatory cytokine. Twenty-six patients with active UC received GMA at one session per week for 5 consecutive weeks. Clinical response was defined as Deltaclinical activity index (DeltaCAI=CAI at entry - CAI at post)>or=4, while clinical remission was defined as CAI<or=4. Twenty-one of twenty-six patients (80.8%) responded to GMA. In the first session, plasma from responder patients showed a significant (P < 0.01) increase in IL-1ra in the Adacolumn outflow. In contrast, there was no change in IL-1ra in nonresponders. In conclusion, release of IL-1ra during GMA might be one mechanism of clinical efficacy associated with this therapy.

Neutrophil Apoptosis, Activation and Anti-Inflammatory Cytokine Response in Granulocyte Colony-Stimulating Factor-Treated Patients with Community-Acquired Pneumonia

Background:Despite antibiotic treatment, the mortality of severe community-acquired pneumonia (CAP), especially in patients with severe comorbidity, remains high. Innate defense mechanisms including polymorphonuclear neutrophil (PMN) activation and survival, orchestrated by cytokines, are primarily responsible for the elimination of bacterial organisms from the alveolus. Objectives: The aim of this study was to evaluate the effect of granulocyte colony-stimulating factor (G-CSF) on PMN activation, apoptosis and cytokine response in patients with CAP. Methods: Patients received a single dose of G-CSF (1 × 300 or 480 µg s.c.) prior to standard antibiotic treatment (n = 8) or standard treatment only (n = 8). Apoptosis rate and expression of CD11b, CD66b, CD64 and CD114 surface molecules on systemic PMN were assessedusing fluorescence-activated cell sorter analysis. Levels of the interleukin-1 receptor antagonist (IL-1RA), the soluble tumor necrosis factor receptor inhibitor (sTNF-p55) and G-CSF were measured by ELISA. Results: In the treatment group, 12 h after G-CSF application, neutrophil count increased, neutrophil activation marker CD11b was stimulated (CD11b: 48.6 ± 9.7 vs. 71.2 ± 17.7, p < 0.01), neutrophil apoptosis decreased (apoptosis: 1.36 ± 0.27 vs. 0.2 ± 0.12%, p < 0.01) and the concentration of IL-1RA and sTNF-p55 increased (IL-1RA 136.4 ± 72.2 vs. 340.1 ± 194.6 ng/ml, p < 0.01; sTNF-p55 382 ± 4,243 vs. 632 ± 4,714 ng/ml, p < 0.01; control group nonsignificant). These effects were not seen in the control group. Conclusions: The application of a single dose of G-CSF in patients with CAP caused a prolonged survival and increased activation of neutrophils combined with a sustained release of anti-inflammatory cytokines.

Serum interleukin-1 receptor antagonist is an early indicator of colitis onset in Gαi2-deficient mice

To study the serum concentration of IL-1beta, IL-1 receptor antagonist (IL-1Ra) and IL-18 in Galphai2-deficient mice at the age of 6 (healthy), 12 (pre-colitic) and 24 wk (colitic) and in healthy control mice. At the time of killing, serum samples were collected and IL-1beta, IL-1Ra and IL-18 levels were measured using enzyme-linked immunosorbent assays. Serum concentration of IL-1Ra was significantly increased in pre-colitic (median: 524 ng/L; P=0.02) and colitic (450 ng/L; P=0.01), but not in healthy (196 ng/L) Galphai2-deficient mice as compared with controls (217 ng/L). Serum concentrations of IL-1beta did not differ between Galphai2-deficient mice and their controls, irrespective of age, IL-18 was significantly increased in colitic, but not in pre-colitic mice compared with controls (510 ng/L vs 190 ng/L; P=0.05). The increased serum concentrations of IL-18 and IL-1Ra in established diseases are suggested as markers of ongoing colitis. Interestingly, the significantly increased serum concentration of IL-1Ra in pre-colitic mice is found to be an early marker of disease progression.

Immune and Nutrition Status in Elderly Koreans with HyperLDL-Cholesterolemia

Although the effects of nutrition and immune status on disease development have been investigated, little attention has been given to changes in immune function in the elderly vulnerable to coronary artery disease (CAD). Our objective was to evaluate the association between immune variables and CAD risk factors, and nutritional factors related to immune and lipid profiles in elderly Koreans (n = 90). The subjects were divided into three groups based on serum low-density lipoprotein cholesterol (LDL-cholesterol) level: risk (> or = 160 mg/dL), borderline (130-160 mg/dL), and control groups (< 130 mg/dL). Concanavalin A-induced lymphocyte proliferation rate and interleukin (IL)-2 secretion were significantly lower in the risk group than the control group. The subjects in the risk group showed the highest serum concentrations of proinflammatory mediators such as complement 3 (C3), IL-1beta, and IL-1 receptor antagonist (IL-1RA). The nutrient intake status of the subjects was generally satisfactory without differences among groups. IL-1RA concentration was negatively associated with intake of vitamin E and C3 was positively related to intake of Ca and Fe in the subjects with LDL-cholesterol > or = 130 mg/dL. This study suggests that elderly individuals with high serum LDL-cholesterol are in a mild chronic inflammation state and micronutrient status such as vitamin E, Ca, and Fe may relate to this state.

Mirthful laughter differentially affects serum pro- and anti-inflammatory cytokine levels depending on the level of disease activity in patients with rheumatoid arthritis

To examine the effect of mirthful laughter in rheumatoid arthritis (RA), we evaluated the levels of serum cytokines before and after patients experienced mirthful laughter. Forty-one patients with RA and 23 healthy subjects were enrolled. They listened to 'Rakugo', a traditional Japanese comic story, to induce mirthful laughter. We measured serum IL-6, IL-1beta, TNF-alpha, IL-4 and IL-1 receptor antagonist (IL-1Ra) concentrations before and after patients listened to the story. The RA subjects were divided into two groups. One was designated the 'difficult-to-control RA' group (CRP > or =1.0 mg/dl); The other group was regarded as the 'easily controlled RA' group (CRP <1.0 mg/dl). The basal levels of serum IL-6 and TNF-alpha in the RA patients were significantly higher than those in the healthy group. After experiencing mirthful laughter, the levels of serum IL-6 decreased significantly in the RA group but not in the healthy subjects. Interestingly, the level of serum TNF-alpha decreased only in the easily controlled RA group. Serum IL-4 concentration in the RA group was significantly higher than that in healthy subjects before the story. After the story, the level of serum IL-4 significantly decreased in the RA group, especially in the difficult-to-control RA group. In contrast, serum IL-1Ra concentration was statistically higher in the RA group than that in healthy subjects before the story, and a further increase was observed after the story, especially in the easily controlled RA group. Our findings suggest that mirthful laughter affects the levels of serum pro- and anti-inflammatory cytokines differentially, depending on the RA disease activity.

Statistics of Assay Validation in High Throughput Cell Imaging of Nuclear Factor κB Nuclear Translocation

This report describes statistical validation methods implemented on assay data for inhibition of subcellular redistribution of nuclear factor kappaB (NF kappaB) in HeLa cells. We quantified cellular inhibition of cytoplasmic-nuclear translocation of NF kappaB in response to a range of concentrations of interleukin-1 (IL-1) receptor antagonist in the presence of IL-1alpha using eight replicate rows in each four 96-well plates scanned five times on each of 2 days. Translocation was measured as the fractional localized intensity of the nucleus (FLIN), an implementation of our more general fractional localized intensity of the compartments (FLIC), which analyzes whole compartments in the context of the entire cell. The NF kappaB antagonist assay (inhibition of IL-1- induced NF kappaB translocation) data were collected on a Q3DM (San Diego, CA) EIDAQtrade mark 100 high throughput microscopy system. [In 2003, Q3DM was purchased by Beckman Coulter Inc. (Fullerton, CA), which released the IC 100 successor to the EIDAQ 100.] The generalized FLIC method is described along with two-point (minimum-maximum) and multiple point titration statistical methods. As a ratio of compartment intensities that tend to change proportionally, FLIN was resistant to photobleaching errors. Two-point minimum-maximum statistical analyses yielded the following: a Z' of 0.174 with the data as n = 320 independent well samples; Z' by row data in a range of 0.393-0.933, with a mean of 0.766; by-plate Z' data of 0.310, 0.443, 0.545, and 0.794; and by-plate means of columns Z' data of 0.879, 0.927, 0.945, and 0.963. The mean 50% inhibitory concentration (IC50) for IL-1 receptor antagonist over all experiments was 213 ng/ml. The combined IC50 coefficients of variation (CVs) were 0.74%, 0.85%, 2.09%, and 2.52% for the four plates. Repeatability IC50 CVs were as follows: day to day 3.0%, row to row 8.0%, plate to plate 2.8%, and day to day 0.6%. The number of cells required for statistically resolvable differences in dose concentrations, plotted in a family of FLIN sigma/deltamicro (SD/range) curves and tabulated, demonstrated cell-by-cell assay precision with our combined sigma/deltamicro = 0.32 that required approximately 10-fold fewer cells than in a previously reported NF kappaB assay with sigma/deltamicro = 1.52. To better understand the relationship between cell-by-cell measurements and IC50 precision, 500 Monte Carlo simulations with varying cell-measurement SDs were used to explore three-, five-, seven-, and 11-point model titrations. The reductions in deltaIC50 90% confidence intervals from 11- to three-point titrations were 10-fold with the previously reported sigma/deltamicro = 1.52 and twofold with our sigma/deltamicro = 0.32. With these normalized parameters, this report provides a common statistical foundation, independent of the assay details, for evaluating the performance of imaging data on any instrument.

A predominantly anti-inflammatory cytokine profile is associated with disease severity in meningococcal sepsis

This study aimed to determine whether an anti-inflammatory profile in meningococcal disease is associated with an increased risk of severe disease or septic shock. Prospective observational study in a tertiary care children's hospital. 63 children with confirmed meningococcal disease. Plasma concentrations of interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF) were assayed on admission. Receiver operator characteristic curve analysis was used to determine optimum thresholds for IL-1Ra:TNF, IL-1Ra:IL-6 and IL-1Ra:IL-8 ratios. Median IL-1Ra:TNF and IL-1Ra:IL-6 ratios were significantly higher in severe disease with septic shock than in severe disease without septic shock and in non severe disease (IL-1Ra:TNF 263 vs. 185 vs. 108; IL-1Ra:IL-6 139 vs. 23 vs. 17). Median IL-1Ra:IL-8 ratios were not significantly different in the three groups. A significantly larger proportion of children with high IL-1Ra:TNF-alpha and IL-1Ra:IL-6 ratios developed severe disease with septic shock than those with a low ratios (95.2% vs. 4.8%; 76.2% vs. 23.8%). An anti-inflammatory profile appears to be associated with the development of severe disease and septic shock in meningococcal sepsis. This may imply that experimental new therapies of pro-inflammatory cytokine inhibition and anti-inflammatory cytokines in meningococcal disease could be detrimental.

Interleukin-1 Receptor Antagonist Inhibits the Expression of Vascular Endothelial Growth Factor in Colorectal Carcinoma

Objective: Interleukin (IL)-1 is known to act as a tumor growth factor by inducing angiogenic factors. We examined the significance of IL-1β and IL-1 receptor antagonist (RA) for inducing the expression of vascular endothelial growth factor (VEGF) in colorectal cancers. Methods: We investigated the expression of VEGF induced by IL-1β in five colon cancer cell lines and the possible involvement of IL-1 RA. We also measured the tissue concentrations of IL-1β, IL-1 RA and VEGF by ELISA in 65 colorectal cancer patients. Results: IL-1β induced VEGF secretion with a 19-fold increase in Caco-2 cells. A significant increase in VEGF secretion was also observed in SW480 and WiDr cells. IL-1 RA inhibited IL-1β-induced VEGF secretion by 87%. Our data from the clinically obtained specimens showed that the IL-1 RA/IL-1β ratio is significantly lower in cancer tissue. Regarding the clinicopathological parameters, the IL-1 RA/IL-1β ratio was significantly lower in patients with vessel involvement than in those without involvement, and IL-1 RA/IL-1β ratio was negatively correlated with the VEGF protein level in colorectal tumors. Conclusions: Our data suggest that IL-1β induces VEGF expression and IL-1 RA acts as the competitive inhibitor, and that the IL-1 RA/IL-1β ratio is significant for VEGF expression in the microenvironment of colorectal cancer tissue. We conclude that IL-1β induces VEGF secretion in a certain population of colorectal cancer patients, and that IL-1 RA is the potential therapeutic agent for antiangiogenic therapy in colorectal cancer patients.

Biocompatibility Parameters of Different Dialysis Membranes Assessed during Systemic Inflammation

Background: We explored whether biocompatible dialyzer membranes modulate the inflammatory response during blood contact in patients with systemic inflammation. Methods: 15 patients with end-stage renal disease and systemic inflammation (mean serum C-reactive protein 86 ± 4 mg/l) were randomly treated with Cuprophan (CU), polyamide (PA) and vitamin-E coated (VEC) membrane-based dialyzers. Results: Changes in blood pressure, capillary blood oxygen saturation and differential blood counts during the hemodialysis session were not significantly different between the three dialyzers. Baseline blood levels of activated circulating complement (C3a) were more than 100 times above normal, and unlike expected they decreased during hemodialysis treatments (CU: from 7,389 ± 783 to 5,423 ± 761 ng/ml; PA: from 7,379 ± 980 to 5,690 ± 714 ng/ml; VEC: from 7.377 ± 714 to 5,360 ± 1,005 ng/ml; all n.s.). No significant differences between treatments were found with respect to changes in blood concentrations of TNF-α, interleukin-6 and interleukin-1 receptor antagonist as well as ICAM-1 (CU: from 451 ± 41 to 477 ± 41 ng/ml; PA: from 437 ± 42 to 449 ± 40 ng/ml; VEC: from 461 ± 43 to 460 ± 47 ng/ml). Furthermore, generation of reactive oxygen species by mononuclear blood cells was comparable during hemodialysis with the CU, PA and VEC dialyzer. Conclusion: The choice of dialyzer membrane material does not affect most aspects of biocompatibility when patients have significant systemic inflammation. This confounding variable should be taken into account in studies exploring the effects of biocompatible dialyzer membranes.

Systemic Inflammation After Drug-Eluting Stent Placement

Systemic inflammation after coronary intervention identifies patients at increased risk of subsequent cardiac events. Cardiac events are less frequent after use of drug eluting stents (DES) compared with bare metal stents (BMS). Thus, we sought to determine whether attenuation of the systemic inflammatory response was contributing to the improved outcomes. A prospective registry was initiated in late 2003. Peripheral venous blood samples from 75 patients undergoing percutaneous coronary intervention (PCI) were obtained before PCI, and both 1 hour and 24 hours after stenting. The concentrations of C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL1-Ra) were determined by ELISA. Eleven patients were excluded from the analysis because they had both DES and BMS. Patients treated with BMS (n=29) compared with DES (n=34) had a higher incidence of marker-positive acute coronary syndromes (40% vs. 17%, p=0.06), vein graft PCI (p=0.02) and a larger final balloon diameter (p=0.04). Consistent with the lower baseline clinical risk, pre-PCI concentrations of cytokines were lower in the DES group (p=0.04 for IL-6 and p=0.08 for CRP). Comparable and significant increases in CRP, IL-6 and IL1-Ra were evident 24 hours after PCI in patients treated with either DES or BMS. After controlling for baseline levels of CRP, there remained a similar and robust (300%) relative increase in CRP for both DES and BMS patients. The inflammatory response to PCI appears similar in those treated with DES and BMS. Accordingly, the reduction in restenosis after DES is likely not mediated by attenuation of the systemic markers CRP, IL-1Ra, or IL-6.

Postoperative Change of Mucosal Inflammation at Strictureplasty Segment in Crohn's Disease: Cytokine Production and Endoscopic and Histologic Findings

This study was designed to examine postoperative change of mucosal inflammation at strictureplasty segment in Crohn's disease mainly by cytokine measurements. Patients who underwent strictureplasty for Crohn's disease in the terminal ileum were investigated. Mucosal samples at the strictureplasty site were obtained during operation. At 3, 6, and 12 months after operation, biopsy specimens were taken from the strictureplasty site and macroscopically normal ileum at endoscopy. Mucosal cytokine concentrations were measured by enzyme-linked immunosorbent assay. The mucosal concentrations of proinflammatory cytokines (interleukin-1beta, interleukin-6, interleukin-8, and tumor necrosis factor-alpha) and anti-inflammatory mediator (interleukin-1 receptor antagonist) at the strictureplasty segment greatly increased at the time of operation. Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-6, interleukin-8, and tumor necrosis factor-alpha concentrations at the strictureplasty segment decreased during a 12-month period after operation. Twelve months after operation there was no significant difference in each cytokine concentration between the strictureplasty and macroscopically normal segments. The mucosal interleukin-1 receptor antagonist/interleukin-1beta ratio at the strictureplasty segment increased during a 12-month period after operation. Twelve months after operation there was no significant difference in the ratio between the strictureplasty and macroscopically normal segments. The endoscopic and histologic severities of mucosal inflammation at the strictureplasty site also decreased; however, their findings were not normalized during the study. During one year after strictureplasty for Crohn's disease, cytokine production at the strictureplasty segment was decreased to the level of the macroscopically normal ileum and an imbalance between proinflammatory and antiinflammatory cytokines was corrected.

Association between vaginal 70-kd heat shock protein, interleukin-1 receptor antagonist, and microbial flora in mid trimester pregnant women

This study investigated the association among the inducible 70-kd heat shock protein, cytokines, and microbial flora in the vagina in mid trimester pregnant women and subsequent preterm delivery. Vaginal samples from 205 pregnant women, which were collected at 18 to 22 weeks of gestation, were analyzed for qualitative and quantitative vaginal microflora and for 70-kd heat shock protein, interleukin-1beta, interleukin-1 receptor antagonist, and tumor necrosis factor-alpha by enzyme-linked immunosorbent assay. Pregnancy outcome data were obtained subsequently. The 70-kd heat shock protein was detected in 38 vaginal samples (18.5%). Its presence was associated with elevated vaginal pH, a diagnosis of bacterial vaginosis, and elevated interleukin-1 receptor antagonist levels (P < .001). Among women with bacterial vaginosis, 70-kd heat shock protein-positive subjects had a >80% increase in median vaginal concentration of interleukin-1 receptor antagonist (P < .05). Vaginal 70-kd heat shock protein expression is associated with the down-regulation of the proinflammatory immune response to abnormal vaginal flora in mid trimester pregnant women.

Self-rated health and vital exhaustion, but not depression, is related to inflammation in women with coronary heart disease

Poor subjective well-being has been associated with increased coronary heart disease (CHD) morbidity and mortality in population-based studies and with adverse outcomes in existing CHD. Little is known about the mechanisms responsible for this association, but immune activity appears to be a potential pathway. Despite the growing evidence linking immune activity to subjective feelings, very few studies have examined patients with CHD, and the results are conflicting. We examined consecutive women patients hospitalized for acute myocardial infarction, and/or underwent percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. We assessed depression, vital exhaustion, and self-rated health by questionnaires. Circulating levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1ra) concentrations were determined. After controlling for potential confounding factors there was a significant positive correlation between IL-6 levels and vital exhaustion and poor self-rated health. The association between hsCRP and vital exhaustion and self-rated health was borderline significant. In contrast, the correlations between psychological factors and IL-1ra levels were weak and non-significant, as were the correlations between inflammatory markers and depression. Similar relationships between the inflammatory markers and the measures of psychological well-being were obtained when the latter ones were categorized into tertiles. In conclusion, inflammatory activity, assessed by IL-6 and hsCRP levels, was associated with vital exhaustion and self-rated health in CHD women. These findings may provide further evidence for a possible psychoneuroimmune link between subjective well-being and CHD. Our observations also raise the possibility that a cytokine-induced sickness response in CHD may be better represented by constructs of vital exhaustion and self-rated health than of depression.

Acute inflammation and negative mood: Mediation by cytokine activation

Inflammatory diseases are commonly associated with depressed mood. This association may be influenced by the production of proinflammatory cytokines. Accordingly, we assessed whether cytokine levels and mood (measured with the profile of mood states) could be altered by a mild, non-sickness inducing, acute inflammatory stimulus. Using a randomised placebo-controlled, double-blind design, 30 healthy male volunteers were injected with Salmonella typhi vaccine or placebo. Assessments of mood, symptoms of illness and temperature were made at baseline and at 1.5, 3, and 6 h post-injection. Plasma concentrations of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and tumour necrosis factor-α (TNF-α) were assessed at baseline and 3 h post-injection. No significant symptoms of illness were reported in either group. Mood was more negative following injection in the vaccine than the placebo group, and the vaccine group experienced a 106% increase in IL-6 concentration. Negative changes in mood following injection were significantly correlated with increases in IL-6 production. No changes in TNF-α or IL-1Ra concentration were recorded in either group. It is concluded that S. typhi vaccination may be a useful model of mild inflammatory challenge, producing a significant transient cytokine-induced decrease in mood in the absence of any febrile response. Implications for depressed mood in physical illness are discussed.

The relationship between circulating concentrations of C-reactive protein, inflammatory cytokines and cytokine receptors in patients with non-small-cell lung cancer

The relationship between circulating C-reactive protein concentrations and potential cytokine and receptor mediators (interleukin-6, leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), soluble IL-6 receptor, soluble gp130, soluble TNF receptor, interleukin-1 receptor antagonist and interleukin-8 (IL-8)) of this acute phase protein were examined in healthy subjects (n=11) and patients with non-small-cell lung cancer (n=50). Leukaemia inhibitory factor and CNTF were below detection limits in all controls and patients. C-reactive protein, interleukin-6, soluble gp130, soluble TNF receptor, interleukin-1 receptor antagonist and IL-8 concentrations were significantly elevated in cancer patients (P⩽0.001). Cancer patients with elevated C-reactive protein concentrations had greater concentrations of interleukin-6 (P<0.01) and interleukin-1 receptor antagonist (P<0.05). On regression analysis only interleukin-6 was independently associated with C-reactive protein (r=0.616, P<0.001). Interleukin-6 is an important independent mediator of elevated C-reactive protein concentrations in patients with non-small-cell lung cancer.

Periodontal therapy: a novel non-drug-induced experimental model to study human inflammation.

Chronic periodontitis causes a low-grade systemic inflammatory response; its standard treatment, however, induces an acute inflammatory response. The aim of this study was to describe the systemic inflammatory reactions to an intensive periodontal treatment regimen. Fourteen otherwise healthy subjects suffering from severe chronic periodontitis were enrolled in a 1 month pilot single-blind trial. Intensive periodontal treatment, consisting of full-mouth subgingival root debridement delivered within a 6-h period, was performed. Periodontal parameters were recorded before and 1 month after completion of treatment. Blood samples were taken at baseline and 1, 3, 5, 7 and 30 days after treatment. Interleukin-1 receptor antagonist (IL-1Ra), Interleukin-6 (IL-6) and C-reactive protein (CRP) serum concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Complete blood counts were also performed. One day after treatment, mild neutrophilia and monocytosis (p < 0.05) and lymphopenia (p < 0.01) were accompanied by a sharp increase in inflammatory markers (IL-1Ra, IL-6, p < 0.01). A 10-fold increase in CRP (p < 0.001) was detected on day 1 and its kinetics followed a pattern of a classical acute phase response (significantly raised concentrations up to 1 week, p < 0.01). At 3-7 days after treatment, subjects presented also with a mild tendency towards a normocytic anaemic state (p < 0.01) and a degree of lympho-thrombocytosis (p < 0.05). The observed changes were similar to those expected following the well-characterized endotoxin-challenge model of inflammation. Intensive periodontal treatment produced an acute systemic inflammatory response of 1 week duration and might represent an alternative to classic endotoxin-challenge or drug-induced models to study acute inflammation in humans.

Increased coronary arterial release of interleukin-1 receptor antagonist and soluble cd40 ligand indicative of inflammation associated with culprit coronary plaques

Blood taken from the coronary artery ostium reflects biochemical changes indicative of thrombosis in the culprit vessel. We sought to determine whether inflammation is manifested by increased concentrations of selected markers in ostial blood sampled from a culprit coronary artery proximal to an atherosclerotic plaque. The concentrations of C-reactive protein (CRP), interleukin (IL)-6, IL-1 receptor antagonist, and soluble CD40 ligand (sCD40L) were measured in blood drawn from 75 patients before percutaneous coronary intervention from the femoral artery and from a guide catheter after engagement of the culprit coronary artery. Results were compared using Student’s t tests. An acute coronary syndrome was present in 88% of patients. The concentrations of CRP and IL-6 were similar in coronary ostial and peripheral blood. Concentrations of IL-1 receptor antagonist were consistently greater in coronary arterial compared with peripheral arterial blood (peripheral 545 378 vs coronary 595 388 pg/ml, p 0.003). Concentrations of sCD40L were also greater in the coronary compared with peripheral blood (peripheral 0.80 0.46 vs coronary 2.12 2.77 ng/ml, p <0.0001). The increased concentration of IL-1 receptor antagonist and sCD40L in blood drawn from the culprit coronary artery compared with that taken from the peripheral artery suggests that these cytokines contribute directly to inflammation in response to coronary intervention and may potentiate a systemic inflammatory state. 2003 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:6 ‐9)