Higher Serum Levels Of IL-6 Research Articles

The association between interleukin-8 levels and the development of withdrawal symptoms during methamphetamine abstinence.

Withdrawal symptoms are common during methamphetamine (METH) abstinence. This study aimed to explore the association between serum interleukins and withdrawal symptoms during METH abstinence. This study recruited 120 METH users, and 94 of them completed the 2-week follow-up. Serum interleukin-1β, 6,8,10 were tested at admission. Withdrawal symptoms were assessed by the Methamphetamine Withdrawal Questionnaire (MAWQ). Serum IL-8 levels were positively correlated with MAWQ scores at the 2-week endpoint (r = .257, p = .013). The variation of the MAWQ scores during the 2-week follow-up was negatively correlated with serum IL-8 levels at admission (r = -.249, p = .026). Serum IL-8 levels remained associated with the severity of METH withdrawal symptoms (β = .363, p = .023), after adjusting for potential confounders. This study did not include normal controls. Most patients were male and cigarette smokers. Patients were only followed up for 2 weeks, and their toxicology data were not collected. Interleukins were only measured at admission, and were tested in serum, not in the cerebrospinal fluid. Our study demonstrated that higher serum IL-8 levels may predict more severe withdrawal symptoms at 2 weeks after METH abstinence.

Quercetin Attenuates Atherosclerosis via Modulating Oxidized LDL-Induced Endothelial Cellular Senescence.

Background and AimsEndothelial senescence is an important risk factor leading to atherosclerosis. The mechanism of quercetin against endothelial senescence is worth exploring.MethodsQuercetin (20 mg/kg/d) was administered to ApoE-/- mice intragastrically to evaluate the effectiveness of quercetin on atherosclerotic lesion in vivo. In vitro, human aortic endothelial cells (HAECs) were used to assess the effect of quercetin on cellular senescence induced by oxidized low-density lipoprotein (ox-LDL). Transcriptome microarray and quantitative RT-PCR was conducted to study the pharmacological targets of quercetin.ResultsApoE-/- mice demonstrated obvious lipid deposition in arterial lumina, high level of serum sIcam-1 and IL-6, and high density of Vcam-1 and lower density of Sirt1 in aorta. Quercetin administration decreased lipid deposition in arterial lumina, serum sIcam-1, and IL-6 and Vcam-1 in aorta, while increased the density of Sirt1 in aorta of ApoE-/- mice. In vitro, quercetin (0.3, 1, or 3 μmol/L) decreased the expression of senescence-associated β-galactosidase and improved cell morphology of HAECs. And quercetin decreased the cellular apoptosis and increased mitochondrial membrane potential (ΔΨm) in dose-dependent manner, and decreased ROS generation simultaneously. Transcriptome microarray suggested 254 differentially expressed (DE) mRNAs (110 mRNAs were upregulated and 144 mRNAs were downregulated) in HAECs after quercetin treatment (fold change > 1.5, P < 0 .05, Que vs Ox-LDL). GO and KEGG analysis indicated nitrogen metabolism, ECM-receptor interaction, complement, and coagulation cascades, p53 and mTOR signaling pathway were involved in the pharmacological mechanisms of quercetin against ox-LDL.ConclusionsQuercetin alleviated atherosclerotic lesion both in vivo and in vitro.

Ameliorating effects of some trematode antigens on arthritis induced in Wistar rats

Introduction: Rheumatoid Arthritis (RA) is an autoimmune disease mediated by T helper 1 immune cells (Th1). Aim: Given that parasitic antigens are capable of polarizing the immune response towards T helper 2 immune cells (Th2), this study aimed to assess the potential effect of Schistosoma mansoni soluble egg antigen (Sm) and fasciola hepatica adult worm antigen (Fh) which are known to induce Th2 type response. Materials and Methods: RA was induced in female Wistar rats by intradermal injection (i.d) of 0.1ml complete Freund’s adjuvant (CFA). After 12 days of CFA injection, rats were treated with i.d injection of 0.1 mL saline, 0.2 mg/mL methotrexate (MXT via intraperitoneal injection, i.p)) once a week four 3 consecutive weeks as a reference drug, 100 μg Sm (i.p) or (i.d), 100 μg Fh (i.p) and (i.d). Rats were treated with antigens daily for two weeks. Results: Compared to control RA rats, treatment with Sm orFh antigens resulted in significant amelioration in the symptoms of the disease, including paw thickness and deformity measured by X-ray. These effects were further confirmed by significant alteration in histopathological changes in the hind paw. Analysis of Th1 and Th2 cytokines axis revealed high serum levels of IL-6 and TNF-a and lower serum levels of IL-4 and IL-10. Analysis of liver function showed that treatment with Sm or Fh antigens resulted in significant amelioration in hepatic enzymes including ALT, AST, and ALP. Treatment with Fh orSm also induced significant amelioration in the increased number of white blood cells and the absolute numbers of neutrophils. Conclusion: Overall, our data indicate that Sm possesses higher anti-arthritic effect than Fh, suggesting that trematode antigens can be used as a potential therapeutic approach to ameliorate arthritis.

Periodontitis Impact in Interleukin-6 Serum Levels in Solid Organ Transplanted Patients: A Systematic Review and Meta-Analysis.

This systematic review aimed to investigate the influence of periodontitis on post-transplant IL-6 serum levels of solid organ transplanted patients as compared to healthy subjects. Four databases (PubMed, Scholar, EMBASE, and CENTRAL) were searched up to February 2020 (PROSPERO CRD42018107817). Case-control and cohort studies on the association of IL-6 serum levels with a periodontal status of patients after solid organ transplantation were included. The risk of bias of observational studies was assessed through the Newcastle-Ottawa Scale (NOS). Random effects meta-analyses were thoroughly conducted. GRADE assessment provided quality evidence. Four case-control studies fulfilled the inclusion criteria (274 transplant recipients and 146 healthy controls), all of low risk of bias. Meta-analyses revealed significantly higher IL-6 levels in transplanted patients than healthy individuals with low-quality evidence (Mean Difference (MD): 2.55 (95% confidence interval (CI): 2.07, 3.03)). Transplanted patients with periodontitis have higher serum IL-6 levels than transplanted patients without periodontitis with moderate quality evidence (MD: 2.20 (95% CI: 1.00, 3.39)). We found low-quality evidence of higher IL-6 levels than healthy patients in patients with heart and kidney transplant. In these transplanted patients, there was moderate quality evidence that periodontitis is associated with higher IL-6 serum levels. Future research should consider the impact of such a difference in organ failure and systemic complications.

DOP52 The phenotype of NOD-scid IL-2Rγnull mice reconstituted with peripheral blood mononuclear cells from patients with Crohn’s disease or ulcerative colitis reflects the respective disease

Abstract Background Recently, we have developed a mouse model that relies on NOD-scid IL-2Rγnull (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMC) derived from patients with ulcerative colitis (UC, NSG-UC). In this model, symptoms of UC are induced by rectal challenge with ethanol. The objective of the study was to adapt this model to Crohn’s disease and to compare the phenotypes of the NSG-UC and NSG-CD mouse models. Methods NSG mice were reconstituted with PBMC from UC (n = 4) or CD (n = 3) patients. Mice were separated into two groups: unchallenged control and ethanol challenged mice. Readout were clinical-, colon and histological scores, analysis of frequencies of subgroups of human T cells, monocytes and B cells isolated from spleen and colon by flow cytometry, and the expression levels of the inflammatory markers TGFß, CRP, MCP-3, and IL-6 in the colon or serum by Luminex analysis. Results The pathological phenotype was markedly different in NSG-UC mice as compared with NSG-CD mice. Firstly, histological analysis revealed that NSG-UC mice exhibited more of a pro-inflammatory phenotype as indicated by a severe influx of inflammatory cells, oedema, crypt loss, crypt abscesses and epithelial hyperplasia. In contrast, NSG-CD mice displayed crypt loss and goblet cell atrophy and pronounced fibrosis indicating ongoing wound healing processes. These observations were corroborated by frequencies of splenic and colonic leucocytes. Antigen experienced CD4+ T (CD45RO+) cells and switched B cells (CD19+ CD27+ IgD-) were significantly increased in NSG-UC mice, whereas significantly higher levels of experienced CD8+ T cells and M1 (CD64+), M2 (CD163+) CD14+ monocytes and unswitched B cells (CD19+ CD27+ IgD+) indicated a monocyte driven inflammation in NSG-CD mice. This observation was also reflected in the colon of mice. Inflammation in UC was characterised by increased frequencies of neutrophils, activated CD4+ T cells (CD69+) and increased levels of CRP and MCP-3, whereas NSG-CD mice were signified by increased frequencies of M2 and M1 monocytes and of TGFß levels. In contrast to NSG-CD mice, NSG-UC mice also displayed higher serum levels of IL-6. Secondly, the impact of ethanol was more pronounced in the NSG-UC mice. In NSG-CD mice, the challenge did not evoke significant differences as compared with unchallenged control mice. Conclusion The comparison of pathological phenotypes of the NSG-UC and NSG-CD mouse models revealed differences, some of which reflect the respective human disease. The NSG-UC and NSG-CD mouse models may constitute powerful tools to get a better understanding of the different inflammatory processes in UC and CD.

Hepatitis C Virus Affects Tuberculosis-Specific T Cells in HIV-Negative Patients.

The occurrence of tuberculosis (TB) and hepatitis C virus (HCV) infections in the same patient presents a unique clinical challenge. The impact of HCV infection on the immune response to TB remains poorly investigated in TB+/HCV+ patients. This study was conducted to evaluate the impact of HCV on the T-cell-mediated immune response to TB in coinfected patients. Sixty-four patients with active TB infections were screened for coinfection with HCV. The expression of immune activation markers IFN-γ, CD38, and HLA-DR on TB-specific CD4+ T cells was evaluated by flow cytometry in TB-monoinfected patients, TB/HCV-coinfected patients, and healthy controls. IL-2, IL-4, IFN-γ, TNF-α, and IL-10 levels were measured using ELISA. The end-of-treatment response to anti-TB therapy was recorded for both patient groups. Significantly lower levels of CD4+IFN-γ+CD38+ and CD4+IFN-γ+HLA-DR+ T cells were detected in TB/HCV-coinfected patients compared to TB monoinfected patients and controls. TB+/HCV+-coinfected patients showed higher serum levels of IL-10. The baseline frequencies of TB-specific activated T-cell subsets did not predict the response to antituberculous therapy in TB+/HCV+ patients. We concluded that different subsets of TB-specific CD4+ T cells in TB/HCV-infected individuals are partially impaired in early-stage HCV infection. This was combined with increased serum IL-10 level. Such immune modulations may represent a powerful risk factor for disease progression in patients with HCV/TB coinfection.

Interleukin-6 serum level and -597 A/G gene polymorphism in moderate and severe chronic obstructive pulmonary disease

Inflammation is a major pathogenic pathway in pulmonary chronic obstructive disease (COPD). Interleukin-6 (IL-6) mediates the local and systemic immune response. The aim consisted in investigating the relationship between IL-6 serum levels and IL-6 -597A/G gene polymorphism (rs1800797) with COPD. Serum levels of IL-6 were determined using an enzyme-linked immune-sorbent assay, in 120 participants (60 COPD patients and 60 healthy subjects), from Transylvanian region. The IL-6 -597A/G gene polymorphism was investigated by high molecular weight genomic DNA extracted from the peripheral blood leukocytes, and subsequently analyzed by the Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) technique. Smoking history, the severity of the disease, expressed by the GOLD stages, and arterial blood partial pressure of oxygen (PaO2) levels were also investigated. COPD patients had significantly elevated blood levels of IL-6 when compared to the control group ( p &lt; 0.05). The frequencies of AA, AG, and GG genotypes were 61.6%, 26.6%, and 11.6% in the COPD cases and 70%, 23.3%, and 6.7% in healthy subjects, respectively. There were no statistically significant differences in IL-6 rs1800797 genotypes and allele frequencies between cases and controls ( χ2 = 0.54, OR = 1.29 and χ2 = 0.21, OR = 1.48, respectively). Higher serum levels of IL-6 were found in the GG genotype subgroup in COPD patients. IL 6 levels are higher in COPD patients, where positively correlate with pack-year index, but not with clinical features. Although COPD patients did not have statistically different rs1800797 allele distribution compared to healthy subjects, the GG genotype is associated with higher IL6 serum levels.

Prognostic Value of Combined Detection of Serum IL6, YKL-40, and C-reactive Protein in Patients with Unresectable Pancreatic Cancer.

IL6 and YKL-40 (also known as chitinase 3-like 1 protein, CHI3L1) are produced by pancreatic cancer cells and macrophages and activate inflammation. C-reactive protein (CRP) is synthesized mainly in hepatic cells and primarily stimulated by IL6. The aim of this study was to determine the prognostic value of combined detection of serum IL6, YKL-40, and CRP in patients with pancreatic cancer receiving palliative chemotherapy. In all, 592 patients with unresectable pancreatic cancer from five hospitals in Denmark were included in the BIOPAC biomarker study between 2008 and 2017. Pretreatment and longitudinal serum values of IL6 and YKL-40 were determined. Baseline CRP and CA19-9 values were available for the whole cohort. Patients were dichotomized as low versus high using cutoffs for IL6 of >4.92 pg/mL, YKL-40 of >95% age-corrected percentile, and CRP of >10 mg/L. The main outcome was overall survival. Combined elevations of serum IL6, YKL-40, and CRP were associated with worse survival in contrast to an isolated high concentration of a single marker. Serum IL6, YKL-40, and CRP were higher in patients with advanced stage disease and in patients with poor performance status. Higher IL6 and YKL-40 levels at the time of tumor progression and serum IL6 measured over time were associated with shorter overall survival. Combined high baseline serum levels of IL6, YKL-40, and CRP are associated with poor survival. Assessment of systemic inflammation via measurements of IL6, YKL-40, and CRP may be important for pancreatic cancer prognostication.

Systemic inflammatory response predicts poor prognoses in Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma with transarterial chemoembolization: a prospective study

Background: Chronic inflammation has been demonstrated to be an important factor in the initiation, promotion, and progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the prognostic values of systemic inflammation markers in Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC. Methods: A prospective non-randomized study was performed from June 2016 to May 2017; 51 of 123 BCLC stage B/C HCC patients were enrolled and received transarterial chemoembolization (TACE). Clinical and laboratory data were recorded. Serum IL-6, IL-10, C-reactive protein (CRP), and blood-neutrophil-to-lymphocyte ratio (NLR) levels were analyzed during the perioperative period. Patient prognosis was investigated. Twenty-eight stage A cases and 10 stage B/C patients who received resection were also collected as controls. Results: Compared to the stage A group, the BCLC stage B/C HCC patients had significantly higher serum IL-6, CRP, and blood NLR levels. Serum IL-6, IL-10, CRP, and blood NLR levels increased significantly 3 days after treatment (TACE/resection) and returned to baseline levels after 30 days. By univariate analyses, tumor size, high pretreatment serum IL-6, CRP, and blood NLR levels predicted worse progression-free survival (PFS) after TACE (log-rank test P Conclusions: Serum IL-6, CRP, and blood NLR levels were significantly elevated in stage B/CHCC. Serum IL-6 and CRP were independent predictors of poor PFS while NLR independently predicted worse OS in BCLC stage B/C HCC.

Association of the HSD11B1rs12086634(T/G) gene polymorphism and IL6 serum level with the risk of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects approximately one in 15 females worldwide. A functional polymorphism of the 11-beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene has been demonstrated to have a relationship with obesity and PCOS. IL-6 is a proinflammatory cytokine that has been shown to be associated with hyperandrogenism and PCOS. The aim of this work is to evaluate the association of the HSD11B1rs12086634(T/G) gene polymorphism and serum IL6 level with polycystic ovary syndrome (PCOS). The 160 individuals involved in this study were divided into 2 groups: 80 patients with PCOS (group I) and 80 healthy subjects as controls (group II). In this study, serum IL6 was measured by ELISA, and the HSD11B1rs12086634(T/G) polymorphism was analyzed using a TaqMan allelic discrimination assay technique. There were statistically significant differences between the two studied groups concerning the serum IL-6 level and HSD11B1rs12086634(T/G) genotype distribution, with increased serum IL6 and increased frequencies of the GG and TG genotypes in patients with PCO. The GG genotype of HSD11B1 rs12086634(T/G) and its associated high level of serum IL-6 may represent genetic risk factors for PCOS.

Systemic inflammatory response predicts poor prognoses in Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma with transarterial chemoembolization: a prospective study.

BackgroundChronic inflammation has been demonstrated to be an important factor in the initiation, promotion, and progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the prognostic values of systemic inflammation markers in Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC.MethodsA prospective non-randomized study was performed from June 2016 to May 2017; 51 of 123 BCLC stage B/C HCC patients were enrolled and received transarterial chemoembolization (TACE). Clinical and laboratory data were recorded. Serum IL-6, IL-10, C-reactive protein (CRP), and blood-neutrophil-to-lymphocyte ratio (NLR) levels were analyzed during the perioperative period. Patient prognosis was investigated. Twenty-eight stage A cases and 10 stage B/C patients who received resection were also collected as controls.ResultsCompared to the stage A group, the BCLC stage B/C HCC patients had significantly higher serum IL-6, CRP, and blood NLR levels. Serum IL-6, IL-10, CRP, and blood NLR levels increased significantly 3 days after treatment (TACE/resection) and returned to baseline levels after 30 days. By univariate analyses, tumor size, high pretreatment serum IL-6, CRP, and blood NLR levels predicted worse progression-free survival (PFS) after TACE (log-rank test P<0.001, P=0.007, P=0.001, respectively). Multivariate analysis revealed that both high serum IL-6 (P=0.018) and CRP (P=0.042) were independent predictors of worse PFS, meanwhile blood NLR was the only inflammatory factor associated to overall survival (OS) (P=0.046).ConclusionsSerum IL-6, CRP, and blood NLR levels were significantly elevated in stage B/CHCC. Serum IL-6 and CRP were independent predictors of poor PFS while NLR independently predicted worse OS in BCLC stage B/C HCC.

Preoperative Serum IL6, IL8, and TNF-α May Predict the Recurrence of Hepatocellular Cancer.

Purpose As we all know, curative resection remains the only effective treatment for hepatocellular cancer (HCC). However, systemic inflammatory response syndrome always correlates with surgery, which may impose an impact on the clinical outcome of HCC patients who had undergone curative treatment. The present study is aimed at exploring the correlation between perioperative inflammatory mediators and recurrence risk of HCC. Methods This study retrospectively included 157 histologically confirmed single HCC patients (88 patients developed HCC again) who had received radical hepatectomy between January 2016 and May 2018 at the Department of Hepatobiliary Surgery, the People's Liberation Army General Hospital (PLAGH), China. The cut-off values for predicting recurrence were determined by receiver operating characteristic (ROC) curve analysis with estimation of the Youden index. Recurrence-free survival (RFS) was assessed using the Kaplan-Meier method, and the difference was compared between groups by the log-rank test. Univariate/multivariate analysis was performed to identify independent risk factors of postoperative tumor recurrence. Results The perioperative serum IL1, IL2, and IL10 levels showed no difference between groups, whereas the serum IL6, IL8, and TNF-α levels showed significant differences between groups. High preoperative serum IL6, IL8, and TNF-α levels were significantly associated with shorter RFS. Multivariate analysis revealed that preoperative serum IL6 > 8.45 pg/ml, preoperative serum IL8 > 68 pg/ml, preoperative serum TNF − α > 14.9 pg/ml, microvascular invasion (MVI), and maximum tumor size > 6 cm were independent predictors of RFS. Conclusions The present study confirmed that high preoperative serum IL6, IL8, and TNF-α levels were distinctly correlated with the postoperative tumor recurrence risk of HCC patients.

Interleukin 8 as predictive factor for response to chemotherapy in colorectal cancer patients

ABSTRACT Background: Colorectal cancer (CRC) represents a major public health problem owing to the fact that many patients are diagnosed in locally advanced or metastatic stage when chemotherapy is the only remaining option. However, treatment response is still unpredictable and depends upon a diversity of factors such as tumor inherited or acquired drug resistance and the host immune response to the malignant cells. The aim of this study was to evaluate the serum levels of interleukin 6, 8, 10 (IL-6, 8, 10) as possible predictive factors for response to chemotherapy and the correlation between the cytokines and the psychological distress. Methods: Forty-nine patients undergoing chemotherapy for locally advanced or metastatic CRC were included, for each patient IL-6, 8 and 10 were assessed through ELISA. Depression and anxiety were quantified through questionnaires. Statistical data were performed with GraphPad. Results: Patients with CRC had high serum levels of IL-8 and IL-6 compared to the healthy control group. High levels of IL-8 before treatment were correlated with progressive disease. There was a high incidence of psychological complication in CRC patients, especially in young male patients, from an urban area, with a positive correlation between serum levels of IL-8 and depression. Conclusions: These results indicate that high serum levels of IL-8 are predictive factors in CRC patients that undergo chemotherapy, but also could be useful in identifying psychological distress associated with this pathology.

Inflammation, brain structure and cognition interrelations among individuals with differential risks for bipolar disorder

Neuro-inflammation might impact on clinical manifestations and cognition function via changing the volumes of key brain structures such as the anterior cingulate cortex (ACC) in bipolar disorder (BD). In this study, we investigated the interrelations among interleukin (IL)-6 cytokine level, grey matter (GM) volume of the anterior cingulated cortex (ACC), and attention function among offspring of parents diagnosed with BD. The offspring were categorized as being either asymptomatic or symptomatic based on whether they manifested pre-defined sub-threshold mood symptoms. We found that the symptomatic offspring showed significantly higher serum levels of IL-6 than the asymptomatic offspring (F(1, 59) = 67.65, p < 0.001). On the brain level, we obtained significant interactive effect of group and IL6 level on the ACC GM (PFWE = 0.017). Specifically, the GM volume of the rostral ACC was negatively associated with the levels of IL-6 in the asymptomatic offspring (PFWE = 0.021), but not the symptomatic offspring (PFWE > 0.05). Mediation analyses revealed that the GM volume of the rostral ACC significantly mediated the negative association between the IL-6 levels and attention performance in the asymptomatic offspring (bootstrapping Confidence Interval (CI) = −6.0432 to −0.0731) but not the symptomatic offspring (bootstrapping CI = −0.3197 to 1.3423). Our data suggest that the asymptomatic and symptomatic bipolar offspring may exhibit different neurocognitive-inflammatory profiles, which could be further validated as viable biosignatures for BD risk and resilience.

Emodin Attenuates Severe Acute Pancreatitis via Antioxidant and Anti-inflammatory Activity.

There is no specific drug to treat severe acute pancreatitis (SAP), which induces substantial medical and social burden. Many studies have reported the beneficial effects of emodin against SAP in vivo and in vitro. However, the underlying mechanism has been unclear. This paper described the design and implementation of anti-inflammatory and antioxidant activity of emodin. Emodin restored the pathological damage of SAP and simultaneously decreased the high levels of serum amylase, lipase, TNF-α, and IL-18 in the peripheral blood of SAP rat. Emodin reversed reactive oxygen species (ROS) in neutrophils derived from SAP rat. The levels of voltage-dependent anion channel 1 (VDAC1), NOD-like receptor protein 3 (NLRP3), caspase-1, and IL-18 were examined to analyze the change of inflammasome-related mediators between SAP and emodin treatment. These findings suggest that emodin plays its protective role on SAP against oxidative stress and inflammasome signals.

Mesenchymal Stem Cells Extract (MSCsE)-Based Therapy Alleviates Xerostomia and Keratoconjunctivitis Sicca in Sjogren’s Syndrome-Like Disease

Sjogren’s syndrome (SS) is an autoimmune disease that manifests primarily in salivary and lacrimal glands leading to dry mouth and eyes. Unfortunately, there is no cure for SS due to its complex etiopathogenesis. Mesenchymal stem cells (MSCs) were successfully tested for SS, but some risks and limitations remained for their clinical use. This study combined cell- and biologic-based therapies by utilizing the MSCs extract (MSCsE) to treat SS-like disease in NOD mice. We found that MSCsE and MSCs therapies were successful and comparable in preserving salivary and lacrimal glands function in NOD mice when compared to control group. Cells positive for AQP5, AQP4, α-SMA, CK5, and c-Kit were preserved. Gene expression of AQP5, EGF, FGF2, BMP7, LYZ1 and IL-10 were upregulated, and downregulated for TNF-α, TGF-β1, MMP2, CASP3, and IL-1β. The proliferation rate of the glands and serum levels of EGF were also higher. Cornea integrity and epithelial thickness were maintained due to tear flow rate preservation. Peripheral tolerance was re-established, as indicated by lower lymphocytic infiltration and anti-SS-A antibodies, less BAFF secretion, higher serum IL-10 levels and FoxP3+ Treg cells, and selective inhibition of B220+ B cells. These promising results opened new venues for a safer and more convenient combined biologic- and cell-based therapy.

C-reactive protein (CRP) promotes malignant properties in pancreatic neuroendocrine neoplasms.

ObjectiveElevated pre-operative C-reactive protein (CRP) serum values have been reported to be associated with poor overall survival for patients with pancreatic neuroendocrine neoplasms (pNEN). The aim of this study was to identify mechanisms linking CRP to poor prognosis in pNEN.MethodsThe malignant properties of pNENs were investigated using the human pNEN cell-lines BON1 and QGP1 exposed to CRP or IL-6. Analyses were performed by ELISA, Western blot, flow cytometry and immunocytochemistry as well as invasion and proliferation assays. To compare cytokine profiles and CRP levels, 76 serum samples of pNEN patients were analyzed using Luminex technology. In parallel, the expression of CRP and growth signaling pathway proteins was assessed on cell lines and paraffin-embedded primary pNEN.ResultsIn BON1 and QGP1 cells, inflammation (exposure to IL-6) significantly upregulated CRP expression and secretion as well as migratory properties. CRP stimulation of BON1 cells increased IL-6 secretion and invasion. This was accompanied by activation/phosphorylation of the ERK, AKT and/or STAT3 pathways. Although known CRP receptors – CD16, CD32 and CD64 – were not detected on BON1 cells, CRP uptake of pNEN cells was shown after CRP exposure. In patients, increased pre-operative CRP levels (≥5 mg/L) were associated with significantly higher serum levels of IL-6 and G-CSF, as well as with an increased CRP expression and ERK/AKT/STAT3 phosphorylation in pNEN tissue.ConclusionThe malignant properties of pNEN cells can be stimulated by CRP and IL-6 promoting ERK/AKT/STAT pathways activation as well as invasion, thus linking systemic inflammation and poor prognosis.

Clinical Impacts of Using Serum IL-6 Level as an Indicator of Cytokine Release Syndrome after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide.

HLA-haploidentical allogeneic hematopoietic cell transplantation with post-transplantation cyclophosphamide (PT/Cy-haplo) is widely used because of such advantages as low procedure cost, high probability of finding a suitable donor, and donor availability at short notice. Cytokine release syndrome (CRS), resulting from bidirectional alloreaction between host and donor, occurs frequently in recipients of PT/Cy-haplo, especially when peripheral blood is used. Severe and life-threatening instances of CRS have been reported. The clinical significance of CRS remains unclear, however. Here we used serum IL-6 level as a surrogate marker of CRS to evaluate the impact of outcomes in 65 consecutive patients receiving PT/Cy-haplo at our institution. Our results indicate that active disease status, high Hematopoietic Cell Transplantation-Specific Comorbidity Index score, and very severe CRS are significantly related to peak serum IL-6 level. In our cohort, high peak serum IL-6 level and severe CRS were significantly associated with the development of grade III or IV acute graft-versus-host disease (GVHD). High peak serum IL-6 level was identified a significant risk factor for poor 3-year overall survival. Our results suggest that even transient CRS following PT/Cy-haplo may contribute to poor survival owing to an increase in severe acute GVHD.

2194-P: Il-6/Stat3 Pathway Contribute to the Islet Failure in High-Fat Diet-Induced Mouse Model of Obesity

Objective: This study was aimed at revealing a new mechanism mediated by IL-6/Stat3 signaling pathway on islet failure in high fat diet-induced obesity through activation of inflammation. Methods: We produced mice with non-obesity, moderate obesity and severe obesity respectively by feeding with normal diet (control), three months’ high fat diet (HFD-3M) and six months’ high fat diet (HFD-6M). Then 200 islets were isolated from the three groups and lysed for RNA extraction, following RNA-Seq analysis with MAPS (Multiplex Analysis of PolyA-linked Sequences) approach. Normal islets were cultured in vitro for IL-6 stimulation and mice with stat3 specific deletion in islet were used to prevent HFD-resulted islet failure. Results: Mice with HFD for three months and six months show significantly higher fast glucose and severe glucose intolerance than control and the morphology of islets from HFD group was obviously abnormal. Additionally, these diabetic symptoms were aggravated in pace with HFD feeding. Further analysis of RNA-seq shows that the expressions of hormones secreted by different endocrine cells were all down-regulated, including INS1, GCG, SST and PPY. On the other hand, expression of IL-6/Stat3 pathway related genes were significantly elevated, including IL-6, CCL2, CCL5, CCL11, CCL28, Tnfrsf11 and NF-kB. Stat3 in islets from HFD-3M and HFD-6M group was also activated by phosphorylation of Y705. Cultured islets with IL-6 treatment show impaired insulin secretion and increased inflammation level. Notably, mice with stat3 specific deletion in islet were able to attenuate the HFD-induced increase of inflammation and secretory deficiency of islet. Conclusions: HFD-induced obesity resulted in islet failure and the high level of serum IL-6 participate in the obesity induced islet failure through IL-6/Stat3 pathway mediated inflammation. Disclosure Z. Jiang: None. F. Teng: None. Y. Xu: None. Funding National Natural Science Foundation of China (81600597)

Elevated pretreatment serum IL-8 and PD-L1 and overall survival in a phase III randomized advanced pancreatic cancer clinical trial.

4131 Background: We previously reported the prognostic and predictive utility of pretreatment serum PD-L1 in the CCTG MA.31 serum bank (SABCS 2018, abstr PD3-10). IL-8 (CXCL8) is a pro-inflammatory cytokine that binds to CXCR1 and CXCR2 and promotes tumor immune escape and progression. High serum IL-8 levels are associated with poor prognosis in many cancers, and have recently been reported to predict for reduced OS to nivolumab in lung cancer and melanoma (ASCO 2018, abstr #3025). In this study, we retrospectively evaluated combined pretreatment serum IL-8 and PD-L1 on overall survival (OS) from a phase III randomized pancreatic cancer trial of first-line therapy (octreotide + 5-FU vs. 5-FU) that had reported no significant OS difference between treatment arms. Methods: This study had 147 patients with serum available for this retrospective biomarker analysis from an advanced pancreatic cancer phase III clinical trial.TheELLA immunoassay platform (ProteinSimple, San Jose, CA) was utilized to quantitate serum levels of IL-8 and PD-L1. Kaplan-Meier life table analysis was used to correlate serum biomarkers with overall survival (OS). Results: In univariate analysis, pretreatment serum IL-8 was a significant biomarker as a continuous variable (HR = 1.004; p = 0.012) and trended significant at the median cutpoint (HR = 1.379; p = 0.098) for OS, however serum PD-L1 was not significant at any cutpoint. When serum PD-L1 and IL-8 levels were analyzed as combined biomarkers (median cutpoints), the serum IL-8 high / PD-L1 high cohort had a significantly shorter OS vs the serum IL-8 low / PD-L1 low cohort (HR = 1.816; p = 0.017). Conclusions: In this phase III randomized clinical trial in advanced pancreatic cancer, pretreatment serum IL-8 was a significant biomarker for OS, but serum PD-L1 was not. Higher combined pretreatment serum levels of PD-L1 and IL-8 (both biomarkers high vs. both low) were prognostic for reduced OS in this phase III pancreatic cancer trial. Further study of circulating IL-8 and PD-L1 is warranted in pancreatic cancer for evaluation of targeted and investigational therapies, including the immune checkpoint inhibitors and anti-IL8 therapy.