Systemic Concentrations Of Interleukin-6 Research Articles

R-ketorolac ameliorates cancer-associated cachexia and prolongs survival of tumour-bearing mice.

Cancer-associated cachexia (CAC) is a debilitating syndrome associated with poor quality of life and reduced life expectancy of cancer patients. CAC is characterized by unintended body weight reduction due to muscle and adipose tissue loss. A major hallmark of CAC is systemic inflammation. Several non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested for CAC treatment, yet no single medication has proven reliable. R-ketorolac (RK) is the R-enantiomer of a commonly used NSAID. The effect of RK on CAC has not yet been evaluated. Ten- to 11-week-old mice were inoculated with C26 or CHX207 cancer cells or vehicle control (phosphate-buffered saline [PBS]). After cachexia onset, 2mg/kg RK or PBS was administered daily by oral gavage. Body weight, food intake and tumour size were continuously measured. At study endpoints, blood was drawn, mice were sacrificed and tissues were excised. Immune cell abundance was analysed using a Cytek® Aurora spectral flow cytometer. Cyclooxygenase (COX) activity was determined in lung homogenates using a fluorometric kit. Muscle tissues were analysed for mRNA and protein expression by quantitative real-time PCR and western blotting analysis, respectively. Muscle fibre size was determined on histological slides after haematoxylin/eosin staining. Ten-day survival rate of C26-bearing animals was 10% while RK treatment resulted in a 100% survival rate (P=0.0009). Chemotherapy resulted in a 10% survival rate 14days after treatment initiation, but all mice survived upon co-medication with RK and cyclophosphamide (P=0.0001). Increased survival was associated with a protection from body weight loss in C26 (-0.61±1.82 vs. -4.48±2.0g, P=0.0004) and CHX207 (-0.49±0.33 vs. -2.49±0.93g, P=0.0003) tumour-bearing mice treated with RK, compared with untreated mice. RK ameliorated musculus quadriceps (-1.7±7.1% vs. -27.8±8.3%, P=0.0007) and gonadal white adipose tissue (-18.8±49% vs. -69±15.6%, P=0.094) loss in tumour-bearing mice, compared with untreated mice. Mechanistically, RK reduced circulating interleukin-6 (IL-6) concentrations from 334±151 to 164±123pg/mL (P=0.047) in C26 and from 93±39 to 35±6pg/mL (P=0.0053) in CHX207 tumour-bearing mice. Moreover, RK protected mice from cancer-induced T-lymphopenia (+1.8±42% vs. -49.2±12.1% in treated vs. untreated mice, respectively). RK was ineffective in ameliorating CAC in thymus-deficient nude mice, indicating that the beneficial effect of RK depends on T-cells. RK improved T-lymphopenia and decreased systemic IL-6 concentrations, resulting in alleviation of cachexia and increased survival of cachexigenic tumour-bearing mice, even under chemotherapy and independent of COX inhibition. Considering its potential, we propose that the use of RK should be investigated in patients suffering from CAC.

IL-17A-mediated expression of epithelial IL-17C promotes inflammation during acute Pseudomonas aeruginosa pneumonia.

Lung epithelial cells are suggested to promote pathogen-induced pulmonary inflammation by the release of chemokines, resulting in enhanced recruitment of circulating leukocytes. Recent studies have shown that the interleukin-17C (IL-17C) regulates innate immune functions of epithelial cells in an autocrine manner. The aim of this study was to investigate the contribution of IL-17C to pulmonary inflammation in a mouse model of acute Pseudomonas aeruginosa pneumonia. Infection with P. aeruginosa resulted in an increased expression of IL-17C in lung tissue of wild-type mice. Numbers of neutrophils and the expression of the neutrophil-recruiting chemokines keratinocyte-derived chemokine and macrophage inflammatory protein 2 were significantly decreased in lungs of IL-17C-deficient (IL-17C-/-) mice infected with P. aeruginosa at 24 h. Systemic concentrations of interleukin-6 (IL-6) were significantly decreased in infected IL-17C-/- mice at 24 h and the survival of IL-17C-/- mice was significantly increased at 48 h. The expression of IL-17C was reduced in infected mice deficient for interleukin-17A (IL-17A), whereas pulmonary concentrations of IL-17A were not affected by the deficiency for IL-17C. Stimulation of primary alveolar epithelial cells with IL-17A resulted in a significantly increased expression of IL-17C in vitro. Our data suggest that IL-17A-mediated expression of epithelial IL-17C amplifies the release of chemokines by epithelial cells and thereby contributes to the recruitment of neutrophils and systemic inflammation during acute P. aeruginosa pneumonia.

Baseline Serum Interleukin-6 Predicts Cardiovascular Events in Incident Peritoneal Dialysis Patients

The utility of local and systemic interleukin 6 (IL-6) as a prognostic marker in incident peritoneal dialysis (PD) patients remains to be fully defined. The present study aimed to explore the capacity of systemic IL-6 concentrations to predict cardiovascular events (CVEs) and mortality in PD patients, and to evaluate the influence of neutral-pH PD solutions low in glucose degradation products (GDPs) on systemic IL-6. The study included 175 incident participants from the balANZ trial with at least one stored serum sample. A composite CVE score was used as the primary clinical outcome measure. Multilevel linear regression and Poisson regression models were fitted to describe, respectively, the trend of serum IL-6 over time and its ability to predict composite CVE. A significant increase in serum IL-6 from baseline to 24 months was observed in the study population (mean difference: 1.68 pg/mL; p = 0.006). The type of PD solution received by patients exerted no significant effect on serum IL-6 (p = 0.12). Composite CVE was significantly and independently associated with baseline serum IL-6 (incidence rate ratio per picogram per milliliter: 1.06; 95% confidence interval: 1.02 to 1.10; p = 0.003). Baseline serum IL-6 was a significant independent predictor of composite CVE. Serum IL-6 concentrations increased with increasing PD duration and were not significantly modified with the use of biocompatible fluid over the study period. The present study is the first to link systemic IL-6 concentrations with CVE outcomes in incident PD patients.

Systemic interleukin-6 concentrations in patients with perimesencephalic non-aneurysmal subarachnoid hemorrhage

Patients with spontaneous non-aneurysmal subarachnoid hemorrhage (non-aSAH) are considered to have a benign illness in contrast to patients with aSAH. The occurrence of the systemic inflammatory response syndrome has been linked to worse outcomes in patients with aSAH. We analyzed systemic interleukin (IL)-6, a proinflammatory cytokine, to determine whether its concentration differs between patients with non-aSAH and those with aSAH, reflecting the more benign illness. Daily systemic IL-6 levels were measured in the acute phase in 11 patients with non-aneurysmal perimesencephalic SAH (pmSAH), with bleeding strictly located around the midbrain, and in nine patients with non-aneurysmal non-perimesencephalic (non-pmSAH), with hemorrhage extending into adjacent cisterns (group 1). IL-6 levels were compared with those from patients suffering from aSAH with cerebral vasospasm (CVS) (group 2) and without CVS (group 3). The mean IL-6 level (±standard error of the mean) was significantly lower in group 1 compared to group 2 (9.9 ± 1.9 vs. 29.1 ± 6.7 pg/mL, p = 0.018). The difference in mean IL-6 level between group 1 and 3 fell short of significance (9.9 ± 1.9 vs. 14.9 ± 1.1 pg/mL, p = 0.073). Patients in group 1 had a significantly better outcome (Glasgow Outcome Scale score 4–5) compared to group 2 ( p < 0.001) and a trend towards better outcome compared to group 3 ( p = 0.102). A subgroup analysis revealed a higher mean IL-6 concentration in patients with non-pmSAH compared to patients with pm-SAH ( p = 0.001). We concluded that systemic IL-6 concentration reflects the severity of the inflammatory stress response and course of the illness. The more benign illness and good prognosis of patients with pmSAH or non-pmSAH in contrast to patients with aSAH is reflected by the lower concentrations of IL-6.

Impaired hepatic removal of interleukin-6 in patients with liver cirrhosis

Systemic concentrations of interleukin-6 (IL-6) are elevated in patients with liver cirrhosis, and impaired hepatic uptake of IL-6 was suggested to contribute to higher levels in these patients. To test this hypothesis IL-6 was measured in portal venous serum (PVS), hepatic venous serum (HVS) and systemic venous serum (SVS) of 41 patients with liver cirrhosis and four patients with normal liver function. IL-6 was higher in PVS than HVS of all blood donors and about 43% of portal vein derived IL-6 was extracted by the healthy liver, and 6.3% by the cirrhotic liver demonstrating markedly impaired removal of IL-6 by the latter. Whereas in patients with CHILD-PUGH stage A IL-6 in HVS was almost 25% lower than in PVS, in patients with CHILD-PUGH stage C IL-6 was similarly abundant in the two blood compartments. Ascites is a common complication in cirrhotic patients and was associated with higher IL-6 levels in all blood compartments without significant differences in hepatic excretion. Hepatic venous pressure gradient did not correlate with the degree of hepatic IL-6 removal excluding hepatic shunting as the principal cause of impaired IL-6 uptake. Furthermore, patients with alcoholic liver cirrhosis had higher IL-6 in all blood compartments than patients with cryptogenic liver cirrhosis. Aetiology of liver cirrhosis did not affect hepatic removal rate indicating higher IL-6 synthesis in patients with alcoholic liver cirrhosis. In summary, the current data provide evidence that impaired hepatic removal of IL-6 is explained by hepatic shunting and liver dysfunction in patients with liver cirrhosis partly explaining higher systemic levels.

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.

Lower Limb Ischemia‐Reperfusion Injury Triggers a Systemic Inflammatory Response and Multiple Organ Dysfunction

Restoration of blood flow to an acutely ischemic lower limb may, paradoxically, result in systemic complications and unexpected mortality. We investigated the effect of acute ischemia-perfusion of the lower limb on cytokine production and end organ function. Plasma concentrations of tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) were determined in five groups of male Wistar rats: control, 3 hours of bilateral hind limb ischemia alone, and 3 hours of bilateral hind limb ischemia followed by 1 hour, 2 hours, or 3 hours of reperfusion, respectively. In a second experiment, the effect of lower limb ischemia-reperfusion on remote organs (lung, liver, and kidney) was assessed biochemically and histologically. There was a significant increase in plasma concentrations of TNF-a in plasma of animals subjected to 3 hours of bilateral hind limb ischemia followed by 1 hour of reperfusion, 40.1 +/- 4.4 pg/ml, when compared with controls, 22.6 +/- 4.4 pg/ml, or animals in the ischemia-alone group, 16.3 +/- 5.2 (p <0.05). Plasma concentration of IL-6 increased progressively and significantly in animals subjected to bilateral hind limb ischemia followed by 1 hour of reperfusion, 720 +/- 107 pg/ml; 2 hours of reperfusion, 1987 +/- 489 pg/ml; or 3 hours of reperfusion, 6284 +/- 1244 (p <0.0001), compared with controls, 104 +/- 43 pg/ml; or animals in the ischemia-alone group, 140 +/- 55 pg/ml. In the study comparing portal and systemic concentrations of IL-6, systemic concentrations of IL-6, 967 +/- 184 pg/ml were significantly higher than those in the portal circulation 577 +/- 127 pg/ml (p <0.05). There was a significant increase in plasma concentrations of urea, creatinine, aspartate transaminase, alanine transaminase, and lactic dehydrogenase in reperfused animals compared with controls (p <0.001). Morbidity and mortality following reperfusion of the acutely ischemic limb may be a manifestation of multiple organ dysfunction caused by a systemic inflammatory response triggered by reperfusion of the ischemic extremities.