Baseline Interleukin-6 Research Articles

THE ROLE OF TUMOR NECROSIS FACTOR‐ALPHA IN COGNITIVE IMPROVEMENT AFTER PEROXISOME PROLIFERATOR‐ACTIVATOR RECEPTOR GAMMA AGONIST PIOGLITAZONE TREATMENT IN ALZHEIMER'S DISEASE

To the Editor: Some clinical trials have shown that agonists of the nuclear receptor peroxisome proliferator-activator receptor gamma (PPRAγ) improve cognition and memory in patients with Alzheimer's disease (AD).1,2 A pilot study demonstrated that 6 months of treatment with a PPARγ agonist, pioglitazone, improved cognition and hyperinsulinemia in patients with mild AD with type II diabetes mellitus,3 although the reason for these benefits is not fully understood. In animal models of AD, pioglitazone treatment resulted in the reduction of numbers of activated microglia associated with a lower plaque burden, partly by suppressing proinflammatory gene expression.4 The aim of the present study was to investigate the role of inflammatory-associated proteins in the improvement of cognition after pioglitazone treatment in patients with mild AD. A 6-month, randomized, open-controlled trial was conducted in patients with mild AD associated with type II diabetes mellitus. Thirty-four patients with probable AD5 were randomly assigned to treatment with pioglitazone 15 mg daily (n=17, pioglitazone group) or not (n=17, control group). Twenty-six of these patients were included in a 2009 study3 of patients with mild AD. The study protocol has been described elsewhere in detail.3 In this study, plasma cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP), were quantified at baseline and Month 6 using commercially available enzyme-linked immunoassays and nephrometry, respectively. The minimum detectable concentrations were 0.5 pg/mL, 0.2 pg/mL, and 0.02 mg/dL, respectively. Values were expressed as means ± standard deviations. Statistical analysis was performed using the Student t-test, chi-square test, Mann-Whitney U test, Wilcoxon signed-rank test, and Spearman rank correlation test. Table 1 shows comparisons of subject characteristics and Alzheimer's Disease Assessment Scale Cognitive Subscale, Japanese version (ADAS-Jcog) scores, plasma cytokines, and hs-CRP changes. There were no significant differences between the pioglitazone group and the control group in terms of age, sex, education, duration of symptoms, Mini-Mental State Examination (MMSE) score, apolipoprotein E ɛ4 status, or prevalence of use of donepezil. At baseline, no significant differences were found in ADAS-Jcog scores, plasma cytokines, or hs-CRP levels between the groups. At Month 6, ADAS-Jcog scores had decreased significantly in the pioglitazone group and increased significantly in the control group. There was a significant difference between the groups in ADAS-Jcog score changes (Month 6–baseline). When compared with baseline values, TNF-α, IL-6, and hs-CRP levels at Month 6 decreased in the pioglitazone group, whereas they increased in the control group, but no statistically significant change in either value was found in the two groups. There was a significant difference in TNF-α level changes (Month 6–baseline) between the groups. Changes in ADAS-Jcog scores significantly correlated with changes in TNF-α (correlation coefficient (r)=0.38, P=.04) but not in IL-6 (r=0.19) and hs-CRP levels (r=0.14). During the study, both groups showed stable fasting plasma glucose and hemoglobin A1c levels. When compared with baseline, fasting immunoreactive insulin levels at Month 6 decreased significantly in the pioglitazone group (from 7.8 ± 3.9 to 5.7 ± 2.4 μU/mL, P<.05) but not in the control group (from 6.7 ± 4.8 to 6.5 ± 2.9 μU/mL). It was found that reduction of TNF-α levels after pioglitazone treatment was associated with cognitive improvement. A previous study found that PPARγ agonists inhibit Aβ production stimulated by inflammatory cytokines.6 Proinflammatory cytokine TNF-α, which plays a role in immune system to brain communication, contributes to an exacerbation of neurodegeneration by microglial activation. A recent study showed that high serum TNF-α is associated with long-term cognitive decline in community-dwelling subjects with AD.7 An increase in TNF-α regulates synaptic scaling and results in disease progression in AD.8 Therefore, treatment to reduce TNF-α levels might provide some therapeutic benefits for AD. Although a number of studies have examined potential mechanisms through which PPARγ might act to ameliorate AD pathogenesis and progression, the anti-inflammatory action of PPARγ agonists is at least one plausible explanation for the beneficial effect on AD. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Haruo Hanyu: study concept and design, acquisition of subjects and data, analysis and interpretation of data, and preparation of letter. Tomohiko Sato, Hirofumi Sakurai, and Toshihiko Iwamoto: acquisition of subjects and data analysis. Sponsor's Role: None.

Effects of Resistance or Aerobic Exercise Training on Interleukin-6, C-Reactive Protein, and Body Composition

To determine the effects of 10 wk of resistance or aerobic exercise training on interleukin-6 (IL-6) and C-reactive protein (CRP). Further, to determine pretraining and posttraining associations between alterations of IL-6 and CRP and alterations of total body fat mass (TB-FM), intra-abdominal fat mass (IA-FM), and total body lean mass (TB-LM). A sample of 102 sedentary subjects were assigned to a resistance group (n = 35), an aerobic group (n = 41), or a control group (n = 26). Before and after intervention, subjects were involved in dual-energy x-ray absorptiometry, muscular strength and aerobic fitness, measurements and further provided a resting fasted venous blood sample for measures of IL-6, CRP, cholesterol profile, triglycerides, glucose, insulin, and glycosylated hemoglobin. The resistance and the aerobic groups completed a respective 10-wk supervised and periodized training program, whereas the control group maintained sedentary lifestyle and dietary patterns. Both exercise training programs did not reduce IL-6; however, the resistance and the aerobic groups reduced CRP by 32.8% (P < 0.05) and 16.1% (P = 0.06), respectively. At baseline, CRP was positively correlated with IL-6 (r = 0.35), (TB-FM) (r = 0.36), and IA-FM (r = 0.31) and was inversely correlated with aerobic fitness measures (all r values > or = -0.24). Compared with the resistance and the control groups, the aerobic group exhibited significant (P < 0.05) improvements in all aerobic fitness measures and significant reductions in IA-FM (7.4%) and body mass (1.1%). Compared with the aerobic and the control groups, the resistance group significantly (P < 0.05) improved TB-FM (3.7%) and upper (46.3%) and lower (56.6%) body strength. Despite no alteration in baseline IL-6 and significantly smaller reductions in measures of adipose tissue as compared with the aerobic training group, only resistance exercise training resulted in significant attenuation of CRP concentration.

Interleukin-10 gene down-expression in circulating mononuclear cells during infusion of drotrecogin-α activated: a pilot study

IntroductionThe purpose of this study was to investigate the gene expression of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) in circulating mononuclear cells harvested from septic shock patients on drotrecogin-α activated (DAA) in order to determine whether this treatment has any effect on the inflammation phase.MethodsWe conducted a prospective cohort study in two intensive care departments. Blood samples were collected at inclusion (T1) and 36 hours later (T2) to measure plasma cytokines and the changes in intracellular TNF-α, IL-10 and IFN-γ mRNA expressions using the real-time quantitative polymerase chain reaction (RT-qPCR). Thirty-two septic shock patients were included: 16 with DAA at 24 μg/kg/h for 96 hours (DAA+) and 16 control (DAA-) eligible but contraindicated for DAA because of low platelet count.ResultsThe basal characteristics were similar in both groups: mortality (50%), plasma cytokine concentrations, and baseline IFN-γ, TNF-α and IL-10 mRNA expressions (DAA+ vs. DAA-). At T2, there was a significant IFN-γ gene down-regulation in DAA+ but not in DAA- patients (-0.34 (-0.62; +1.54) vs. +1.41 (+0.35; +5.87), P = 0.008). In survivors, DAA administration was associated with a down-expression of both IFN-γ (-0.65 (-0.93; 0.48) vs. +0.7 (-0.04; +1.26), P = 0.01) and IL-10 (-0.78 (-0.92; -0.6) vs. -0.18 (-0.68; +0.46), P = 0.038). In the non-survivors, DAA infusion was associated with IL-10 over-expression when compared with survivors (+0.54 (-0.35; +11.52) vs. -0.78 (-0.92; -0.6), P < 0.001).ConclusionsIn this study, lack of IL-10 gene down-expression despite a 36-hour infusion of DAA is an ominous sign in septic shock patients suggesting that DAA is not able to reverse the outcome. Our results suggest that DAA can decrease the expression of anti-inflammatory cytokines in septic shock patients. IL-10 or IFN-γ gene down-expression could represent markers of DAA response.

Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial

IntroductionRecent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation.MethodsWe performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality.ResultsOne hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury.ConclusionsMechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation.Trial registrationISRCTN82533884

Predictors of Interleukin‐6 Elevation in Older Adults

To investigate the characteristics of older adults who develop high interleukin-6 (IL-6) levels at 3-year follow-up. Population-based study of adults living in Tuscany, Italy. Community. Adults aged 65 and older and were selected for this study. Of 1,155 baseline participants aged 65 and older, 741 had IL-6 measurements at baseline and 3-year follow-up. The uppermost quartile of IL-6 was used as the threshold for defining high IL-6 (> or =4.18 pg/mL). Serum IL-6 levels were assessed using enzyme immunoassay. Of the 581 participants with IL-6 levels less than 4.18 pg/mL at baseline, 106 (18.2%) had developed high IL-6 at follow-up. Although women had lower IL-6 levels at baseline than men, the risk of developing high IL-6 did not differ according to sex. High adiposity, defined as a body mass index of 30.0 kg/m(2) or higher (odds ratio (OR)=2.63, 95% confidence interval (CI)=1.40-4.96), and large waist circumference, defined as 102 cm or greater for men and 88 cm or greater for women (OR=2.05, 95% CI=1.24-3.40), were significant predictors of developing high IL-6 at follow-up. Other significant predictors were presence of three or more chronic diseases (OR=3.66, 95% CI=1.54-8.70), higher baseline IL-6 (OR=1.82, 95% CI=1.39-2.38) and higher white blood cell count (OR=1.24, 95% CI=1.06-1.45). Faster walking speed associated with decreased risk of progressing to elevated IL-6 (OR=0.83, 95% CI=0.74-0.92). Older age, greater adiposity, slower walking speed, higher disease burden, and higher white blood cell count were associated with greater risk of IL-6 elevation over a 3-year period. Future research should target older adults with these characteristics to prevent progression to a proinflammatory state.

Effect of dexamethasone on respiratory syncytial virus‐induced lung inflammation in children: results of a randomized, placebo controlled clinical trial

Inflammatory mediators play a major role in the pathogenesis of respiratory syncytial virus (RSV) infection. The objective of this study was to evaluate the effect of i.v. dexamethasone on cytokine concentrations in tracheal aspirates (TA) of children with severe RSV disease and to correlate them with disease severity. Twenty-five cytokines were measured in TA obtained from children <2 yr old intubated for severe RSV disease, and enrolled in a double-blind study of i.v. dexamethasone (0.5 mg/kg; n = 22) vs. placebo (n = 19). Cytokine concentrations, measured at baseline and days 1 and 5 post-randomization using a multiplex assay, were compared within both treatment groups and correlated with: (i) tracheal white blood cell counts, (ii) tracheal RSV loads by culture and (iii) parameters of disease severity, including number of days of requirement for mechanical ventilation, intensive care unit (ICU), and hospitalization. At baseline interleukin (IL)-13 and IL-15 concentrations were significantly higher in the dexamethasone treatment group. On day 1 post-treatment, only MCP-1, eotaxin and IL-6 concentrations were significantly different but higher in the placebo group. On day 5: IL-13, IL-7, IL-8 and MIP-1alpha concentrations were higher in dexamethasone-treated patients. In both groups MIP-1beta inversely correlated with the days of ventilator support; MIP-1alpha, MIP-1beta and eotaxin inversely correlated with ICU days; and IL-6 inversely correlated with hospitalization regardless of the treatment assigned. Systemic administration of dexamethasone did not have a consistent effect on TA concentrations of pro-inflammatory cytokines. This may help explain, at least in part, the lack of clinical benefit of steroid treatment in children with severe RSV bronchiolitis.

SWOG S0354: A phase II trial of CNTO328, a monoclonal antibody against interleukin-6 (IL-6), in chemotherapy pretreated patients (pts) with castration- resistant prostate cancer (CRPC)

5143 Background: IL-6 facilitates cancer cell survival via pleiotrophic effects on proliferation, apoptosis, angiogenesis, differentiation, and chemo-resistance. A multicenter phase II study of CNTO328 in chemo pretreated CRPC pts was conducted. Methods: Eligible pts had one prior chemotherapy, Zubrod performance status 0–2, and adequate end-organ function. Regimen: CNTO328 6 mg/kg IV q2 weeks x 12 cycles. Response assessment was q6 weeks. Primary endpoint was PSA response rate (RR) defined as ≥50% reduction. Accrual was completed in 2 stages, with planned accrual of 20 eligible pts in the first stage and 40 overall. Plasma cytokines were measured by Luminex in 44 pts. Results: Of 62 pts, 54 were eligible; all had received prior taxane therapy. Two (3.7%; 95% CI: 0.5%, 12.8%) had PSA response. Of 47 pts evaluable by RECIST, none had a response and 10 (21%) had stable disease (SD). With median follow-up of 6.6 months, median progression-free survival is 1.6 months (95% CI: 1.6, 1.7). Grade 4 toxicity included 1 case of DIC and 1 CNS ischemia; grade 3 toxicities included elevated AST (1), gastritis/esophagitis (2), thrombocytopenia (2), pain (2), leucopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (IQR: 2.5, 41.5). Pts with levels &gt;12.5 pg/mL had worse 6-month survival vs. &lt; 12.5 pg/mL (53% vs 94%, p = 0.02). Post-cycle 1, IL-6 levels were &gt; 250-fold higher, indicating antibody-target complex formation. 33/39 pts had a decline in C-reactive protein (CRP) plasma levels at 6 weeks. Conclusions: CNTO328 was well-tolerated and resulted in a PSA RR of 3.7% and RECIST SD rate of 21%. Declining CRP levels during treatment reflect biologic activity. Elevated baseline IL-6 levels portend a poor prognosis. Additional translational studies will be presented. Additional study of CNTO328 in combination may be warranted. [Table: see text]

Correlation of serum interleukin-6 (IL-6) levels and clinical outcome in hormone-independent (HI) prostate cancer (PC) patients (PTS) treated with docetaxel

e16044 Background: IL-6 acts as an autocrine and paracrine growth factor in PC, linked to HI progression. We previously reported preliminary data on the correlation of serum IL-6 and D response in metastatic HI PC pts. We present here a larger group of pts tested to asses the clinical relevance of IL-6 in these pts. Methods: Pts with HIPC treated with D were prospectively tested for IL-6 levels by ELISA before D. Prostate-specific antigen (PSA) response, time to PSA progression, overall survival (OS) and PC specific survival (SpS) were analyzed. Evaluated variables were age, performance status, PSA, Gleason, number (n) of D cycles, time to HI progression, presence of visceral metastasis, n of bone metastasis, hemoglobin, lactate deshydrogenase and alkaline phosphatase. Results: Seventy-two pts were included. At the time of the analysis 5 pts had died from non-PC related causes, two from treatment toxicity and 29 (40%) from PC. Mean of age was 69 ± 7 years. Median baseline IL-6 level was 14 pg/ml (range 0.1–1100). Thirty-five pts (49 %) had IL-6 levels &gt; 14 pg/ml. IL-6 &gt; 14 pg/ml correlated with lower D response (13 % vs 40%, p= 0.039); lower time to PSA progression (4 months vs 6, p=0.023); lower OS (10 months vs 25, p= 0.001) and lower PC SpS (12 months vs 26, p= 0.001), in contrast to pts with IL-6 ≤ 14pg/ml. In the multivariate analysis, serum IL-6 (p=0.002), n of bone metastasis (p=0.008) and n of D cycles (p=0.002), were independent prognostic factor for OS and PC SpS. Conclusions: High serum IL-6 correlates with an adverse clinical outcome of pts with HIPC treated with D. IL-6 determination may be a potential tool to select patients for D-based or targeted therapies. FIS ( PI070388 ) No significant financial relationships to disclose.

Dispositional optimism and stress-induced changes in immunity and negative mood

Evidence suggests that optimism may be protective for health during times of heightened stress, yet the mechanisms involved remain unclear. In a double-blind placebo-controlled study, we recently showed that acute psychological stress and an immune stimulus (Typhim-Vi typhoid vaccine) synergistically increased serum levels of interleukin-6 (IL-6) and negative mood in 59 healthy men. Here we carried out further analysis of this sample to investigate the relationship between dispositional optimism and stress-induced changes in immunity and mood. Volunteers were randomly assigned to one of four experimental conditions in which they received either typhoid vaccine or saline placebo, and then rested or completed two mental tasks. In the stress condition, optimism was inversely related to IL-6 responses, independent of age, BMI, trait CES-D depression and baseline IL-6. This relationship was present across both stress groups (combining vaccine and placebo) and was not present in the vaccine/stress group alone, suggesting that optimism protects against the inflammatory effects of stress rather than vaccine per se. Typhoid vaccine induced a significant increase in participants’ circulating anti-Vi antibody levels. Stress had no effect on antibody responses overall. However, in the vaccine/stress group, there was a strong positive association between optimism and antibody responses, indicating that stress accentuated the antibody response to vaccine in optimists. Across the complete sample, more optimistic individuals had smaller increases in negative mood and less reduction in mental vigour. Together these findings suggest that optimism may promote health, by counteracting stress-induced increases in inflammation and boosting the adjuvant effects of acute stress.

Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults

Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%–20% higher baseline IL-6 concentration per copy among CHS European–American (EA) participants (all p<10−4). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415 – longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all three studies, the “risk” of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62–1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.

Systemic Inflammatory Response After Extremity or Truncal Fracture Operations

The purpose of this study was to assess proinflammatory markers in blunt trauma patients regarding the relationship of these and blood loss and duration of surgery in different fracture locations. Prospective, multicenter, nonrandomized cohort study. Three level I trauma centers. Sixty-eight blunt trauma patients, who did not require emergency operations and had sustained truncal or extremity fractures, were included. In two index patient groups, patients with spinal fractures (group SF, n = 24) and pelvic and acetabular fractures (group PAF, n = 21) underwent fixation of their fractures and were compared with a group of patients with isolated fractures (group FF, n = 28). Ten healthy volunteers served as controls. Internal fixation of pelvic, acetabular and spinal fractures, intramedullary nailing of femoral fractures, measurement of proinflammatory cytokines. From serially sampled central venous blood, the perioperative concentrations of interleukin-6 (IL-6) and IL-8 were evaluated during a 24-hour period and set into relation with the duration of surgery and the degree of blood loss. Intramedullary instrumentation for isolated PAF caused a significant perioperative increase in the concentrations of IL-6 (preoperative: 16 pg/mL +/- 12 pg/mL, 7 hours: 89 pg/mL +/- 15 pg/mL, and 24 hours: 107 pg/mL +/- 27 pg/mL, p < 0.05). This increase was comparable with the isolated femoral fracture (group FF: IL-6 preoperative, 52 pg/mL +/- 12 pg/mL; 7 hours, 78 pg/mL +/- 14 pg/mL; and 24 hours, 120 pg/mL +/- 23 pg/mL, p = 0.02). The changes observed after spinal fracture fixations (group SF) were considerably lower (IL-6 preoperative: 11 pg/mL +/- 6 pg/mL, 7 hours: 16 pg/mL +/- 11 pg/mL, and 24 hours: 56 pg/mL +/- 19 pg/mL). The percent change of baseline IL-6 and IL-8 concentrations, and the blood loss in group PAF at 24 hours were positively correlated (IL-6 r = 0.72, p < 0.03, IL-8 0.67, p = 004) after insertion. No correlation with the duration of surgery was found. The release of proinflammatory cytokines was higher in patients when their pelvic fractures were operated than in patients with spine fracture fixations, and was associated with the degree of blood loss. A higher increase in cytokine levels occurred when they were performed early (day 1-2) across all patient groups. The level of the released markers seems to be related to the magnitude of surgery, rather than to the duration of the procedure. This study supports the value of immunologic markers in determining subclinical changes during and after orthopedic surgical procedures.

Exercise Training and Plasma C‐Reactive Protein and Interleukin‐6 in Elderly People

To determine the effects of a long-term exercise intervention on two prominent biomarkers of inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) in elderly men and women. Single-blind, randomized, controlled trial: The Lifestyle Interventions and Independence for Elders (LIFE) Trial. The Cooper Institute, Dallas, Texas; Stanford University, Stanford, California; University of Pittsburgh, Pittsburgh, Pennsylvania; and Wake Forest University, Winston-Salem, North Carolina. Four hundred twenty-four elderly (aged 70-89), nondisabled, community-dwelling men and women at risk for physical disability. A 12-month moderate-intensity physical activity (PA) intervention and a successful aging (SA) health education intervention. CRP and IL-6. After adjustment for baseline IL-6, sex, clinic site, diabetes mellitus, treatment group, visit, and group-by-visit interaction, the PA intervention resulted in a lower (P=.02) IL-6 concentration than the SA intervention. Adjusted mean IL-6 at month 12 was 8.5% (0.21 pg/mL) higher in the SA than the PA group. There were no significant differences in CRP between the groups at 12 months (P=.09). Marginally significant interaction effects of the PA intervention according to baseline functional status (P=.05) and IL-6 (above vs below the median; P=.06) were observed. There was a greater effect of the PA intervention on participants with lower functional status and those with a higher baseline IL-6. Greater PA results in lower systemic concentrations of IL-6 in elderly individuals, and this benefit is most pronounced in individuals at the greatest risk for disability and subsequent loss of independence.

Poster 136: Measurement Properties of Circulating Interleukin-6 and Oncostatin-M For Quantifying Musculoskeletal Injury

Objective: This study was performed to examine changes in serum concentrations of interleukin-6 (IL-6) and oncostatin M following total knee replacement (TKR) surgery in order to examine biomarker measurement properties including sensitivity to injury and variability across individuals in time to peak concentrations. Design: Repeated measures, measurement evaluation. Setting: Orthopedic surgery clinic in a teaching hospital in Hamilton, ON, Canada. Participants: 4 men and 10 women undergoing unilateral TKR. Interventions: Not applicable. Main Outcome Measures: Serial blood samples were taken in the preoperative waiting areas, immediately after surgery, at 6, 12, and 24 hours, and then at 24-hour intervals to 7 days. IL-6 and oncostatin-M concentrations were measured by enzyme-linked immunosorbent assay. Data on individual subjects were plotted over time to visualize the injury response curves. Results: Mean peak IL-6 (651pg/ml; range, 96–2750) significantly exceeded mean presurgery baseline (2pg/ml; range, 0–22). There were no sex differences in baseline or peak IL-6 concentrations. Time to peak ranged between 12 to 48 hours across individuals. There were no sex differences in the timing of the peak. The time window remained the same for low IL-6 secreters (peak below 130pg/ml), moderate secreters (peak 131–400pg/ml), and high secreters (peak >400pg/ml). There was no serum Oncostatin M injury response detectable in any subject. Conclusions: IL-6 has good sensitivity to the state of injury following TKR. The variable time course of IL-6 indicates potential problems with the previous comparison of surgical procedures at common time points (eg, 24h) and necessitates serial measures within 12 to 48 hours to estimate the peak. Oncostatin M did not provide a biochemical index of musculoskeletal injury.

High plasma glutamate concentrations are associated with infarct growth in acute ischemic stroke

Excitotoxic and inflammatory mechanisms have been demonstrated as mediating early neurologic deterioration (END) in patients with cerebral infarction. Here we investigate whether molecular markers associated with END are related to the volume and outcome of the diffusion weighted image (DWI) lesion in acute ischemic stroke. MRI was performed on admission and at 72 hours in 197 patients with acute hemispheric infarction of <12 hours' duration. DWI lesion enlargement was calculated as the absolute difference between volumes on admission and day 3 of evolution. NIH Stroke Scale was scored at the same intervals. END was defined as an increase >/=4 points within the 3 days. Glutamate, l-arginine, interleukin-6 (IL-6), and tumor necrosis factor-alpha levels were analyzed in blood samples obtained on admission. DWI lesion growth was found in 144 (73%) patients (median increase 38 [6.5, 83.4] cm(3)) and END occurred in 58 (29.4%) patients. Baseline glutamate (r = 0.71), l-arginine (r = -0.35), and IL-6 levels (r = 0.50) showed a high and significant correlation with the DWI lesion enlargement (all p < 0.001). After adjustment for potential confounders, glutamate levels were the only molecular marker associated with DWI lesion enlargement at 72 hours (beta = 0.21; SD = 0.07; p = 0.004). Molecular markers of early neurologic deterioration may play a role as mediators of lesion growth in cerebral ischemia. Plasma glutamate concentration is the most powerful and independent predictor biomarker of lesion enlargement in the acute phase of ischemic stroke, and so may well be useful as a signature of tissue at risk of infarction.

The Commensal Streptococcus salivarius K12 Downregulates the Innate Immune Responses of Human Epithelial Cells and Promotes Host-Microbe Homeostasis

Streptococcus salivarius is an early colonizer of human oral and nasopharyngeal epithelia, and strain K12 has reported probiotic effects. An emerging paradigm indicates that commensal bacteria downregulate immune responses through the action on NF-kappaB signaling pathways, but additional mechanisms underlying probiotic actions are not well understood. Our objective here was to identify host genes specifically targeted by K12 by comparing their responses with responses elicited by pathogens and to determine if S. salivarius modulates epithelial cell immune responses. RNA was extracted from human bronchial epithelial cells (16HBE14O- cells) cocultured with K12 or bacterial pathogens. cDNA was hybridized to a human 21K oligonucleotide-based array. Data were analyzed using ArrayPipe, InnateDB, PANTHER, and oPOSSUM. Interleukin 8 (IL-8) and growth-regulated oncogene alpha (Groalpha) secretion were determined by enzyme-linked immunosorbent assay. It was demonstrated that S. salivarius K12 specifically altered the expression of 565 host genes, particularly those involved in multiple innate defense pathways, general epithelial cell function and homeostasis, cytoskeletal remodeling, cell development and migration, and signaling pathways. It inhibited baseline IL-8 secretion and IL-8 responses to LL-37, Pseudomonas aeruginosa, and flagellin in epithelial cells and attenuated Groalpha secretion in response to flagellin. Immunosuppression was coincident with the inhibition of activation of the NF-kappaB pathway. Thus, the commensal and probiotic behaviors of S. salivarius K12 are proposed to be due to the organism (i) eliciting no proinflammatory response, (ii) stimulating an anti-inflammatory response, and (iii) modulating genes associated with adhesion to the epithelial layer and homeostasis. S. salivarius K12 might thereby ensure that it is tolerated by the host and maintained on the epithelial surface while actively protecting the host from inflammation and apoptosis induced by pathogens.

Self-esteem levels and cardiovascular and inflammatory responses to acute stress

Acute mental stress tests have helped to clarify the pathways through which psychosocial factors are linked to disease risk. This methodology is now being used to investigate potentially protective psychosocial factors. We investigated whether global self-esteem might buffer cardiovascular and inflammatory responses to acute stress. One hundred and one students completed the Rosenberg Self-Esteem Scale. Heart rate and heart rate variability (HRV) were recorded for 5 min periods at baseline, during two mental stress tasks, (a speech and a color-word task) and 10, 25 and 40 min into a recovery period. Plasma levels of tumor-necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1Ra) were assessed at baseline, immediately post-stress and after 45 min recovery. Repeated measures analysis of variance demonstrated that heart rate levels were lower across all time points in those with high self-esteem, although heart rate reactivity to stress was not related to self-esteem. There were no differences in baseline HRV, TNF-α, IL-6 or IL-1Ra. Multiple linear regressions revealed that greater self-esteem was associated with a smaller reduction in heart rate variability during the speech task, but not the color-word task. Greater self-esteem was associated with smaller TNF-α and IL-1Ra responses immediately following acute stress and smaller IL-1Ra responses at 45 min post-stress. In conclusion, global self-esteem is associated with lower heart rate and attenuated HRV and inflammatory responses to acute stress. These responses could be processes through which self-esteem protects against the development of disease.

Randomized comparison of early inflammatory response after sirolimus-eluting stent vs bare metal stent implantation in native coronary lesions

Background The clinical significance of early inflammatory response after coronary stent implantation has been controversial. Sirolimus-eluting stent (SES) has been shown to be better outcomes compared with bare metal stent (BMS). We prospectively investigated the early inflammatory response after SES or BMS implantation in patients with single-vessel lesion, and evaluated the relationship between inflammation and late clinical outcomes in a randomized design. Methods Forty-eight patients with single-vessel disease were randomized into SES or BMS implantation group ( n = 24 respectively). Blood samples were taken before stenting, 1 h, 24 h and 8 months afterward. The plasma concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) were determined by ELISA. The clinical and angiographic follow-up were performed at 8 months after stenting. Results There was no difference in baseline characteristics, plasma CRP and IL-6 concentrations between the 2 groups. However, plasma IL-6 concentrations at 1 h after stenting were higher in both groups than in baseline ( p < 0.01). In addition, the plasma CRP and IL-6 concentrations at 24 h after stenting were significantly higher in both groups compared with baseline ( p < 0.01 respectively). Likewise, plasma CRP and IL-6 concentrations were significantly higher in BMS group compared with SES group at 24 h after stenting ( p < 0.05 respectively). At the follow-up (mean 8 months after stenting), the rate of in-stent restenosis (ISR) and target lesion revascularization (TLR) were higher in BMS group than in SES group ( p < 0.05 respectively) although the plasma CRP and IL-6 concentrations are similar between the groups. Conclusions Single coronary stenting could trigger an early inflammatory response. However, patients undergoing SES implantation has less augmentation of early inflammatory markers after stenting compared to patients treated with BMS, which was positively related the incidence of ISR and TLR at follow-up. This may reflect the potential impact of SES implantation on the early inflammatory response and late clinical outcomes.

Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study

A lack of longitudinal studies has made it difficult to establish the direction of associations between circulating concentrations of low-grade chronic inflammatory markers, such as C-reactive protein and interleukin-6, and cognitive symptoms of depression. The present study sought to assess whether C-reactive protein and interleukin-6 predict cognitive symptoms of depression or whether these symptoms predict inflammatory markers. In a prospective occupational cohort study of British white-collar civil servants (the Whitehall II study), serum C-reactive protein, interleukin-6 and cognitive symptoms of depression were measured at baseline in 1991-1993 and at follow-up in 2002-2004, an average follow-up of 11.8 years. Symptoms of depression were measured with four items describing cognitive symptoms of depression from the General Health Questionnaire. The number of participants varied between 3339 and 3070 (mean age 50 years, 30% women) depending on the analysis. Baseline C-reactive protein (beta=0.046, p=0.004) and interleukin-6 (beta=0.046, p=0.005) predicted cognitive symptoms of depression at follow-up, while baseline symptoms of depression did not predict inflammatory markers at follow-up. After full adjustment for sociodemographic, behavioural and biological risk factors, health conditions, medication use and baseline cognitive systems of depression, baseline C-reactive protein (beta=0.038, p=0.036) and interleukin-6 (beta=0.041, p=0.018) remained predictive of cognitive symptoms of depression at follow-up. These findings suggest that inflammation precedes depression at least with regard to the cognitive symptoms of depression.

Proteomic and Metabolomic Analysis of Smooth Muscle Cells Derived From the Arterial Media and Adventitial Progenitors of Apolipoprotein E–Deficient Mice

We have recently demonstrated that stem cell antigen 1-positive (Sca-1(+)) progenitors exist in the vascular adventitia of apolipoprotein E-deficient (apoE(-/-)) mice and contribute to smooth muscle cell (SMC) accumulation in vein graft atherosclerosis. Using a combined proteomic and metabolomic approach, we now characterize these local progenitors, which participate in the formation of native atherosclerotic lesions in chow-fed apoE(-/-) mice. Unlike Sca-1(+) progenitors from embryonic stem cells, the resident Sca-1(+) stem cell population from the vasculature acquired a mature aortic SMC phenotype after platelet-derived growth factor-BB stimulation. It shared proteomic and metabolomic characteristics of apoE(-/-) SMCs, which were clearly distinct from wild-type SMCs under normoxic and hypoxic conditions. Among the differentially expressed proteins were key enzymes in glucose metabolism, resulting in faster glucose consumption and a compensatory reduction in baseline interleukin-6 secretion. The latter was associated with a marked upregulation of insulin-like growth factor binding proteins (IGFBPs) 3 and 6. Notably, reconstitution of interleukin-6 to levels measured in the conditioned medium of wild-type SMCs attenuated the elevated IGFBP expression in apoE(-/-) SMCs and their vascular progenitors. This coregulation of apoE, interleukin-6, and IGFBPs was replicated in wild-type SMCs from hypercholesterolemic mice and confirmed by silencing apoE expression in SMCs from normocholesterolemic mice. In summary, we provide evidence that Sca-1(+) progenitors contribute to native atherosclerosis in apoE(-/-) mice, that apoE deficiency and hypercholesterolemia alter progenitor cell behavior, and that inflammatory cytokines such as interleukin-6 act as metabolic regulators in SMCs of hyperlipidemic mice.

Long-Term Interleukin-6 Levels and Subsequent Risk of Coronary Heart Disease: Two New Prospective Studies and a Systematic Review

BackgroundThe relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context.Methods and FindingsMeasurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28–0.53, over 4 y, and 0.35, 95% CI 0.23–0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29–1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45–3.15) with long-term average (“usual”) IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42–1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45–4.56] per 2 SD increase in usual [long-term average] IL-6 levels).ConclusionsLong-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6–mediated pathways to CHD.