Cytokine Ratio Research Articles

Incidence and risk factors for exacerbations of asthma during pregnancy

BackgroundAsthma is one of the most common chronic diseases among pregnant women. Acute exacerbations of asthma during pregnancy have an unfavorable impact on pregnancy outcome. This review provides an overview of current knowledge of incidence, mechanisms, and risk factors for acute exacerbations of asthma during pregnancy.MethodsA narrative literature review was carried out using the PubMed database.ResultsDuring pregnancy, up to 6% of women with asthma are hospitalized for an acute exacerbation. The maternal immune system is characterized by a very high T-helper-2:T-helper-1 cytokine ratio during pregnancy and thereby provides an environment essential for fetal survival but one that may aggravate asthma. Cells of the innate immune system such as monocytes and neutrophils are also increased during pregnancy, and this too can exacerbate maternal asthma. Severe or difficult-to-control asthma appears to be the major risk factor for exacerbations during pregnancy, but studies also suggest that nonadherence with controller medication and viral infections are important triggers of exacerbations during pregnancy. So far, inconsistent findings have been reported regarding the effect of fetal sex on exacerbations during pregnancy. Other risk factors for exacerbation during pregnancy include obesity, ethnicity, and reflux, whereas atopy does not appear to be a risk factor.DiscussionThe incidence of asthma exacerbations during pregnancy is disturbingly high. Severe asthma – better described as difficult-to-control asthma – nonadherence with controller therapy, viral infections, obesity, and ethnicity are likely to be important risk factors for exacerbations of asthma during pregnancy, whereas inconsistent findings have been reported with regard to the importance of sex of the fetus.

Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers

Immune signatures in breast tumors differ by estrogen receptor (ER) status. The purpose of this study was to assess associations between ER phenotypes and circulating levels of cytokines that co-ordinate cell-mediated [T-helper type 1 (Th1)] and humoral [T-helper type 2 (Th2)] immunity. We conducted a case-case comparison of 523 women with newly diagnosed breast cancer to evaluate associations between 27 circulating cytokines, measured using Luminex XMap technology, and breast cancer phenotypes [ER(-) vs. ER(+); triple negative breast cancer (TNBC) vs. luminal A (LumA)]. Ratios of Th1 to Th2 cytokines were also evaluated. Levels of interleukin (IL)-5, a Th-2 cytokine, were higher in ER(-) than in ER(+) tumors. The highest tertile of IL-5 was more strongly associated with ER(-) (OR = 2.33, 95 % CI 1.40-3.90) and TNBCs (OR = 2.78, 95 % CI 1.53-5.06) compared to ER(+) and LumA cancers, respectively, particularly among premenopausal women (OR = 4.17, 95 % CI 1.86-9.34, ER(-) vs. ER(+); OR = 5.60, 95 % CI 2.09-15.01, TNBC vs. LumA). Elevated Th1 cytokines were also detected in women with ER(-) and TNBCs, with women in the highest tertile of interferon α2 (OR = 2.39, 95 % CI 1.31-4.35) or tumor necrosis factor-α (OR = 2.27, 95 % CI 1.21-4.26) being twice as likely to have TNBC versus LumA cancer. When cytokine ratios were examined, women with the highest ratios of Th1 cytokines to IL-5 levels were least likely to have ER(-) or TNBCs compared to ER(+) or LumA cancers, respectively. The strongest associations were in premenopausal women, who were up to 80 % less likely to have TNBC than LumA cancers (IL-12p40/IL-5, OR = 0.19, 95 % CI 0.07-0.56). These findings indicate that immune function is associated with ER(-) and TNBC and may be most relevant among younger women, who are likely to be diagnosed with these aggressive phenotypes.

Expression of IL-4, IL-10 and IFN-γ in the liver tissue of cattle that are naturally infected with Fasciola hepatica

The role of interleukin IL-4, IL-10 and interferon gamma cytokines on natural Fasciola hepatica infection was investigated by quantifying the mRNA levels in liver tissue from chronically infected cattle. IL-4 and IL-10 had higher expression relative to interferon gamma in the liver tissue of infected animals when compared with the control group. The higher levels of IL-10 and IL-4 observed in the present study suggest a synergism between these cytokines, as well as involvement in the suppression of TH1 cell responses and a consequent induction of decreased interferon gamma expression in chronic cattle fascioliasis. The cytokine ratios were positively correlated, indicating a predominance of IL-4 in the chronic phase of infection with respect to interferon gamma and IL-10. Interferon gamma was predominant expressed in the controls, suggesting the involvement of IL-10 in modulating the immune response in favor of IL-4 in infected animals. Our results suggest that the TH2 polarized host immune response previously observed in experimental infection may also be responsible for establishing chronic phase and the maintenance of the natural infection of cattle from endemic areas that are in continuous contact with parasite.

The Impact of Self-Reported Psychological Stress Levels on Changes to Peripheral Blood Immune Biomarkers in Recreational Marathon Runners during Training and Recovery

Objective: Marathon training is both physically and psychologically stressful, both of which can lead to altered immunity. The purpose of this study was to determine if the overall immunoregulatory changes associated with the physical stress of marathon training are affected by psychological stress. Methods: Nineteen recreational marathoners completed the Perceived Stress Scale (PSS), State-Trait Anxiety Inventory (STAI) and Penn State Worry Questionnaire (PSWQ), and had levels of T cell subpopulations and cytokine (IFNγ, IL4 and IL10) production determined 4 weeks before (baseline), 24-48 h before (prerace) and 1 week after (recovery) participation in a marathon. Results: PSS scores decreased at the prerace visit compared to baseline and remained low at recovery. Compared to baseline, there were significant changes to numerous immune measures at the prerace visit, including decreases in Th1/Th2 ratio, Tc1/Tc2 ratio, Tr1 and Th3 cell populations as well as decreases in IFNγ/IL4 cytokine ratio and IL10 production. Most immune parameters had returned to near baseline values at the recovery visit. Higher levels of perceived stress, anxiety and worry exacerbated many of the alterations in immunity that were observed at the prerace visit. Higher levels of perceived stress and worry had significant effects on changes to Treg, IL4 production and the IFNγ/IL4 cytokine ratio. Stress had an additional impact on changes in IL10 production. High anxiety levels resulted in significant changes to Treg, Tr1 and Th3. Conclusion: These data suggest that recreational marathon runners with higher levels of psychological stress may be more at risk for the immune alterations that are common during periods of prolonged physical training.

Persistence at one year of age of antigen-induced cellular immune responses in preterm infants vaccinated against whooping cough: Comparison of three different vaccines and effect of a booster dose

Due to their high risk of developing severe Bordetella pertussis (Bp) infections, it is recommended to immunize preterm infants at their chronological age. However, little is known about the persistence of their specific immune responses, especially of the cellular responses recognized to play a role in protection. We compared here the cellular immune responses to two major antigens of Bp between three groups of one year-old children born prematurely, who received for their primary vaccination respectively the whole cell vaccine Tetracoq® (TC), the acellular vaccine Tetravac® (TV), or the acellular vaccine Infanrix-hexa® (IR). Whereas most children had still detectable IFN-γ responses at one year of age, they were lower in the IR-vaccinated children compared to the two other groups. In contrast, both the TV- and the IR-vaccinated children displayed higher Th2-type immune responses, resulting in higher antigen-specific IFN-γ/IL-5 ratios in TC- than in TV- or IR-vaccinated children. The IFN-γ/IL-5 ratio of mitogen-induced cytokines was also lower in IR- compared to TC- or TV-vaccinated children. No major differences in the immune responses were noted after the booster compared to the pre-booster responses for each vaccine. The IR-vaccinated children had a persistently low specific Th1-type immune response associated with high specific Th2-type immune responses, resulting in lower antigen-specific IFN-γ/IL-5 ratios compared to the two other groups. We conclude that antigen-specific cellular immune responses persisted in one year-old children born prematurely and vaccinated during infancy at their chronological age, that a booster dose did not significantly boost the cellular immune responses, and that the Th1/Th2 balance of the immune responses is modulated by the different vaccines.

Immunoregulatory cytokines in mouse placental extracts inhibit in vitro osteoclast differentiation of murine macrophages

IntroductionPrevious studies showed that placental extracts (PE) alleviates arthritic symptoms in animal models of arthritis. MethodsTo evaluate whether murine PEs obtained at embryonic days 7.5 (PE7) and 17.5 (PE18) regulate RANKL-induced osteoclast differentiation, RAW 264.7 cells were cultured with RANKL and MCSF in presence or not of PEs. Tartrate-resistant acid phosphatase (TRAP) was stained and multinucleated TRAP positive cells were visualized under a light microscope. Cathepsin K and metalloprotease expression was assessed by RT-PCR and gelatin zymography respectively. NFATc1 expression was determined by immunoblot. To analyze NFAT-dependent transcription, macrophages were transfected with a luciferase reporter plasmid. Cytokines were determined in PEs by ELISA and immunoblot. Transforming growth factor (TGF)- beta and Interleukin (IL)-10 receptor were inhibited in cell cultures with specific antibodies. ResultsPE7 and PE18 inhibited RANKL-induced multinucleated TRAP positive cells, Cathepsin K expression and metalloprotease activity, as well as NFATc1 expression and activity, thereby inhibiting osteoclast differentiation of RAW cells. Inflammatory/Regulatory cytokine ratio was higher in PE7 than in PE18. Blocking TGF-beta abolished the effect of both, PE7 and PE18, on multinucleated TRAP positive cells and metalloprotease expression, whereas blocking IL-10 receptor reverted the effect of PE18 but not of PE7. DiscussionInhibition of osteoclast differentiation by PEs was not unexpected, since cytokines detected in extracts were previously found to regulate osteoclast differentiation. ConclusionsPEs inhibited osteoclast differentiation of macrophages in vitro. Downregulation of NFATc1 might be involved in this effect. Regulatory/Th2 cytokines play a role in the effect of PEs on osteoclast differentiation.

1944 – HMGB1 danger signaling modulates t cells phenotype and cytokine profile in response to redox status in depressed patients. an effect on glucocorticoid receptor function

Objectives We aimed to study HMGB1, pro- and antioxidant status alongside with T cells phenotype and Th1 and Th17 proinflammatory cytokine profiles in depressed patient. We also investigated the glucocorticoid response. Methods Blood was collected from patients diagnosed with recurrent depressive disorder (rDD) (N = 15) and from healthy controls (N = 19). We measuredplasma hydrogen peroxide (H2O2) and reduced glutathione (GSH), malondialdehyde (MDA) levels as well as SOD1, GPx, GR activities in red blood cells. HO1 and NOX4 levels in plasma were also assayed. IL-2, IL-6, IL-8, IFN-g, TNF-a, IL-17, HMGB1, neopterin and cortisol were analyzed in sera. Further, we examined surface phenotype expression of T regulatory and T effector cells with flow cytometer. The glucocorticoid response was measured by dexamethasone-induced inhibition of IL-6 produced by LPS-stimulated peripheral blood. Results We observed pro- and antioxidant imbalance in depressed patients expressed by significant changes in the enzyme activities, increased MDA, decreased GSH, increased H2O2. Shifted Th1/Th17 cytokine ratios, increased Treg/Teffector cells ratio and increased levels of neopterin were also detected. Moreover, we revealed a distinct role of HMGB1 in maintaining cytokine and Treg/Teffector cells balance in depressed patients. HMGB1 remained also in relation with oxidant potential of the blood. The important role of IL-17 and inhibitory effect of MDA on glucocorticoids response was also revealed. Conclusions Strong immunomodulatory role of HMGB1 might be related to the change of its activity caused by redox imbalance in depressed patients. The shifted immune balance alongside with prooxidative environment modulates glucocorticoid response in these patients.

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.

Sepsis Chronically in MARS: Systemic Cytokine Responses Are Always Mixed Regardless of the Outcome, Magnitude, or Phase of Sepsis

The paradigm of systemic inflammatory response syndrome-to-compensatory anti-inflammatory response syndrome transition implies that hyperinflammation triggers acute sepsis mortality, whereas hypoinflammation (release of anti-inflammatory cytokines) in late sepsis induces chronic deaths. However, the exact humoral inflammatory mechanisms attributable to sepsis outcomes remain elusive. In the first part of this study, we characterized the systemic dynamics of the chronic inflammation in dying (DIE) and surviving (SUR) mice suffering from cecal ligation and puncture sepsis (days 6-28). In the second part, we combined the current chronic and previous acute/chronic sepsis data to compare the outcome-dependent inflammatory signatures between these two phases. A composite cytokine score (CCS) was calculated to compare global inflammatory responses. Mice were never sacrificed but were sampled daily (20 μl) for blood. In the first part of the study, parameters from chronic DIE mice were clustered into the 72, 48, and 24 h before death time points and compared with SUR of the same post-cecal ligation and puncture day. Cytokine increases were mixed and never preceded chronic deaths earlier than 48 h (3- to 180-fold increase). CCS demonstrated simultaneous and similar upregulation of proinflammatory and anti-inflammatory compartments at 24 h before chronic death (DIE 80- and 50-fold higher versus SUR). In the second part of the study, cytokine ratios across sepsis phases/outcomes indicated steady proinflammatory versus anti-inflammatory balance. CCS showed the inflammatory response in chronic DIE was 5-fold lower than acute DIE mice, but identical to acute SUR. The systemic mixed anti-inflammatory response syndrome-like pattern (concurrent release of proinflammatory and anti-inflammatory cytokines) occurs irrespective of the sepsis phase, response magnitude, and/or outcome. Although different in magnitude, neither acute nor chronic septic mortality is associated with a predominating proinflammatory and/or anti-inflammatory signature in the blood.

Abstract 52: Pretreatment levels of circulating Th1 and Th2 cytokines and their ratios are associated with ER-negative and triple-negative breast cancers.

Abstract Purpose: Immune signatures differ between estrogen receptor negative (ER−) and ER positive (ER+) breast tumors. The purpose of this study was to assess associations between ER phenotypes and circulating cytokine levels that co-ordinate cell-mediated and humoral immunity. Patients and Methods: We conducted a case-case comparison of 523 women with incident invasive breast cancer to evaluate associations between 27 circulating cytokines measured prior to surgery and/or adjuvant treatment using Luminex XMap technology and breast cancer phenotypes (ER−versus ER+ ; triple negative breast cancer (TNBC) versus luminal A). Ratios of T helper (Th) 1 to Th2 cytokines were also evaluated since different functional subsets of T helper cells regulate each other, often through antagonistic activity. Case-case comparisons were performed using unconditional logistic regression to examine associations between cytokine measures and odds of ER−versus ER+ tumors and TNBC versus luminal A cancers. Results: Both ER− and TNBCs were associated with high levels of circulating IL-5, a Th2 cytokine specific in driving eosinophil-dependent inflammatory diseases typically associated with allergic diseases such as asthma. Overall, women in the highest tertile compared to the lowest had approximately 2.5-fold increased odds of being diagnosed with ER− breast cancer or TNBC. Associations were strongest among premenopausal women, showing over 4-fold increased odds of ER−breast cancer (OR=4.17, 95% CI: 1.86 to 9.34) and over 5.5-fold increased odds of TNBC (OR=5.60, 95% CI: 2.09-15.01). Both ER-and TNBCs were associated with more pronounced Th1 immune activation, with women in the highest tertile of IFNα2 (OR=2.39, 95% CI: 1.31, 4.35) or TNFα (OR=2.27, 95% CI: 1.21, 4.26) being twice as likely to have TNBC. Relationships were again stronger among premenopausal women, with those in the highest tertile of IFNα2 being &amp;gt; 4 times more likely to have ER−(OR=4.11, 95% CI: 1.70, 9.92) and TNBC (OR=4.55, 95% CI: 1.58, 12.34). Several cytokine ratios indicating a strong Th1/IL5 balance were inversely associated with both ER− and TNBC. Women in the highest tertile were approximately 2 to 2.5 times less likely to have ER− breast cancer and 2.5 to 3 times less likely to have TNBC. Associations were strongest among premenopausal women, who were approximately 3 times less likely to have ER− disease and up to 5-times less likely to have TNBC (IL-12p40/IL-5, OR=0.19, 95% CI, 0.07 to 0.56). Conclusion: These findings, taken together, support the hypothesis that immune function is associated with development of ER− and TNBC, and that immune pathways might be physiologically most relevant among younger women who are most likely to be diagnosed with these aggressive phenotypes, and point to the possibility that these breast cancer patients may benefit from immunotherapies such as IFNα2, which increase Th1 versus Th2 balance, or eosinophil or IL-5-targeted therapies that have been developed to neutralize IL-5 or target IL-5R for the treatment of eosinophilic diseases. Citation Format: Chi-Chen Hong, Song Yao, Susan McCann, Ree Y. Dolnick, Paul K. Wallace, Zhihong Gong, Lei Quan, Elizabeth A. Repasky, Sharon Evans, Stephen B. Edge, Kelvin Lee, Christine B. Ambrosone. Pretreatment levels of circulating Th1 and Th2 cytokines and their ratios are associated with ER-negative and triple-negative breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 52.

The hybrid between the ABC domains of synapsin and the B subunit of Escherichia coli heat-labile toxin ameliorates experimental autoimmune encephalomyelitis

The B subunit of Escherichia coli heat-labile enterotoxin (LTB) acts as efficient mucosal carrier for conjugated antigens. We expressed two heterologous proteins using E. coli as a host: a hybrid consisting of LTB and the A, B and C domain of synapsin (LTBABC) and the separated ABC peptide of this synaptic protein. Refolded LTBABC and LTB bound to the GM1 receptor and internalized into CHO-K1GM1+ cells. LTBABC showed enhanced solubility and cell binding ability respect to the former hybrid LTBSC. Several oral doses of LTBABC were administered to rats with experimental autoimmune encephalomyelitis (EAE) from induction to the acute stage of the disease. This treatment decreased disease severity, delayed type hypersensitivity reaction and lymph node cell proliferation stimulated by myelin basic protein. Amelioration of EAE was also associated with modulation of the Th1/Th2 cytokine ratio, increased TGF-β secretion in mesenteric lymph nodes as well as expansion of CD4+CD25+Foxp3+ regulatory T cell population. These results indicate that the fusion protein LTBABC is suitable for further exploration of its therapeutic effect on EAE development.

Impaired intestinal tolerance in the absence of a functional complement system

Cells of the innate immune system regulate both adaptive immune responses and the maintenance of tolerance, especially in the gut. However, relatively little is known about the effects of complement on lymphocyte homeostasis. This study explored complement C3 deficiency in mice and human subjects for its effect on intestinal tolerance. C3-deficient mice and control C57BL/6 mice were fed ovalbumin (OVA) by means of gavage, and subsequent response to immunization with OVA in Freund's adjuvant was monitored. Serum antibodies against commensal microbes were measured, and the activation status of peripheral blood lymphocytes bearing mucosal homing markers was determined from 2 rare cases of C3-deficient patients. We show in C3-deficient mice and human patients that intestinal tolerance fails in the absence of functional complement. In contrast to wild-type control animals, in which oral tolerance was induced, intragastric administration of OVA did not result in a significantly decreased response to subsequent subcutaneous OVA challenge in C3-deficient mice. In the jejunum of C3-deficient mice the cytokine ratio between IL-10 and IFN-γ or IL-17 levels was decreased, indicating a shift in favor of proinflammatory cytokines. In 2 C3-deficient childrenthe frequency of gut-homing T cells expressing activation markers was increased, and the patients had increased serum IgG levels against gut commensal microbes. The data also suggest that the impaired oral tolerance was at least partly caused by the absence of signaling through C3-binding complement regulators in T cells. Taken together, our results identify complement as an important and nonredundant regulator of intestinal tolerance.

Ratio of IL 10 over IL 12 is a Novel Surrogate to Evaluate the Severity of Non Alcoholic Steatohepatitis (NASH) - A Prospective Clinical Pilot Study

Purpose: Non alcoholic steatohepatitis (NASH) is a growing global epidemic progressing to cirrhosis, liver failure, HCC, warrants liver transplant. The natural history is still not well defined, inflammatory cytokines, intrahepatic immune traffic, degree of apoptosis and path of fibrogenesis are the sequel of the disease process. This study evaluates a novel inflammatory cytokine (IL 10 and IL 12) ratio to predict NAFLD to NASH and its severity index. Methods: Ninety (n=90) patients, mean age of 45 (28-54) were divided into Group A (n=30) BMI (mean) <25% with normal lipids, healthy control. Group B with NAFLD (n=30) BMI >29% with NAFLD (hepatic steatosis, Waist/Hip ratio > 0.9, high lipids, HOMA>1.8, mean normal ALT, AST, RBP4,2.5, Leptin, Adiponectin, TNF alpha, serum NASH score <0.8, mean fibrotic score < 0.1, mean IL 10/IL 12 ratio < 1.0. Group C with NASH (n=30), BMI>30, W/H ratio > 1.1, high lipids, HOMA> 2.2, high AST, ALT, RBP>4.5, high leptin, low adiponectin, high TNF alpha, IL10/IL12 ratio> 4.5. Serums NASH score > 0.6, fibrotic score over 0.2. Liver biopsy in NASH group, macrovascular fat 18/30(60%), balloning 12/30(40%), Mallory body 7/30(23%), METAVIR score F2 12/30(40%), F3 9/30(30%), F4 3/30(10%). Exclusion Criteria: Diabetes, viral hepatitis, autoimmune liver disease, alcoholic liver disease with daily alcohol consumption over 20 gm, steatogenic medications including herbs and HIV. Results: See Table.Table: ResultsConclusion: IL 10/12 ratio correlated with the progression of NAFLD to NASH.IL 10/12 ratio >4.5 has NASH with high steatosis, fibrotic score. Larger study will establish the predictive index of IL10/IL 12 NASH in the severity and prognosis. Alcoholic hepatitis should be considered in the multivariate analysis.

TH1/TH2 Cytokine profile in relapsing-remitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab

BackgroundThe balance between T helper cells Th2- and Th1-related cytokines plays a key role in multiple sclerosis (MS). A shift from a Th1 towards a Th2 cytokine profile could have a beneficial effect on the clinical course of the disease. The objective of this study was to assess Th2/Th1 cytokine profile in relapsing-remitting MS (RRMS) patients receiving an immunosuppressive treatment with natalizumab (NAT), or an immunomodulatory treatment with glatiramer acetate (GA) after one year of treatment.MethodsThis was an observational cross-sectional study. All consecutive patients diagnosed with RRMS who had received GA or NAT for 12 months were included in the study. We determined serum levels of Th1 and Th2 cytokines (interleukin [IL]-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, monocyte chemotactic protein [MCP]-1, tumor-necrosis factor [TNF]-α, interferon [IFN]-γ and granulocyte macrophage colony stimulating factor [GM-CSF]) by flow cytometry. Th2/Th1 bias was defined based on the ratio of IL-4, IL-5, IL-6 or IL-10 Th2 cytokines and proinflammatory INF-γ or TNF-α Th1 cytokines.ResultsEleven patients under treatment with NAT and 12 patients treated with GA were evaluated. RRMS patients treated with NAT showed significantly higher levels of IL-6 (p < 0.05), MCP-1 (p < 0.01), and GM-CSF (p < 0.05) compared to GA patients after one year of treatment. A trend for increasing of IL-12p70, IL-1b, TNF- α and IFN- γ levels was also found in patients receiving NAT compared to GA patients. IL-4/IFN-γ, IFN-γ/TNF-α and IL-10/IFN-γ ratios as markers of Th2/Th1 ratio were significantly elevated in GA patients compared to those receiving NAT (p < 0.05).ConclusionIn conclusion, our findings suggest that GA promotes a superior Th2-biased anti-inflammatory response as compared with NAT in the systemic circulation of RRMS patients. Future studies with larger cohorts will determine whether this immune Th2 shift in GA patients is associated with a beneficial effect on disease outcome.

Elevated serum level of type-2 cytokine and low IL-17 in first episode psychosis and schizophrenia in relapse

Schizophrenia is chronic and debilitating mental disorder. In broad spectrum of possible causes or contributing factors, immune system and cytokines were investigated in the onset and development of schizophrenia. The aim of our study was to analyze the serum concentrations of type-1 cytokines: TNF-α, IFN-γ, type-2 cytokines: IL-4, IL-10, type-17 cytokine: IL-17 and regulatory cytokines: TGF-β, IL-27, IL-6, in drug-naive patients with First Episode Psychosis – FEP (n = 88) and Schizophrenia in relapse – SC in relapse patients (n = 45), comparing to healthy controls (n = 36). Also, we attempted to determine potential correlation between cytokine levels and/or cytokine ratios with clinical parameters, such as severity of illness, positive, negative and general psychopathology. Our results showed decreased levels of IL-17 (p = 0.018), demonstrating that type-17 response is blunted in psychotic episode. Increased levels of IL-4 (p = 0.033) showed that type-2 response is overweight in psychotic episode. Also, levels of IL-4 in serum of SC in relapse patients were higher than controls (p < 0.0005) and patient with FEP (p = 0.003). This alteration was accompanied with increase in production of TGF-β in psychotic patients (p = 0.009) and also in FEP (p < 0.0005) and SC in relapse (p < 0.0005). Analysis showed that TGF-β can be a valuable marker for psychosis. The presence of enhanced anti-inflammatory/immunosuppressive activity in schizophrenia may be an attempt to counteract or limit ongoing pro-inflammatory processes and downregulating chronic inflammation. Finally we have documented decreased levels of IL-17 and IL-17/TGF-β ratio in these types of psychotic patients, suggesting the new aspects of schizophrenia pathophysiology.

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.

PWE-271 Ratio of IL 10 over IL 12 is a novel surrogate to evaluate the severity of non-alcoholic steatohapatitis (NASH)—a prospective clinical pilot study

IntroductionNon-alcoholic steatohepatitis (NASH) is a growing global epidemic progressing to cirrhosis, liver failure, HCC, warrants liver transplant. The natural history is still not well defined, inflammatory cytokines, intrahepatic immune traffic,...

Characterization and antitumor activities of the water-soluble polysaccharide from Rhizoma Arisaematis

A water soluble polysaccharide (RAP-W1) was purified from Rhizoma Arisaematis and its antitumor activity was evaluated in BALB/c mice bearing human breast cancer MCF-7. RAP-W1 had the following physicochemical properties: total carbohydrate content (95.9%); no protein; molecular weight (≈57kDA); monosaccharides composition (rhamnose:fucose:arabinose:mannose:galactose:glucose=0.4:0.5:0.3:0.6:0.9:5.3). After 14 days’ treatment to tumor-bearing mice, RAP-W1 could significantly inhibit the growth of tumor transplanted in mice and increase the body weight and the spleen index. Moreover, RAP-W1 could significantly stimulate Con A- or LPS-induced splenocyte proliferation in tumor-bearing mice, as well as enhance the CTL activity. The level of Th1 cytokines (INF-γ and IL-2) in the serum of tumor-bearing mice was increased by RAP-W1 treatment, whereas the Th2 cytokine (IL-10) secretion displayed a dramatic reduction. All the data implied that RAP-W1 can activate T cells by up-regulating Th1/Th2 cytokine ratio, which might partially cause the inhibition of tumor growth.

Interleukin-6 and interleukin-8 levels in the urine of children with renal scarring

Acute pyelonephritis (APN) is one of the most significant bacterial infections in infancy and early childhood, and can lead to permanent kidney damage and chronic renal failure. To evaluate interleukin-6 (IL-6) and interleukin-8 (IL-8) levels in the urine of children with renal scarring (RS), searching for clinical information about the immuno-inflammatory process that contributes to RS. Urine concentrations of IL-6 and IL-8 were evaluated in 50 children, 33 with RS detected after an episode of acute pyelonephritis (group A) and 17 children with a history of acute pyelonephritis, but without RS (group B). These children were divided into four groups: group A(1), 23 children with RS and vesicoureteral reflux (VUR); group A(2), 10 children with RS without VUR; group B(1), 13 children without RS and without VUR; group B(2), 4 children without RS, but with VUR. None of them had had urinary tract infection for a minimum of 6 months. To avoid dilution effects, urinary levels of IL-6 and IL-8 were expressed as the ratio of cytokine to urinary creatinine (pg/mg). Urinary IL-8 levels were below the lower detection limit in all samples. IL-6 was detectable in the majority of children with RS and below the detection limits in the urine samples of children without RS. There were no statistically significant differences between urinary interleukin-6 levels in children with and those without VUR. There was a significant relationship between the grade of renal scars, the time passed since the last episode of acute pyelonephritis and the urinary levels of IL-6 (p < 0.0001 and p < 0.04 respectively). Further experimental studies are required to demonstrate the correlation between histopathology and urinary cytokine levels.

Peripheral T Cell Cytokine Responses for Diagnosis of Active Tuberculosis

BackgroundA test for diagnosis of active Tuberculosis (TB) from peripheral blood could tremendously improve clinical management of patients.MethodsOf 178 prospectively enrolled patients with possible TB, 60 patients were diagnosed with pulmonary and 27 patients with extrapulmonary TB. The frequencies of Mycobacterium tuberculosis (MTB) specific CD4+ T cells and CD8+ T cells producing cytokines were assessed using overnight stimulation with purified protein derivate (PPD) or early secretory antigenic target (ESAT)-6, respectively.ResultsAmong patients with active TB, an increased type 1 cytokine profile consisting of mainly CD4+ T cell derived interferon (IFN)-γ was detectable. Despite contributing to the cytokine profile as a whole, the independent diagnostic performance of one cytokine producing T cells as well as polyfunctional T cells was poor. IFN-γ/Interleukin(IL)-2 cytokine ratios discriminated best between active TB and other diseases.ConclusionT cells producing one cytokine and polyfunctional T cells have a limited role in diagnosis of active TB. The significant shift from a “memory type” to an “effector type” cytokine profile may be useful for further development of a rapid immune-diagnostic tool for active TB.