Anti-inflammatory Cytokine Ratios Research Articles

Perineal Injury During Childbirth Increases Risk of Postpartum Depressive Symptoms and Inflammatory Markers.

Perineal lacerations during childbirth affect more than 65% of women in the United States. Little attention has been given to the long-term biologic consequences associated with perineal lacerations or possible associations with postpartum mental health. In this article, we describe the results of a study that explored inflammatory cytokines in women who reported perineal lacerations during childbirth and the relationship with stress and depressive symptoms during the first 6 months postpartum. A repeated measures design was used to explore the relationship between varying degrees of perineal lacerations, inflammatory cytokines, postpartum stress, and depressive symptoms in 153 women over 6 months. Depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS), and maternal stress was measured using the Perceived Stress Scale. Plasma was analyzed for proinflammatory (tumor necrosis factor alpha, interleukin 6 (IL-6), interleukin-1 beta, interferon gamma) and anti-inflammatory (interleukin 10) cytokines. Levels of cytokines were compared between women with or without varying degrees of injury. A relationship was identified between symptoms of depression and a second-degree or more severe perineal laceration starting at one month postpartum (P = .04) and continuing through 3 months postpartum (P = .03). Similarly, stress symptoms were higher at 3 months postpartum (P = .02). Markers of inflammation were significantly higher among this group, with IL-6 increased at 2 weeks postpartum (P = .02) and remaining elevated through 2 months postpartum (P = .003); there were also significant differences in pro- to anti-inflammatory cytokine ratios out to 6 months postpartum. Regression analysis indicated that second-degree or more severe lacerations accounted for 5.9% of the variance in EPDS score at one month postpartum (P = .024, F = 2.865, t = 2.127), increasing substantially when the one month stress score was included as well. This study suggests that perineal lacerations, inflammation, stress, and depressed mood are associated; however, more research is needed to elucidate the actual relationship between inflammation and mental health in women who experience such injuries.

Dl-trans-3,4-Dihydroxy-1-selenolane (DHSred) heals indomethacin-mediated gastric ulcer in mice by modulating arginine metabolism

BackgroundThe importance of the arginine metabolism in gastric ulcer-healing is given relatively less attention. Hence the role of controlling this pathway by dl-trans-3,4-dihydroxy-1-selenolane (DHSred) and omeprazole against indomethacin-induced stomach ulceration in mouse was investigated. MethodsSwiss albino mice were ulcerated with indomethacin followed by treatment with the test samples, and the activities of myeloperoxidase (MPO), total nitric oxide synthase (NOS) and arginase, the expressions of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), and the pro-/anti-inflammatory cytokine levels were assayed. NOS-inhibitors were also used to establish the biochemical mechanism. ResultsIndomethacin induced maximum ulceration in mice on the 3rd day, associated with reduced arginase activity, eNOS expression, along with increased MPO and total NOS activities, nitric oxide (NO) generation, iNOS expression, and pro-/anti-inflammatory (Th1/Th2) cytokine ratio. Treatment with DHSred (2.5mgkg−1×3days) restored the cytokine balance to shift the iNOS/NO axis to the arginase/polyamine axis as revealed from the increased arginase activity and eNOS expression, and reduced iNOS expression, total NOS activity and NO level. ConclusionsThe ulcer-healing property of DHSred, but not of omeprazole was due to a favorable pro-/anti-inflammatory cytokine ratio that shifted the arginine metabolism to the polyamine pathway and increased the eNOS/iNOS ratio. The healing action of omeprazole was not significantly associated with these parameters. General significanceThe shift in the ariginine-metabolism from the iNOS/NO axis to the arginase/polyamine axis is guided by Th1/Th2 cytokines ratio and plays an important role in gastric ulcer-healing. The favourable effects of the non-toxic and water-soluble compound, DHSred on these pathways and other COX-dependent and antioxidative parameters suggested it to be a promising anti-ulcer formulation for further studies.

2. Dysregulation of psychoneuroimmune function in women symptomatic of postpartum depression

500,000 U.S. women develop postpartum depression (PPD) annually. Although psychosocial risks are known, the underlying biology remains unclear. We hypothesized that exaggerated inflammation early after childbirth would increase PPD risk, alone or synergistically with abnormal cortisol secretion, indicating dysregulation of psychoneuroimmune function. Plasma pro- and anti-inflammatory cytokines were measured on Days 7 and 14, and Months 1, 2, 3, and 6 after childbirth. Saliva was collected 5 times the day preceding blood draws for cortisol area under the curve (AUC). Depressive symptoms were measured using the Edinburgh Postpartum Depression Survey (EPDS) and evaluated in light of cytokines and cortisol, independently and together. 152 women completed the EPDS; 18% scored symptomatic of depression (EPDS > 10) by 6-months. Cortisol AUC was higher in symptomatic women on Day 14 ( p = .017). Bivariate analysis indicated change in IFNγ/IL10 (pro- to anti-inflammatory cytokine) ratio on Day 14 from Day 7 and Day 14 cortisol AUC were important predictors of depressive symptoms. Multiple logistic regression indicated joint effects of cortisol AUC and change in IFN/IL10 ratio were highly significant in predicting symptoms. A unit increase in Day 14 IFN/IL10 was associated with 91% increase in odds (OR: 1.91, p = 0.036) of depressive symptoms while a 20-min increase in AUC was associated with a 33% increase in odds (cortisol AUC OR: 1.333, p = 0.012). Findings suggest dysregulation of psychoneuroimmune function is a biological risk for PPD.

Biobehavioral Factors Mediate Exercise Effects on Fatigue in Breast Cancer Survivors

This study aimed to examine mediators of fatigue response to an exercise intervention for breast cancer survivors in a pilot randomized controlled trial. Postmenopausal breast cancer survivors (n = 46; ≤stage 2), off primary treatment, and reporting fatigue and/or sleep dysfunction were randomized to a 3-month exercise intervention (160 min·wk of moderate-intensity aerobic walking, twice weekly resistance training with resistance bands) or control group. Six discussion group sessions provided behavioral support to improve adherence. Fatigue, serum cytokines, accelerometer physical activity, cardiorespiratory fitness, sleep dysfunction, and psychosocial factors were assessed at baseline and 3 months. The exercise intervention effect sizes for fatigue were as follows: fatigue intensity d = 0.30 (P = 0.34), interference d = -0.38 (P = 0.22), and general fatigue d = -0.49 (P = 0.13). Using the Freedman-Schatzkin difference-in-coefficients tests, increase in fatigue intensity was significantly mediated by interleukin 6 (IL-6) (82%), IL-10 (94%), IL-6/IL-10 (49%), and tumor necrosis factor-α (TNF-α):IL-10 (78%) with reduced sleep dysfunction increasing the relationship between intervention and fatigue intensity rather than mediating intervention effects (-88%). Decrease in fatigue interference was mediated by sleep dysfunction (35%), whereas IL-10 and pro-anti-inflammatory cytokine ratios increased the relationship between intervention and interference (-25% to -40%). The reduction in general fatigue was significantly mediated by minutes of physical activity (76%), sleep dysfunction (45%), and physical activity enjoyment (40%), with IL-10 (-40%) and IL-6/IL-10 (-11%) increasing the intervention-fatigue relationship. In the intervention group, higher baseline fatigue, anxiety, depression, and perceived exercise barrier interference predicted a greater decline in fatigue interference and/or general fatigue during the intervention. Biobehavioral factors mediated and enhanced intervention effects on fatigue, whereas psychosocial factors predicted fatigue response. Further study is warranted to confirm our results and to improve understanding of relationships that mediate and strengthen the intervention-fatigue association.

The Gingival Crevicular Fluid Levels of Interleukin‐11 and Interleukin‐17 in Patients With Aggressive Periodontitis

The balance (ratio) of anti-inflammatory and proinflammatory cytokines is thought to play an important role in the pathogenesis of chronic periodontitis. Moreover, the imbalance of anti-inflammatory/proinflammatory cytokines may modulate disease progression in aggressive periodontitis (AgP). This study aims to investigate the levels of interleukin (IL)-11 and IL-17 and their ratio in gingival crevicular fluid (GCF) in patients with AgP. This study included 20 patients with generalized AgP (GAgP) and 18 healthy controls (HC). For each patient, the values of clinical parameters, such as gingival index, plaque index, probing depth, and clinical attachment level, were recorded. Levels of IL-11 and IL-17 in GCF samples were evaluated using enzyme-linked immunosorbent assay. The values of clinical parameters, cytokine levels, and the ratios of cytokines were evaluated. The values of all the clinical parameters were significantly higher in the GAgP group than in the HC group (P < 0.001). The total amount and concentration of IL-11 and the concentration of the IL-17 and IL-11/IL-17 ratio were significantly lower in the GAgP group than in the HC group (P < 0.001). The total amount of IL-17 was not significantly different between the groups (P = 0.317). The IL-11/IL-17 ratio was decreased in the GAgP group because of the decreased IL-11 levels. The IL-11/IL-17 axis and the link between IL-17 and neutrophil function disorders in AgP should be investigated to clarify the role of the IL-11/IL-17 axis and its balance and imbalance in the pathogenesis of AgP.

EPA and DHA Differentially Affect In Vitro Inflammatory Cytokine Release by Peripheral Blood Mononuclear Cells from Alzheimer’s Patients

It has been hypothesized that pro-inflammatory cytokines may play a pathogenic role in Alzheimer's disease (AD), and that n-3 polyunsaturated fatty acids may be protective against the development and progression of this disease. A reduced release of inflammatory cytokines by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) from AD patients dietary supplemented with a mixture of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) was recently reported. On this basis, we investigated the possible differential effects of the two purified fatty acids on inflammatory cytokine release, a subject still not explored, even though of great pharmacological interest. We treated in vitro phytohaemagglutinin (PHA)- or LPS-stimulated PBMCs from AD patients and age-matched healthy controls (HCs) with purified EPA or DHA. Higher pro- to anti-inflammatory cytokine ratios, indicative of a pro-inflammatory profile, were observed in PHA-stimulated PBMCs from AD patients in basal conditions. The addition of both EPA and DHA markedly reduced the cytokine release, with DHA showing always a more prominent effect than EPA. However, whereas DHA reduced only the high IL-1β/IL-10 ratio, EPA was able to reduce also the IL-6/IL-10 ratio. In stimulated PMBCs from HCs the reducing effect on cytokine release was not always observed, or observed at a lower degree. In conclusion, whereas DHA appeared more powerful in inhibiting each single inflammatory cytokine, the proinflammatory profile of the AD patients' cells was better reverted by EPA to a profile more similar to that found in HCs. A combination of both the fatty acids, seems to be still the best solution.

Molecular mechanism of the anti-inflammatory activity of a natural diarylnonanoid, malabaricone C

The spice-derived phenolic, malabaricone C (mal C), has recently been shown to accelerate healing of the indomethacin-induced gastric ulceration in mice. In this study, we explored its anti-inflammatory activity and investigated the underlying mechanism of the action. Mal C suppressed the microvascular permeability and the levels of tumor necrosis factor-α, interleukin-1β, and nitric oxide in the lipopolysaccharide (LPS)-administered mice. At a dose of 10mg/kg, it showed anti-inflammatory activity comparable to that of omeprazole (5mg/kg) and dexamethasone (50mg/kg). It also reduced the expression and activities of inducible nitric oxide synthase, cyclooxygenase-2, as well as the pro- vs anti-inflammatory cytokine ratio in the LPS-treated RAW macrophages. Mal C was found to inhibit LPS-induced NF-kB activation in RAW 264.7 cells by blocking the MyD88-dependent pathway. Mal C suppressed NF-κB activation and iNOS promoter activity, which correlated with its inhibitory effect on IκB phosphorylation and degradation, and NF-κB nuclear translocation, in the LPS-stimulated macrophages. It also inhibited LPS-induced phosphorylation of p38 and JNK, which are also upstream activators of NF-κB, without affecting Akt phosphorylation. Mal C also effectively blocked the PKR-mediated activation of NF-κB. These findings indicate that mal C exerts an anti-inflammatory effect through NF-κB-responsive inflammatory gene expressions by inhibiting the p38 and JNK-dependent canonical NF-κB pathway as well as the PKR pathway, and is a potential therapeutic agent against acute inflammation.

Developmental regulation of the neuroinflammatory responses to LPS and/or hypoxia-ischemia between preterm and term neonates: An experimental study

BackgroundPreterm and term newborns are at high risk of brain damage as well as subsequent cerebral palsy and learning disabilities. Indeed, hypoxia-ischemia (HI), pathogen exposures, and associated intracerebral increase of pro-inflammatory cytokines have all been linked to perinatal brain damage. However, the developmental effects of potential variations of pro- and anti-inflammatory cytokine ratios remain unknown.MethodsUsing rat models of perinatal brain damage induced by exposures to lipopolysaccharide (LPS) and/or HI at distinct levels of maturity, we compared cytokine expression at stages of cerebral development equivalent to either preterm (postnatal day 1, P1) or term (P12) newborns.ResultsAt P1, expression of anti-inflammatory cytokine within the brain was either not modulated (IL-6, IL-10) or down-regulated (IL-1ra, TGF-β1) by HI, LPS or LPS+HI. In contrast, there was at P12 an up-regulation of all anti-inflammatory cytokines studied in HI or LPS+HI condition, but not after LPS exposure. Interestingly, IL-1β was the main pro-inflammatory cytokine up-regulated moderately at P1, and strongly at P12, with a weak co-expression of TNF-α observed mainly at P12. These age-dependant inflammatory reactions were also accompanied, under HI and LPS+HI conditions, at P12 only, by combined: (i) expression of chemokines CINC-1 and MCP-1, (ii) blood-brain barrier (BBB) leakage, and (iii) intracerebral recruitment of systemic immune cells such as neutrophils. In contrast, sole LPS induced IL-1β responses mainly within white matter at P1 and mainly within gray matter at P12, that were only associated with early MCP-1 (but no CINC-1) induction at both ages, without any recruitment of neutrophils and CD68+ cells.ConclusionHI and LPS+HI induce pro-inflammatory oriented immune responses in both preterm and term like brains, with a maximal inflammatory response triggered by the combination of LPS+HI. The profile of these neuroinflammatory responses presented striking variations according to age: no or down-regulated anti-inflammatory responses associated with mainly IL-1β release in preterm-like brains (P1), in sharp contrast to term-like brains (P12) presenting stronger anti-and pro-inflammatory responses, including both IL-1β and TNF-α releases, and BBB leakage. These developmental-dependant variations of neuroinflammatory response could contribute to the differential pattern of brain lesions observed across gestational ages in humans. This also highlights the necessity to take into consideration the maturation stage, of both brain and immune systems, in order to develop new anti-inflammatory neuroprotective strategies.

Causes of Multiple Organ Dysfunction During Cardiosurgical Operations under Extracorporeal Circulation

Objective: to reveal possible causes of postoperative multiple organ dysfunction syndrome (MODS) in patients after surgery under extracorporeal circulation (EC), by measuring the level and balance of pro- and anti-inflammatory cytokines. Subjects and methods. The investigation enrolled 162 patients who had undergone operations on the heart and thoracic aorta. The levels of interleukins (IL)-6, IL-8, and IL-10 were determined by ELISA. Results. At surgery under EC, MODS was encountered in 5.7%, mortality was 55.6%. The principal causes of MODS were prolonged EC concurrent with bleeding (23%), massive hemorrhage (16%), perioperative myocardial infarction and cardiogenic shock (15%), prolonged EC (12%), acute lung injury (12%), disseminated intravascular coagulation (10%), allergic and anaphylactic reactions (9%), and intravascular hemolysis (6%). The levels of pro- and anti-inflammatory cytokines were substantially increased in all the patients after surgery under EC irrespective of the presence of MODS in the postoperative period. The patients with MODS displayed pro- and anti-inflammatory cytokine imbalance due to a preponderance of the proinflammatory activity of a systemic response. During massive hemorrhage (more than 20 ml/kg), the patients with MODS exhibited a reduction in the two pools of cytokines. In the absence of MODS, there was a parallel increase in both pro- and anti-inflammatory cytokines. The magnitude of a change in the level of cytokines is related to the volume of blood loss. During prolonged EC (more than 170 min), the patients with MODS had a higher pro- and anti-inflammatory cytokine ratio due to the elevated levels of both pools, but the elevation of anti-inflammatory cytokines was more pronounced. In the patients without MODS, the values of both groups of interleukins were sigmficantly unchanged with longer duration of EC. Key words: multiple organ dysfunction syndrome, systemic inflammatory reaction, interleukins 6, 8, 10, extracorporeal circulation, operations on the heart and thoracic aorta.

Dietary Plasma Protein Supplements Prevent the Release of Mucosal Proinflammatory Mediators in Intestinal Inflammation in Rats

Spray-dried plasma (SDP) is a complex mixture of active proteins that modulates the immune response of gut-associated lymphoid tissue. We examined whether SDP and Ig concentrate (IC) supplementation could modulate cytokine expression and inflammatory mediators in rats challenged with Staphylococcus aureus enterotoxin B (SEB). Wistar-Lewis rats were fed diets supplemented with SDP (8% wt:wt), IC (1.5% wt:wt), or milk proteins (control diet) from weaning (d 21) to d 34 after birth. On d 32 and 35, the rats were given SEB (0.5 mg/kg; intraperitoneal). Six hours after the second SEB dose, jejunal mucosa and Peyer’s patches (PP) from the small intestine were collected. The cytokines interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), interleukin (IL)-6, IL-10, transforming growth factor-β (TGFβ), and leukotrienne B4 (LTB4) were analyzed using commercial kits. SEB increased the release of proinflammatory mediators (IFNγ, TNFα, IL-6, and LTB4) in PP (P < 0.05) and in the mucosa (P < 0.05). In both tissues, SDP prevented the increase in IFNγ, IL-6, and LTB4 induced by SEB (P < 0.05). IC reduced the expression of TNFα and LTB4 in PP and mucosa (P < 0.05). SDP supplementation increased IL-10 and mature TGFβ concentrations in intestinal mucosa from both inflamed and noninflamed rats. Both SDP and IC increased the mature:total TGFβ ratio (all P < 0.05). Both supplements were effective at preventing the SEB-induced increase in proinflammatory:antiinflammatory cytokine ratios in PP and mucosa and in serum. The preventive effects of plasma supplements on intestinal inflammation involve modulation of intestinal cytokines, characterized by an increased expression of antiinflammatory cytokines.

Disease Activity and Cytokine Production in Mitogen-Stimulated Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis

Objective: To test whether there are differences in the levels and ratios of 6 pro- and 3 anti-inflammatory cytokines produced by mitogen-stimulated peripheral blood mononuclear cells (PBMCs) in rheumatoid arthritis (RA) subjects compared to controls. Subjects and Methods: 79 participants (42 seropositive RA patients and 37 healthy controls) were enrolled in this study. The production levels in mitogen-stimulated PBMCs of the 6 proinflammatory cytokines (IFN-γ, TNF-α, TNF-β, IL-8, IL-17, IL-18) and 3 anti-inflammatory cytokines (IL-4, IL-10, IL-13) were assayed by ELISA using kits obtained from Immunotech SA. The ratios of pro- to anti-inflammatory cytokines were calculated for all participants. Results: There were significantly elevated levels of IL-8 and IL-10, and reduced levels of IFN-γ, IL-4, and IL-17 in mitogen-stimulated PBMC culture supernatants of RA subjects compared to controls. Of the 18 pro-/anti-inflammatory cytokine ratios, 3 ratios (TNF-α/IL13, IL-8/IL-4 and IL-8/IL-13) were significantly higher in RA patients compared to controls; and 6 were higher in controls (IFN-γ/IL-4; IFN-γ/IL-10; IFN-γ/IL-13; TNF-β/IL10; IL-17/IL-10; IL-18/IL-10). Conclusions:Activated PBMCs of RA patients, regardless of disease activity, showed higher-level production of IL-8 and IL-10 compared to controls; lower-level production of IFN-γ, IL-4, and IL-17; and elevated ratios of TNF-α/IL-13, IL-8/IL-4 and IL-8/IL-13.

Correlation Between Interleukin 6 and Interleukin 10 in Acute Myocardial Infarction

The aim of this study was to analyze (i) ratios between pro-inflammatory cytokines interleukin 6 (IL-6), interleukin 1 (IL-1), tumour necrosis factor alpha (TNF-alpha) and anti-inflammatory cytokine interleukin 10 (IL-10) in patients with acute myocardial infarction (AMI) and stable angina pectoris (ii) as well as correlation between IL-6 and IL-10 in AMI and (iii) correlation between IL-6 and lipoproteins in AMI.The total of 71 patients were enrolled in this study, 41 of them with AMI (study group) and 30 with stable angina pectoris (control group). The concentrations of cytokines and lipoproteins were measured from blood samples. Pro-inflammatory to anti-inflammatory cytokine ratios were calculated by dividing concentrations of pro-inflammatory cytokines with IL-10. In statistical analyses we used descriptive statistics, normality tests and analysis of correlation.IL-6: IL-10 ratio is significantly higher in AMI than in stable angina (P < 0,001), TNF-alpha: IL-10 is also higher in study group but the difference is not significant. We found positive linear correlation between IL-6 and IL-10 (r =0,43; p = 0,015) and negative linear correlation between IL-6 and high density lipoprotein HDL (r = -0,47; p= 0,008) in AMI.IL-6: IL-10 ratio is higher in AMI than in stable angina. There is linear correlation between IL-6 and IL-10 and IL-6 and HDL in AMI.

Inflammatory bowel disease, a dysregulated host‐microbiota interaction: Are probiotics a new therapeutic option?

Inflammatory bowel disease, a dysregulated host‐microbiota interaction: Are probiotics a new therapeutic option?

Effect of cardiopulmonary bypass on cytokine network and myocardial cytokine production

In addition to the well-investigated proinflammatory cytokine expression, there is an ever increasing interest in the field of anti-inflammatory response to cardiopulmonary bypass (CPB). Evidence suggests that myocardium serves as an important source of cytokines during reperfusion and application of CPB. The effect of coronary artery bypass graft (CABG) without CPB on myocardial cytokine production has not as yet been investigated. Cardiopulmonary bypass can cause long-term disturbance in pro- and anti-inflammatory cytokine balance, which may impede a patient's recovery following surgery. Therefore, the effect of CPB on the balance of the pro-/anti-inflammatory cytokines network and myocardial cytokine outflow was assessed throughout a longer period after surgery. Twenty patients were scheduled for CABG with CPB and 10 had off-pump surgery. Blood samples were taken before, during, and over the first week following surgery. Coronary sinus blood samples were collected during surgery. The ratio of pro- and anti-inflammatory cytokines was calculated and the cytokine concentration of peripheral and coronary sinus blood were compared in both groups. Pro-/anti-inflammatory cytokine ratio decreased early after CPB followed by a delayed and marked increase. A more balanced ratio was present following off-pump surgery. Coronary sinus levels of certain cytokines exceeded the concentration of systemic blood in the course of CPB but not during off-pump operation. Patients show pro-inflammatory predominant cytokine balance at a later stage after CPB in contrast to those without CPB. The heart produces a remarkable amount of cytokines only in the course of surgery with CPB.

Cytokine Imbalance in Infants Receiving Extracorporeal Membrane Oxygenation for Respiratory Failure

Background: It is likely that the imbalance between the pro- and anti-inflammatory cytokines will determine the outcome in infants with severe respiratory failure receiving extracorporeal membrane oxygenation (ECMO). Aims: We determined if there was an imbalance between pro- and anti-inflammatory cytokines in serial bronchoalveolar lavage (BAL) fluid obtained from survivors and non-survivors of ECMO. Methods: We therefore measured the cellular changes and the molar ratios of pro-inflammatory and anti-inflammatory cytokines in serial BAL fluid obtained from survivors and non-survivors of ECMO. Fifteen infants surviving ECMO (median age 1 day, range 1–120) and 7 who did not (28 days, range 1–402) were studied. Results: In the lungs of survivors, the increased proportion of airway neutrophils at presentation decreased with time and was matched by a parallel increase in percent alveolar macrophages as the infants’ condition improved. The pro- and anti-inflammatory pulmonary cytokine ratios were static in the survivors. In the non-survivors, the ratio of tumour necrosis factor-α (TNF-α) against soluble TNF-receptor 1 (sTNF-R1) and soluble TNF receptor 2 (sTNF-R2) was increased at days 2–3 when compared to the survivors, but the molar ratio interleukin-1β (IL-1β)/soluble IL-1 receptor antagonist (sIL-1RA) was largely undetectable due to undetectable IL-1β. Conclusions: These data suggest that the infants who survive ECMO resolve their pulmonary inflammation and that in non-survivors the ratio of TNF-α against its receptor antagonists is increased and is associated with a poor outcome. Furthermore, this group of infants were unable to produce significant concentrations of IL-1β.

Inhibition of inflammatory responses by FC-77, a perfluorochemical, in lipopolysaccharide-treated RAW 264.7 macrophages

This study tested whether FC-77, a perfluorochemical, inhibits inflammatory responses in lipopolysaccharide (LPS) stimulated RAW 264.7 macrophages. The possible anti-inflammatory mechanisms involved were also investigated. RAW 264.7 macrophages were simultaneously incubated with pure FC-77 at final volume of 10% or 30% (v/v) and LPS (1 microg/ml) for 12 or 24 h on a mechanical shaker. In some tests FC-77 was added after cells stimulated by LPS for 12 h. Then the levels of prostaglandin E2(PGE2), tumor necrosis factor alpha (TNF-alpha), and interleukins (IL)-1beta, -6), and -10 were measured in medium. Alterations in cyclooxygenase (COX) 2 expression and nuclear transcription factor (NF) kappaB activation in cells were also evaluated. Pre- or posttreatment with FC-77 dose-dependently reduced the LPS-induced TNF-alpha, IL-1beta, and IL-6 formation and enhanced IL-10 production compared to LPS-stimulated alone cells. FC-77 also attenuated the LPS-induced PGE2 formation accompanied by suppressing COX-2 expression, the degradation of cytosolic inhibitor of kappaB-alpha and NF-kappaB activation. FC-77 inhibits inflammatory responses in LPS-stimulated macrophages by a mechanism that involves the attenuation of NF-kappaB dependent induction of COX-2/PGE2 pathway and the pro- /anti-inflammatory cytokine ratio.

Soluble α 2-macroglobulin receptor is increased in endotracheal aspirates from infants and children after cardiopulmonary bypass

Cytokine dysregulation contributes to the systemic inflammatory response after cardiopulmonary bypass. Clearance of cytokine binding proteins may be important in the resolution of inflammation. Our aim was to determine whether the cytokine binding protein alpha 2 -macroglobulin and its soluble receptor were upregulated in endotracheal aspirates from infants and children undergoing cardiopulmonary bypass. Seventy tracheal aspirates were collected before and after cardiopulmonary bypass from 35 infants and children undergoing surgical correction of congenital heart defects. alpha 2 -Macroglobulin and the soluble alpha 2 -macroglobulin receptor were identified by Western blot. With the use of multi-analyte cytokine profiling, pro-inflammatory and anti-inflammatory cytokines were quantified, normalized to total protein, and expressed as ratios. Paired t tests and Wilcoxon signed-rank tests were performed between prebypass and postbypass samples. Correlations were examined among alpha 2 -macroglobulin, soluble alpha 2 -macroglobulin receptor, cytokine ratios, and the clinical variables of cardiopulmonary bypass, aortic crossclamp, and circulatory arrest times. alpha 2 -Macroglobulin increased by 50% (mean densitometry increase 82,683 +/- 184,594, P = .012), and soluble alpha 2 -macroglobulin receptor increased by 17% (mean densitometry increase 506,148 +/- 687,037, P = .0001) after cardiopulmonary bypass. The ratio of interleukin-8/interleukin-4 increased by 136% ( P = .0001), and interleukin-8/interleukin-10 increased by 102% ( P = .001). The increase in soluble alpha 2 -macroglobulin receptor was positively correlated with the ratios of interleukin-8/interleukin-4 and interleukin-8/interleukin-10. There were no statistically significant positive correlations between the increase in alpha 2 -macroglobulin or soluble alpha 2 -macroglobulin receptor and measured clinical variables. We report for the first time the upregulation of alpha 2 -macroglobulin and soluble alpha 2 -macroglobulin receptor in tracheal aspirates after cardiopulmonary bypass in infants and children. Soluble alpha 2 -macroglobulin receptor correlates with increased alpha 2 -macroglobulin and a disproportionate increase in pro-inflammatory to anti-inflammatory cytokine ratios.

IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection.

In hepatitis C virus infection an inappropriate ratio of pro-inflammatory and anti-inflammatory cytokines may either determine different outcomes of the infection or affect the benefit of antiviral treatment. Given that polymorphisms in regulatory regions of cytokine genes influence cytokine production, we determined frequency of polymorphisms of IL-10, IFNgamma, and TNFalpha genes in HCV-infected patients and healthy controls, and investigated their association with either ongoing or cleared HCV infection, or with response to treatment. Genomic DNA from 270 patients and 145 controls sharing the same ethnic background was studied by polymerase chain reaction, restriction enzyme digestion, direct sequencing, and microsatellite analysis. The IL-10 ATA haplotype was more frequent in patients with spontaneous HCV RNA clearance (36.0%) than in patients with persistent infection (23%) (p=0.009, p corrected = 0.036). Neither TNF -308 and -238 polymorphisms nor IFNgamma alleles variability were associated with different HCV outcome. However, the combination of ATA homozygous state and IFNgamma 119 allele was more frequent in patients with spontaneous HCV clearance than in patients with ongoing disease (p=0.012; p corrected = 0.048). We could not confirm the reported effect of genetic influence on the response to treatment. Our findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining a spontaneous favourable outcome of HCV infection.

Dexamethasone Decreases the Pro- to Anti-Inflammatory Cytokine Ratio During Cardiac Surgery

Dexamethasone Decreases the Pro- to Anti-Inflammatory Cytokine Ratio During Cardiac Surgery

Elevation of serum levels of the anti-inflammatory cytokine interleukin-10 and decreased risk of coronary events in patients with unstable angina

Background Inflammation is an important phenomenon in atherosclerotic plaque growth and in plaque instability. Cytokines are nuclear mediators in the inflammatory response; some have proinflammatory and others anti-inflammatory roles. Proinflammatory cytokines have been associated with worse outcomes in unstable angina. The aims of this study were to determine the role of the anti-inflammatory cytokine interleukin (IL)-10 and the proinflammatory to anti-inflammatory ratios in the short-term prognosis of patients with unstable angina. Methods Serum levels of proinflammatory cytokines IL-1β, IL-6, and IL-8, and of the anti-inflammatory cytokine IL-10 were determined on admission in 127 consecutive patients with severe unstable angina, and comparisons were made between patients who had cardiovascular events (death, nonfatal myocardial infarction, readmission for refractory angina) (n = 20) and patients without coronary events (n = 107) during a follow-up period of 3 months. Results IL-10 levels were lower (0.67 ± 1.13 vs 1.33 ± 1.67 pg/mL, P =.04) and IL-8 levels were higher (3.6 ± 2.41 vs 2.23 ± 2.47 pg/mL, P =.029) in patients in whom cardiovascular events subsequently developed compared with those without events, with resulting higher proinflammatory to anti-inflammatory cytokine ratios in the former group, whereas no significant differences were seen in IL-1β or IL-6 levels between the groups, except for the subgroup of patients with prolonged rest angina and persistent electrocardiographic changes. A greater ratio of IL-8 to IL-10 serum levels was observed in patients who had coronary events (28 ± 25 vs 12 ± 21, P =.007). The risk of subsequent coronary events increased in patients in the highest quartile of proinflammatory to anti-inflammatory cytokine ratio (IL-8/IL-10). Patients in the highest quartile had a relative risk 3.8 times higher than those in the lowest quartile (P =.01). Conclusions Lower levels of IL-10, with higher proinflammatory to anti-inflammatory cytokine ratios, were observed on admission in patients with unstable angina who subsequently had cardiovascular events. Higher levels of the anti-inflammatory cytokine IL-10 may be needed to provide protection in unstable angina. (Am Heart J 2002;144:811-7.)