Higher Interleukin-6 Research Articles

High serum interleukin-6 concentration upon admission is predictive of disease severity in paediatric trauma patients.

Trauma is the leading cause of death among children worldwide. The inflammatory response of paediatric patients to multiple injuries can be monitored using serum interleukin-6 (IL-6) levels. This study aimed to assess the value of IL-6 levels in predicting the severity of paediatric trauma and its clinical association with disease activity. We prospectively tested serum IL-6 levels and evaluated the Paediatric Trauma Score (PTS) and other clinical data among 106 paediatrics trauma patients from January 2022 to May 2023 at the Emergency Department of the Xi'an Children's Hospital in China. The relationship between IL-6 and trauma severity levels by PTS was analyzed statistically. IL-6 levels were elevated in 76 (71.70%) of the 106 paediatric patients with trauma. Spearman's test showed a significant negative linear correlation between IL-6 and PTS (rs = -0.757, p < 0.001). IL-6 levels were moderate positively correlated with alanine aminotransferase, aspartate aminotransferase, white blood cells, blood lactic acid and interleukin 10 (rs = 0.513, 0.600, 0.503, 0.417, 0.558, p < 0.01). IL-6 levels were positively correlated with hypersensitive C-reactive protein and glucose (rs = 0.377, rs = 0.389, respectively, p < 0.001). IL-6 levels were negatively correlated with fibrinogen and PH (rs = -0.434, p < 0.001; rs = -0.382, respectively, p < 0.001). Binary scatter plots further demonstrated higher levels of IL-6 correlated with lower PTS scores. Serum IL-6 levels significantly increased with increasing severity of paediatric trauma. Serum levels of IL-6 can function as important indicators for predicting disease severity and activity in paediatric trauma patients.

Increased serum IL-12 levels are associated with adverse IVF outcomes

Interleukin-12 (IL-12) is involved in the occurrence and development of many diseases, such as preeclampsia, intrauterine growth restriction, preterm labor, and recurrent pregnancy losses. This study aimed to determine whether a high serum level of IL-12 was associated with adverse in vitro fertilization (IVF) outcomes. Included infertile women with high serum IL-12 levels who underwent IVF cycles and infertile controls with pure tubal etiology. The impact of serum IL-12 on baseline and clinical characteristics, immune-related indicators, IVF laboratory, and pregnancy outcomes were compared. In addition, the correlation of follicular fluid IL-12 and serum IL-12 level and the role of IL-12 in apoptosis of granulosa cells (GCs) was investigated. Women with high serum IL-12 levels had lower numbers of retrieved oocytes, embryos, perfect and available embryos, lower rates of perfect and available embryos, and blastocyst formation. Additionally, significantly higher levels of serum Th1, Th2, and Th17-related cytokines were observed in women with high serum IL-12 levels than in the controls. Meanwhile, the follicular fluid IL-12 levels were positively correlated with serum IL-12 levels, and IL-12 promoted apoptosis of GCs in vitro. We concluded that women with serum high IL-12 levels may have adverse IVF outcomes, partly by promoting apoptosis of GCs. Therefore, early screening for cytokines, especially IL-12, and appropriate consultation for couples receiving IVF-ET should be considered. In addition, specific immune and inflammatory mechanisms associated with high serum IL-12 levels should be further explored.

Circulating Biomarkers, Fraction of Exhaled Nitric Oxide, and Lung Function in Patients With Human Immunodeficiency Virus and Tuberculosis.

Identification of proinflammatory factors responding to Mycobacterium tuberculosis is important to reduce long-term sequelae of pulmonary tuberculosis (TB). We examined the association between plasma biomarkers, the fraction of exhaled nitric oxide (FeNO), and lung function among a prospective cohort of 105 adults newly diagnosed with TB/human immunodeficiency virus (HIV) in South Africa. Participants were followed for 48 weeks from antiretroviral therapy (ART) initiation with serial assessments of plasma biomarkers, FeNO, lung function, and respiratory symptoms. Linear regression and generalized estimating equations were used to examine the associations at baseline and over the course of TB treatment, respectively. At baseline, higher FeNO levels were associated with preserved lung function, whereas greater respiratory symptoms and higher interleukin (IL)-6 plasma levels were associated with worse lung function. After ART and TB treatment initiation, improvements in lung function were associated with increases in FeNO (rate ratio [RR] = 86 mL, 95% confidence interval [CI] = 34-139) and decreases in IL-6 (RR = -118 mL, 95% CI = -193 to -43) and vascular endothelial growth factor ([VEGF] RR = -178 mL, 95% CI = -314 to -43). Circulating IL-6, VEGF, and FeNO are associated with lung function in adults being treated for TB/HIV. These biomarkers may help identify individuals at higher risk for post-TB lung disease and elucidate targetable pathways to modify the risk of chronic lung impairment among TB survivors.

Systemic pro- and anti-inflammatory profiles in acute non-specific low back pain: An exploratory longitudinal study of the relationship to six-month outcome.

Pro-inflammatory molecules are thought to underpin the development of chronic low back pain (LBP). Although research has begun to explore the association between pro-inflammatory molecules in acute LBP and long-term outcome, no study has explored the role of anti-inflammatory molecules. We aimed to explore whether levels of systemic pro- and anti-inflammatory molecules 1) changed over a period of six months from the onset of acute LBP; 2) differed between people who were recovered (N = 11) and unrecovered (N = 24) from their episode of LBP at six months; 3) baseline psychological factors were related to inflammatory molecule serum concentrations at baseline, three and six months. We retrospectively included participants with acute LBP included from a larger prospective trial and examined blood samples for the measurement of pro- and anti-inflammatory molecules and measures of pain, disability, and psychological factors at baseline, three and six months. The serum concentrations of pro- and anti-inflammatory molecules did not differ over time when compared between participants who recovered and those who did not recover at six-month follow-up. At three months, the unrecovered group had higher interleukin (IL)-8 and IL-10 serum concentrations than the recovered group. Baseline psychological factors were not related to inflammatory molecules at any time point. This exploratory study showed that levels of systemic inflammatory molecules did not change over the course of LBP, irrespective of whether people were recovered or unrecovered at six months. There was no relationship between acute-stage psychological factors and systemic inflammatory molecules. Further investigation is needed to elucidate the contribution of pro- and anti-inflammatory molecules to long-term LBP outcome.

Generation of IL-2-Fc-antibody conjugates by click chemistry.

Immunocytokines (ICKs) are antibody directed cytokines produced by genetic fusion of an antibody to a cytokine. We now show that antibodies conjugated by click chemistry to interleukin-2 (IL-2)-Fc form fully active conjugates, and in one example, equivalent activity to a genetically produced ICK. An IL-2-Fc fusion protein was optimized for click chemistry at hinge cysteines using protein stabilizing IL-2 mutations at Lys35 and Cys125 and Fc hinge mutations at Cys142 and Cys148. The IL-2-Fc fusion protein with K35E and C125S mutations with 3 intact hinge cysteines, designated as IL-2-Fc Par, was selected based on its minimal tendency to aggregate. IL-2-Fc-antibody clicked conjugates retained high IL-2 activity and bound target antigens comparable to parent antibodies. An IL-2-Fc-anti-CEA click conjugate showed comparable anti-tumor activity to an anti-CEA-IL-2 ICK in immunocompetent CEA transgenic mice bearing CEA positive orthotopic breast tumors. Significant increases in IFNγ+ /CD8+ and decreases in FoxP3+ /CD4+ T-cells were found for the clicked conjugate and ICK therapies, suggesting a common mechanism of tumor reduction. The production of antibody targeted IL-2 therapy via a click chemistry approach is feasible with comparable activity to genetically produced ICKs with the added advantage of multiplexing with other monoclonal antibodies.

#5655 NEUTROPHIL TO LYMPHOCYTE RATIO, TOTAL IRON BINDING CAPACITY, SERUM ALBUMIN AND SYSTEMIC INFLAMMATION IN CHILDREN WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney disease (CKD) is widely linked to chronic inflammation, with a higher incidence in the advanced stages of the disease. Recognition of systemic inflammation may be useful for prompt diagnosis and management of various CKD related disorders and may open the door towards the development and application of anti-inflammatory strategy treatments. This case-control and cross-sectional study investigates the association of neutrophil to lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), total iron binding capacity (TIBC) and serum albumin with high serum interleukin-6 (IL-6) in children with chronic kidney disease (CKD). Method NLR and PLR were measured in 53 patients (median age: 12.9 years) and 25 healthy controls, stratified by age and sex. Lipid and iron profile, glucose tolerance parameters, serum albumin, uric acid and IL-6 were measured in the patient group. Results Compared to controls, NLR and PLR were higher in patients (p = 0.004 and p = 0.032 respectively), and particularly in those with CKD on dialysis (CKD 5D) (17 patients) (p&amp;lt;0.001 and p = 0.001). LnIL-6 was correlated to NLR (rs = 0.344, p = 0.014), albumin (rs = -0.350, p = 0.011) and TIBC (rs = -0.345, p = 0.012) after adjustment for CKD stage, while the correlation between lnIL-6 and PLR was not significant (rs = 0.206, p = 0.151). Patients with NLR ≥1.7, TIBC ≤300 μg/dl and albumin ≤3.8 g/dl presented a higher risk for increased IL-6 (15 patients) regardless CKD stage (OR 5.499, 95% CI 1.272-22.017, p = 0.016, OR 9.818, 95% CI 2.311-41.706, p = 0.002 and OR 7.543, 95% CI 1.891-30.083, p = 0.004). NLR ≥1.7 and TIBC≤ 300 μg/dl predicted high IL-6 with the highest sensitivity (73.3%), while NLR ≥1.7, TIBC≤ 300 μg/dl and serum albumin ≤ 3.8 g/dl with the highest specificity (97.4%). Conclusion Both NLR and PLR increase in pediatric CKD, especially in CKD 5D. NLR rather than PLR may serve as diagnostic marker of systemic inflammation in pediatric CKD, along with TIBC and serum albumin.

#3437 THE ASSOCIATION OF INTERLEUKIN-6 TO ALBUMIN RATIO WITH MORTALITY IN PATIENTS WITH KIDNEY FAILURE

Abstract Background and Aims Systemic inflammation - characterized by high interleukin-6 (IL-6) and low albumin circulating concentrations - associates with worse outcomes in patients with kidney failure (KF). We examined the value of IL-6 to albumin ratio (IAR) to stratify risk of death in KF patients. Method In 435 incident dialysis patients (median age 56 years, 61.8% male, 31% diabetes mellitus (DM), 38.4% cardiovascular (CV) disease (CVD)), plasma IL-6 and albumin were measured at baseline to calculate IAR. We performed receiver operating characteristic curve (ROC) to compare the discriminatory performance of albumin, IL-6 and IAR for predicting all-cause and CV mortality. We divided patients into IAR tertiles and analysed: 1) cumulative incidence of all-cause mortality and CV mortality censored for renal transplantation during follow up of up to 60 months; 2) the association of IAR and all-cause and CV mortality risk according to Fine-Gray analysis taking renal transplantation as competing risk; and 3) the restricted mean survival time (RMST) and differences of RMST (∆RMST) between IAR tertiles to describe quantitative differences of survival time. Results Among 435 patients, 146 patients (33.6%) died, and 175 (40.2%) patients underwent renal transplantation during median 24.9 months of follow-up; 83 (56.8%) of the 146 deaths were due to CVD. The area under the ROC curve (AUC) of IAR (0.696 for all-cause mortality; 0.657 for CV mortality) was higher than that of both albumin and IL-6. As shown in Fig. 1 A and B: 1) the cumulative incidence of all-cause and CV mortality of patients in middle and high IAR tertiles was significantly higher than in low IAR tertile; 2) higher IAR associated with higher risk of all-cause (sub-hazard ratio (sHR) 1.93, 95% confidence interval (CI) 1.22-3.06 for high IAR tertile) and CV mortality (sHR 1.99, 95% CI 1.03-3.87 for middle IAR tertile) risk after adjusting for age, sex, DM, CVD, and smoking; and 3) ∆RMST at 59 months showed shorter survival time in middle and high IAR tertiles compared with low IAR tertile for all-cause (∆RMST -6.21 months for middle vs low tertile; ∆RMST -11.4 months for high vs low tertile) and CV mortality (∆RMST -4.73 months for middle vs low tertile; ∆RMST -7.49 months for high vs low tertile). Conclusion Higher IAR was independently associated with significantly higher all-cause and CV mortality risk in KF patients. These results suggest that IAR may provide useful prognostic information in patients with KF.

#3195 PATIENTS ON HD WITH CENTRAL CATHETERS LOCKED WITH TAUROLIDINE HAVE A SIMILAR INFLAMMATORY PROFILE TO SUBJECTS WITH NATIVE ARTERIOVENOUS FISTULA

Abstract Background and Aims Inflammation is a near-universal condition in haemodialysis (HD) patients, which contributes to increased complications, morbidity and mortality. The inflammatory profile is enhanced in subjects who need a central venous catheter (CVC) as vascular access in comparison with patients with native arteriovenous fistula (AVF), the optimal vascular access for HD. The aim of the present study was to analyse the inflammatory profile of HD patients according to their vascular access (CVC vs AVF), and to evaluate whether Taurolidine-citrate-heparin lock solution (TCH; taurolidine 1.35%, citrate 4% and heparin 500 IU) is able to modulate the inflammatory state of patients with CVC towards an inflammatory profile similar to that observed in subjects with AVF. Method A total of 109 patients with AVF or tunneled CVC under regular haemodialysis for more than 6 months were screened. Exclusion criteria included intercurrent infections in the previous 3 months, active inflammatory or immunologic diseases, and treatment with antibiotics or drugs affecting the immune system. Finally, 85 patients were included in the study and classified according to the vascular access: 25 patients with AVF and 60 with CVC. Subsequently, two subgroups were formed from the group of patients with tunneled CVC according to a heparin-containing catheter lock solution with (CVC-TCH) and without taurolidine-citrate (CVC-Hep). Subsequently, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) concentrations in serum and messenger ribonucleic acid (mRNA) gene expression levels of IL-6 and TNF-alpha in peripheral blood mononuclear cells (PBMC) were measured at inclusion and after three months follow-up. Results Altogether eighty-five subjects (42 males and 43 females; mean age 61 ± 9 yrs; 39% diabetics) were initially included in the study. In 25 subjects the vascular access was AVF, while the rest used tunneled CVC; of these 31 used standard CVC-Hep and 29 used CVC-TCH. Five patients dropped out the study and thus 80 patients completed the 3-month follow-up and were finally evaluated. At inclusion, patients with CVC had significantly higher serum and expression levels of inflammatory parameters compared to subjects with AVF. After 3 months, there were no significant changes in inflammatory markers in subjects with AVF compared to baseline, whereas in subjects with CVC-Hep a significant increase in serum and gene expression of IL-6 could be observed. On the contrary, subjects with CVC-TCH experienced a decrease of all parameters compared to baseline, of which differences in serum IL-6 and gene expression levels of IL-6 and TNF-alpha were significant. After 3 months of follow-up there was no significant difference in any inflammatory parameter when comparing patients with CVD-TCH with those with AVF (Table). Conclusion In patients under HD with cuffed tunneled CVC, the use of TCH lock solution after each HD session is associated with a significant improvement in the inflammatory serum and gene expression state. Thus, the inflammatory profile of patients with CVC using TCH does not differ from that of patients with native AVF after at least three months of CVC-TCH use.

Clinical Profiles and Il-6 Level Analysis of Critical Covid-19 Patients Receiving Lopinavir-Ritonavir

Highlights:1. Lymphocyte, procalcitonin, D-dimer and high IL-6 levels in COVID-19 patients are associated with a poor prognosis.2. IL-6 serial measurement for COVID-19 patients may be a potential indicator for evaluating the severity and patient outcome. Abstract The COVID-19 pandemic has affected over 760 million individuals worldwide, resulting in more than 6.8 million reported deaths. Early detection of patient deterioration can assist in predicting outcomes and prioritizing healthcare services based on evidence-based indicators. Interleukin-6 (IL-6) is a cytokine that plays a role in the inflammatory process, making it a potential parameter for assessing a patient's inflammatory state. This study aimed to analyze the characteristics, laboratory profiles, and IL-6 levels of COVID-19 patients. This study used a retrospective cohort study design with medical record data. The characteristics (n=68) and IL-6 levels (n=52) of the patients on the first, third, and sixth days of treatment were recorded consecutively. The mean age of the patients was 49 years, with the majority being male (72%) and the most prevalent comorbidity being hypertension (29%). The average duration of hospitalization was 10.94 days. Shortness of breath was the most commonly reported symptom (45.6%). The medians of neutrophil-lymphocyte ratio, C-reactive protein, procalcitonin, ferritin, and D-dimer were above normal. Significant differences were observed in lymphocytes (p=0.046), procalcitonin (p=0.023), and D-dimer (p=0.000) between survivor and non-survivor patients. Significant dynamic changes in IL-6 levels were observed from the first day to the sixth day (p=0.014) and from the third day to the sixth day (p=0.041). In conclusion, risk stratification, laboratory profiles, and IL-6 levels play a role in assessing the severity and outcomes of COVID-19 patients.

The roles of different forms of IL-15 in human melanoma progression.

Melanoma is a lethal skin cancer, and the risk of developing it is increased by exposure to ultraviolet (UV) radiation. The production of cytokines such as interleukin-15 (IL-15), induced by the exposure of skin cells to UV rays, could also promote melanoma development. The aim of this study is to investigate the possible role of Interleukin-15/Interleukin-15 Receptor α (IL-15/IL-15Rα) complexes in melanoma development. The expression of IL-15/IL-15Rα complexes by melanoma cells was evaluated both ex vivo and in vitro by tissue microarray, PCR, and flow cytometry. The presence of the soluble complex (sIL-15/IL-15Rα) in the plasma of metastatic melanoma patients was detected using an ELISA assay. Subsequently, we investigated the impact of natural killer (NK) cell activation after rIL-2 starvation followed by exposure to the sIL-15/IL-15Rα complex. Finally, by analyzing public datasets, we studied the correlation between IL-15 and IL-15Rα expressions and melanoma stage, NK and T-cell markers, and overall survival (OS). Analysis of a melanoma tissue microarray shows a significant increase in the number of IL-15+ tumor cells from the benign nevi to metastatic melanoma stages. Metastatic melanoma cell lines express a phorbol-12-myristate-13-acetate (PMA)-cleavable membrane-bound IL-15 (mbIL-15), whereas cultures from primary melanomas express a PMA-resistant isoform. Further analysis revealed that 26% of metastatic patients present with consistently high plasmatic levels of sIL-15/IL-15Rα. When the recombinant soluble human IL-15/IL-15Rα complex is added to briefly starved rIL-2-expanded NK cells, these cells exhibit strongly reduced proliferation and levels of cytotoxic activity against K-562 and NALM-18 target cells. The analysis of public gene expression datasets revealed that high IL-15 and IL-15Rα intra-tumoral production correlates with the high levels of expression of CD5+ and NKp46+ (T and NK markers) and significantly correlates with a better OS in stages II and III, but not in stage IV. Membrane-bound and secreted IL-15/IL-15Rα complexes are continuously present during progression in melanoma. It is notable that, although IL-15/IL-15Rα initially promoted the production of cytotoxic T and NK cells, at stage IV promotion of the development of anergic and dysfunctional cytotoxic NK cells was observed. In a subgroup of melanoma metastatic patients, the continuous secretion of high amounts of the soluble complex could represent a novel NK cell immune escape mechanism.

Nanosilver alleviates foreign body reaction and facilitates wound repair by regulating macrophage polarization.

Foreign body reactions induced by macrophages often cause delay or failure of wound healing in the application of tissue engineering scaffolds. This study explores the application of nanosilver (NAg) to reduce foreign body reactions during scaffold transplantation. An NAg hybrid collagen-chitosan scaffold (NAg-CCS) was prepared using the freeze-drying method. The NAg-CCS was implanted on the back of rats to evaluate the effects on foreign body reactions. Skin tissue samples were collected for histological and immunological evaluation at variable intervals. Miniature pigs were used to assess the effects of NAg on skin wound healing. The wounds were photographed, and tissue samples were collected for molecular biological analysis at different time points post-transplantation. NAg-CCS has a porous structure and the results showed that it could release NAg constantly for two weeks. The NAg-CCS group rarely developed a foreign body reaction, while the blank-CCS group showed granulomas or necrosis in the subcutaneous grafting experiment. Both matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were reduced significantly in the NAg-CCS group. The NAg-CCS group had higher interleukin (IL)-10 and lower IL-6 than the blank CCS group. In the wound healing study, M1 macrophage activation and inflammatory-related proteins (inducible nitric oxide synthase (iNOS), IL-6, and interferon-‍γ (IFN-‍γ)) were inhibited by NAg. In contrast, M2 macrophage activation and proinflammatory proteins (arginase-1, major histocompatibility complex-II (MHC-II), and found in inflammatory zone-1 (FIZZ-1)) were promoted, and this was responsible for suppressing the foreign body responses and accelerating wound healing. In conclusion, dermal scaffolds containing NAg suppressed the foreign body reaction by regulating macrophages and the expression of inflammatory cytokines, thereby promoting wound healing.

BLOOD PRESSURE, HIGH-SENSITIVITY C-REACTIVE PROTEIN, INTERLEUKIN-6 AND WHITE BLOOD CELLS IN THE COMMUNITY-DWELLING OLDER ADULTS

Objective: Increasing evidence indicates an association between blood pressure (BP) and vascular inflammation, although these relationship remains unknown in older adults. Understanding this association in this population is particularly important in the context of increased prevalence of hypertension, as well as role of inflammatory responses in age related comorbidities. Design and method: We examined the relationship between BP, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and white blood cells (WBC) among 3571 older (aged &gt; = 65 years) and 587 middle-aged (57 ± 1 years old) adults recruited as a part of the PolSenior health survey . Results: BP levels differed in relation to hs-CRP and WBC quartiles in older patients. In particular, systolic BP were 145 ± 22 mmHg and 149 ± 24 mmHg, in the first and fourth quartile of hs-CRP (P = 0.002), and 145 ± 20 mmHg and 150 ± 23 mmHg, respectively for the WBC (P &lt; 0.001). In contrast, systolic BP did not differ between IL-6 quartiles (146 ± 21 mmHg and 145 ± 22 mmHg, P = 0.8). Moreover, the age, gender and body mass index (BMI) adjusted odds ratio (OR) for high BP in subjects with hs-CRP &gt; = 3.7 mg/L was 1.29 (95% CI, 1.05-1.58, P = 0.01) compared with those with hs-CRP &lt; 1 mg/L; in patients with WBC&gt; = 7.1 x 109/L OR was 1.42 (95% CI, 1.16-1.75, P &lt; 0.001) compared with those with WBC &lt; 5.2 x 109/L. Interestingly, in subjects with IL-6 &gt; = 3.4 pg/mL adjusted OR was 0.84 (95% CI, 0.68-1.04, P = 0.11) compared with those with IL-6 &lt; 1.4 pg/mL. In the fully-adjusted model applied in older adults, higher hs-CRP remained associated with high BP, independently of age, gender, BMI, IL-6 and WBC (adjusted OR = 1.12, 95% CI, 1.03 to 1.22, P = 0.008). Conclusions: CRP and WBC, but not IL-6, are positively associated with high blood pressure in the population of community-dwelling older adults, independently of age, gender, and BMI. Results of our study may suggest an important role of inflammation in the pathogenesis of increased blood pressure, also in the older population.

A randomized, open-label, phase II study of high-dose interleukin 2 vs high-dose interleukin 2 plus entinostat in renal cell carcinoma.

e16540 Background: Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies such as high dose interleukin 2 (HD-IL2). We previously reported that the histone deacetylase (HDAC) inhibitor entinostat has antitumor effects in combination with HD-IL2 by decreasing Tregs function in a preclinical model of kidney cancer. Based on these preliminary data, we hypothesized that HDAC inhibition may enhance or resensitize patients (pts) with clear cell renal cell carcinoma (ccRCC) to HD-IL2. Our group has previously conducted a Phase II, single arm, clinical trial of entinostat in combination with HD-IL2 in ccRCC, which showed an objective response rate (ORR) of 37% and a median progression-free survival (mPFS) of 13.6 months as compared to historical data with single agent HD-IL2 of 20-25% and 4.2 months, respectively. Thus, we designed a multi-center, randomized, open label Phase II study with entinostat in combination with HD-IL2 in ccRCC patients. Methods: The primary objective was to estimate and compare PFS in pts randomized to receive either HD-IL2 plus entinostat (Arm 1) or HD-IL2 (Arm 2) and stratified by no prior therapies vs prior therapies. Due to unforeseen circumstances, enrollment halted after the first 10 patients. The treatment schedule was HD-IL2 600,000 units/kg administered IV every 8 hrs on Days 1-5 and Days 15-19 (maximum 28 doses) +/- entinostat 5 mg orally given every 2 weeks starting on Day-14, continuously. The study was originally designed to detect a 100% improvement of median PFS to 8.4 months in ARM 1. A one-sided stratified log-rank test with an overall sample size of 46 subjects (23 per group) achieves 80% power at a 0.10 significance level to detect a hazard ratio of 0.5 (median PFS of 4.2 months vs 8.4 months). Results: 10 pts (6 pts in Arm 1 and 4 pts in Arm 2) were enrolled. Among the 10 pts, only one had prior therapy (Arm 1). The most common treatment-related toxicities ( &gt; 50%, any grade) were diarrhea, hypotension, nausea, hypomagnesemia, hypophosphatemia, pruritus, hypocalcemia and thrombocytopenia, hypophosphatemia, proteinuria, diarrhea, fatigue, and neutropenia. The most common ≥ grade 3 toxicities were hypotension (80%), hypophosphatemia (70%), and thrombocytopenia (60%). Two pts (33%: CI 4.3%-77.7%) achieved a partial response in Arm 1 and no pts in Arm 2. The median PFS was 12.4 months (CI 2.3-NE) in Arm 1 (13.3 months in pts with no prior therapies) and 2.8 months (CI 1.2-3.3) in Arm 2 (Logrank p-value 0.0167). We have collected blood samples to conduct several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study confirm that the combination of entinostat and HD-IL2 may be more active than HD-IL2 alone in pts with ccRCC. Clinical trial information: NCT03501381 .

IL-6 and IL-8 secretion by human glioma cells proliferating after Gamma-knife irradiation

One of the modern methods of treating patients with primary and recurrent brain tumors is radiosurgical irradiation using Gamma Knife, which allows therapeutic doses to be delivered to tumors not exceeding 2.5 cm in diameter in 1–2 sessions. Tumor cells on the periphery of this tissue volume that receive lower radiation doses can resume proliferation and serve as a source of recurrence. The increase of radiation dose may cause necroses formation and a worsening prognosis. The properties of glioblastoma cells that survive and resume proliferation long after stereotactic irradiation are still poorly known. The aim of the work was to evaluate the expression of IL-6 and IL-8 by glioblastoma A172, R1, T2, and T98G cell lines that resumed proliferation after sublethal Gamma Knife irradiation. Cells were irradiated once at doses ranging from 6 to 16 Gy, and then cultured for 40 days. Cell number was counted weekly; lethal and sublethal irradiation doses for each glioblastoma cell line were determined. In cultures descendant from proliferation of single most resistant cells, the level of IL-6 and IL-8 secretion after 96 hours cultivation (ng/1000 cells) was determined by ELISA. The cells of all four glioblastoma lines secreted IL-6 and IL-8 into culture medium. The highest production of cytokines, never before demonstrated for glioblastomas, was discovered in R1 cells. Glioblastoma T2 also had high interleukin production levels. In contrast to these lines, glioblastoma A172 (highly sensitive to the action of cytostatic drugs and radiation) secreted IL-6 at 30 times lower level than R1 cells. Glioblastoma T98G (highly resistant to the action of cytostatic drugs and radiation) also exhibited low interleukins production level. R1, T2, and T98G glioblastoma cells that resumed proliferation after irradiation had increased secretion of IL-6 and, to a lesser extent, IL-8. The dependence of cytokine production increase on irradiation dose for these cells was not linear. In contrast, A172 cells reduced IL-6 and IL-8 secretion under irradiation. The multidirectional changes in IL-6 and IL-8 production by cells of different glioblastoma lines were long-term and persisted for more than a month. The presented results cast doubt on the possibility to use IL-6 and IL-8 production by glioblastoma cells as potential biomarkers for early diagnosis, therapy monitoring as well as prognostic markers of the disease course.

Effect of fluvoxamine on plasma interleukin-6 in patients with major depressive disorder: a prospective follow-up study.

Major depressive disorder (MDD) is associated with low-grade inflammation, and anti-inflammatory treatment can help improve depressive symptoms. A recent study found that fluvoxamine (FLV) can reduce Interleukin-6 (IL-6) production via sigma-1 receptor in inflammation models. However, the anti- IL-6 effect of FLV in treating patients with MDD and whether it can contribute to antidepressant effects remain unclear. A total of 65 patients with MDD and 34 healthy controls were recruited at baseline, and 50 patients completed the FLV treatment for 2 months. We assessed depression and anhedonia and collected plasma IL-6 levels at baseline, 1 month, and 2 months after baseline. This study evaluated the changes in clinical measures and IL-6 during treatment and analyzed their association. Further subgroup analyses were conducted in patients with MDD with high, medium, or low IL-6. Depression and anhedonia were significantly improved in patients with MDD, while the IL-6 did not significantly change after the FLV treatment. However, IL-6 significantly declined after the FLV treatment among patients with MDD with higher baseline IL-6. No significant associations were found between the changes in depressive symptoms and IL-6. Our study provided preliminary evidence suggesting that the anti-IL-6 effect of FLV might not play a vital role in its antidepressant treatment, at least in patients with MDD with low inflammation. However, for patients with MDD with higher IL-6, FLV can help reduce IL-6 significantly in the antidepressant treatment, which may help guide the individual treatment of MDD with higher IL-6 levels. https://clinicaltrials.gov/ct2/show/NCT04160377, identifier NCT04160377.

Interleukin-6-to-Albumin Ratio as a Superior Predictor of Mortality in End-Stage Kidney Disease Patients

Introduction: In patients with chronic kidney disease (CKD), high interleukin-6 (IL-6) and low albumin circulating concentrations are associated with worse outcomes. We examined the IL-6-to-albumin ratio (IAR) as a predictor of risk of death in incident dialysis patients. Methods: In 428 incident dialysis patients (median age 56 years, 62% men, 31% diabetes mellitus, 38% cardiovascular disease [CVD]), plasma IL-6 and albumin were measured at baseline to calculate IAR. We compared the discrimination of IAR with other risk factors for predicting 60-month mortality using receiver operating characteristic curve (ROC) and analyzed the association of IAR with mortality using Cox regression analysis. We divided patients into IAR tertiles and analyzed: (1) cumulative incidence of mortality and the association of IAR with mortality risk in Fine-Gray analysis, taking kidney transplantation as competing risk and (2) the restricted mean survival time (RMST) to 60-month mortality and differences of RMST (∆RMST) between IAR tertiles to describe quantitative differences of survival time. Results: For all-cause mortality, the area under the ROC curve (AUC) for IAR was 0.700, which was greater than for IL-6 and albumin separately, while for CV mortality, the AUC for IAR (0.658) showed negligible improvement over IL-6 and albumin separately. In Cox regression analysis, IAR was significantly associated with all-cause mortality but not with CV mortality. Both high versus low and middle versus low tertiles of IAR associated with higher risk of all-cause mortality, subdistribution hazard ratio of 2.22 (95% CI 1.40–3.52) and 1.85 (95% CI 1.16–2.95), respectively, after adjusting for age, sex, diabetes mellitus, CVD, smoking, and estimated glomerular filtration rate. ∆RMST at 60 months showed significantly shorter survival time in middle and high IAR tertiles compared with low IAR tertile for all-cause mortality. Conclusions: Higher IAR was independently associated with significantly higher all-cause mortality risk in incident dialysis patients. These results suggest that IAR may provide useful prognostic information in patients with CKD.

The Association between Inflammation, Testosterone and SHBG in men: A cross-sectional Multi-Ethnic Study of Atherosclerosis.

Earlier studies have investigated the role of obesity-related inflammation and endogenous sex hormones in men. The role of interleukin-6 (IL-6) and C-reactive protein (CRP) with testosterone and sex hormone binding globulin (SHBG) levels in men is still debated. To investigate the independent association between levels of high sensitivity CRP (hsCRP) and IL-6 with endogenous sex hormones in men. Cross-sectional observational study using data from the Multi-Ethnic Study of Atherosclerosis. A community-based sample of 3212 men aged 45-84 years was included. After exclusions, 3041 men remained for the analyses. Serum concentrations of testosterone, SHBG, hsCRP, IL-6, and sTNFR were measured from the baseline exam. Multivariable linear regressions were used to examine the association of inflammatory markers with sex hormones. An inverse association was found between levels of hsCRP and levels of testosterone and SHBG, even after adjustment for confounders and IL-6 (Total Testosterone; B = -0.14, Bioavailable Testosterone; B = -0.06, and SHBG; B = -0.66). Similar results were found for IL-6, although a positive association was found for SHBG (B = 0.95). Notably, an inverse association was found for IL-6 with bioavailable testosterone in African Americans and Hispanic Americans aged 45-54 years. No associations were found for sTNFR and endogenous sex hormones. Our results indicate that inflammatory markers have independent associations with levels of testosterone (total and bioavailable) and furthermore, appear to associate differently with SHBG levels.

High glucose-induced IL-7/IL-7R upregulation of dermal fibroblasts inhibits angiogenesis in a paracrine way in delayed diabetic wound healing

It is widely acknowledged that diabetes leads to slow wound healing and ulceration, and severe serious diabetic foot ulceration may result in amputation. In recent years, much emphasis has been placed on exploring diabetic wound healing to protect patients from adverse events. We recently found interleukin-7 (IL-7), a growth factor for B-cells and T-cells, and its receptor was significantly upregulated in high glucose-induced fibroblasts and skin of diabetic mice. Moreover, IL-7 stimulated fibroblasts secreted ANGPTL4, which inhibited angiogenesis of endothelial cells resulting in delayed wound healing. In our previous study, fibroblasts, endothelial cells and keratinocytes were exposed to normal glucose (5.5 mM) or high glucose (30 mM) medium for 24 h, and RNA sequencing showed that IL-7 and IL-7R were significantly upregulated in fibroblasts. To remove the effect of high glucose and explore the influence of IL-7, exogenous rMuIL-7 used to treat normal mice led to delayed wound healing by inhibiting angiogenesis. Vitro experiments revealed that IL-7-induced fibroblasts inhibited endothelial cell proliferation, migration and angiogenesis. Further experiments showed that fibroblast angiopoietin-like-4 (ANGPTL4) secretion exhibited the inhibitory effect which was blocked by culture with the corresponding neutralizing antibody. Overall, our study revealed signaling pathways associated with diabetic wound healing and provided the foothold for further studies on delayed wound healing in this patient population.Graphical abstractMechanism that high glucose activates IL-7-IL-7R-ANGPTL4 signal pathway in delayed wound healing. High glucose upregulates IL-7 and IL-7R in dermal fibroblasts. IL-7 stimulates dermal fibroblasts secreting Angptl4 which inhibits proliferation, migration and angiogenesis of endothelial cells in a paracrine way.

Postoperative serum interleukin-6 levels correlate with survival in stage I-III colorectal cancer

AimsThe preoperative serum levels of inflammatory mediators, including C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6), have been demonstrated to be correlated with patient outcomes in colorectal cancer (CRC); however, the prognostic role of these levels has been less well-studied in postoperative settings.Materials and methodsA total of 122 stage I-III CRC patients were retrospectively enrolled. Serum levels of CRP, PCT and IL-6 were measured after surgery, and their prognostic value was evaluated. Kaplan-Meier analysis was used to determine the differences in disease-free survival (DFS) and overall survival (OS) between patients with different levels of these mediators, and the Cox proportional hazards model was used to estimate the risk factors.ResultsIn contrast to CRP and PCT, only the level of IL-6 was significant in predicting DFS (P = 0.01) but not OS (P = 0.07). A total of 66.39% (81/122) of patients were assigned to the low IL-6 group and no significant differences were found in the collected clinicopathological parameters among the low or high IL-6 subgroups. The level of IL-6 was negatively correlated with postoperative (1 w) (R=-0.24, P = 0.02) absolute lymphocyte counts. Patients with low levels of IL-6 had better DFS (log rank = 6.10, P = 0.01) but not OS (log rank = 2.28, P = 0.13). Finally, the level of IL-6 was an independent risk factor for DFS (HR: 1.81, 95% CI: 1.03–3.15, P = 0.04).ConclusionsCompared to CRP and PCT, the level of IL-6 was observed to be the only significant factor in predicting the prognosis of stage I-III CRC patients after surgery, and a low level of IL-6 was associated with good DFS.

Alterations in inflammatory markers after a 12-week exercise program in individuals with schizophrenia-a randomized controlled trial.

In individuals with schizophrenia, inflammation is associated with depression, somatic comorbidity and reduced quality of life. Physical exercise is known to reduce inflammation in other populations, but we have only limited knowledge in the field of schizophrenia. We assessed inflammatory markers in plasma samples from individuals with schizophrenia participating in an exercise intervention randomized controlled trial. We hypothesized that (i) physical exercise would reduce levels of inflammatory markers and (ii) elevated inflammatory status at baseline would be associated with improvement in cardiorespiratory fitness (CRF) following intervention. Eighty-two individuals with schizophrenia were randomized to a 12-week intervention of either high-intensity interval training (HIIT, n = 43) or active video gaming (AVG, n = 39). Participants were assessed at baseline, post intervention and four months later. The associations between exercise and the inflammatory markers soluble urokinase plasminogen activator receptor, c-reactive protein, tumor necrosis factor (TNF), soluble TNF receptor 1 and interleukin 6 (IL-6) were estimated using linear mixed effect models for repeated measures. For estimating associations between baseline inflammation and change in CRF, we used linear regression models. Our main findings were (i) TNF and IL-6 increased during the intervention period for both groups. Other inflammatory markers did not change during the exercise intervention period; (ii) baseline inflammatory status did not influence change in CRF during intervention, except for a positive association between baseline IL-6 levels and improvements of CRF to post intervention for both groups. In our study, HIIT and AVG for 12-weeks had no reducing effect on inflammatory markers. Patients with high baseline IL-6 levels had a positive change in CRF during intervention. In order to increase our knowledge regarding association between inflammatory markers and exercise in individuals with schizophrenia, larger studies with more frequent and longer exercise bout duration are warranted.