IL-6 Activity Research Articles

Nobiletin attenuates inflammation via modulating proinflammatory and antiinflammatory cytokine expressions in an autoimmune encephalomyelitis mouse model

The aim of this study is to investigate the potential preventive and therapeutic effects of nobiletin by evaluating the expression of cytokines associated with inflammatory reactions in an autoimmune encephalomyelitis mouse model. A total of 60 male C57BL/6 mice aged between 8 and 10 weeks were used. Mice were divided into six groups (n = 10 mice per group): control, EAE, low-prophylaxis, high-prophylaxis, low-treatment and high-treatment. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG) and pertussis toxin. Nobiletin was administered in low (25 mg/kg) and high (50 mg/kg) doses, intraperitoneally. The prophylactic and therapeutic effects of nobiletin on brain tissue and spinal cord were evaluated by expression of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interferon gamma (IFNγ), IL-6, IL-10 and transforming growth factor-beta (TGF-β) using immunohistochemistry and real-time polymerase chain reaction (RT-PCR). Prophylactic and therapeutic use of nobiletin inhibited EAE-induced increase of TNF-α, IL-1β and IL-6 activities to alleviate inflammatory response in brain and spinal cord. Moreover, nobiletin supplement dramatically increased the IL-10, TGF-β and IFNγ expressions in prophylaxis and treatment groups compared with the EAE group in the brain and spinal cord. The results obtained from this study show that prophylactic and therapeutic nobiletin modulates expressions of proinflammatory and antiinflammatory cytokines in brain and spinal cord dose-dependent manner in EAE model. These data demonstrates that nobiletin has a potential to attenuate inflammation in EAE mouse model. These experimental findings need to be supported by clinical studies.

Heme-Oxygenase-1 Attenuates Oxidative Functions of Antigen Presenting Cells and Promotes Regulatory T Cell Differentiation during Fasciola hepatica Infection

Fasciola hepatica is a fluke that infects livestock and humans causing fasciolosis, a zoonotic disease of increasing importance due to its worldwide distribution and high economic losses. The parasite regulates the host immune system by inducing a strong Th2 and regulatory T (Treg) cell immune response through mechanisms that might involve the expression or activity of heme-oxygenase-1 (HO-1), the rate-limiting enzyme in the catabolism of free heme that also has immunoregulatory and antioxidant properties. In this paper, we show that F. hepatica-infected mice upregulate HO-1 on peritoneal antigen-presenting cells (APC), which produce decreased levels of both reactive oxygen and nitrogen species (ROS/RNS). The presence of these cells was associated with increased levels of regulatory T cells (Tregs). Blocking the IL-10 receptor (IL-10R) during parasite infection demonstrated that the presence of splenic Tregs and peritoneal APC expressing HO-1 were both dependent on IL-10 activity. Furthermore, IL-10R neutralization as well as pharmacological treatment with the HO-1 inhibitor SnPP protected mice from parasite infection and allowed peritoneal APC to produce significantly higher ROS/RNS levels than those detected in cells from infected control mice. Finally, parasite infection carried out in gp91phox knockout mice with inactive NADPH oxidase was associated with decreased levels of peritoneal HO-1+ cells and splenic Tregs, and partially protected mice from the hepatic damage induced by the parasite, revealing the complexity of the molecular mechanisms involving ROS production that participate in the complex pathology induced by this helminth. Altogether, these results contribute to the elucidation of the immunoregulatory and antioxidant role of HO-1 induced by F. hepatica in the host, providing alternative checkpoints that might control fasciolosis.

Immunogenicity profile in African green monkeys of a vaccine candidate based on a mutated form of human Interleukin-15

BackgroundInterleukin (IL)-15 is a proinflammatory T-cell growth factor overexpressed in several autoimmune diseases such as rheumatoid arthritis. Our initial strategy to neutralize the increased levels of IL-15 consisted in a vaccine candidate based on the recombinant modified human IL-15 (mhIL-15) mixed with the alum adjuvant. A previous study in non-human primates Macaca fascicularis has shown that vaccination induces neutralizing antibodies against native IL-15, without affecting animal behavior, clinical status, or the percentage of IL-15-dependent cell populations. However, the mhIL-15 used as an antigen was active in the IL-2-dependent cytotoxic T-cell line CTLL-2, which could hinder its therapeutic application. The current article evaluated the immunogenicity in African green monkeys of a vaccine candidate based on IL-15 mutant D8SQ108S, an inactive form of human IL-15.ResultsIL-15 D8SQ108S was inactive in the CTLL-2 bioassay but was able to competitively inhibit the biological activity of human IL-15. Immunization with 200 µg of IL-15 mutant combined with alum elicited anti-IL-15 IgG antibodies after the second and third immunizations. The median values of anti-IL-15 antibody titers were slightly higher than those generated in animals immunized with 200 µg of mhIL-15. The highest antibody titers were induced after the third immunization in monkeys vaccinated with 350 µg of IL-15 D8SQ108S. In addition, sera from immunized animals inhibited the biological activity of human IL-15 in CTLL-2 cells. The maximum neutralizing effect was observed after the third immunization in sera of monkeys vaccinated with the highest dose of the IL-15 mutant. These sera also inhibited the proliferative activity of simian IL-15 in the CTLL-2 bioassay and did not affect the IL-2-induced proliferation of the aforementioned T-cell line. Finally, it was observed that vaccination neither affects the animal behavior nor the general clinical parameters of immunized monkeys.ConclusionImmunization with inactive IL-15 D8SQ108S mixed with alum generated neutralizing antibodies specific for human IL-15 in African green monkeys. Based on this fact, the current vaccine candidate could be more effective than the one based on biologically active mhIL-15 for treating autoimmune disorders involving an uncontrolled overproduction of IL-15.

THE ROLE OF PREDICTIVE MARKERS IN THE DEVELOPMENT OF HIV ENCEPHALOPATHY IN CHILDREN

This article presented the clinical-neurological and immunological examination results of 260 children with HIV-encephalopathy (HIVE) of various severity. All children included in the study studied the activity of HIV replication in mononuclear and other indicators that are candidates for the role of a predictive marker of the course of HIVE. Furthermore, the relationship between these indicators and the severity of HIVE was also studied. In addition, the study evaluated the activity of Il-6, IL-10, TNF-α, C-reactive protein, C3, C4 complement components and the predictor significance of various parameters of systemic inflammation in the aspect of the development of symptomatic HIVE.

Fermented Oyster Extract Attenuated Dexamethasone-Induced Muscle Atrophy by Decreasing Oxidative Stress.

It is well known that oxidative stress induces muscle atrophy, which decreases with the activation of Nrf2/HO-1. Fermented oyster extracts (FO), rich in γ-aminobutyric acid (GABA) and lactate, have shown antioxidative effects. We evaluated whether FO decreased oxidative stress by upregulating Nrf2/HO-1 and whether it decreased NF-κB, leading to decreased IL-6 and TNF-α. Decreased oxidative stress led to the downregulation of Cbl-b ubiquitin ligase, which increased IGF-1 and decreased FoxO3, atrogin1, and Murf1, and eventually decreased muscle atrophy in dexamethasone (Dexa)-induced muscle atrophy animal model. For four weeks, mice were orally administered with FO, GABA, lactate, or GABA+Lactate, and then Dexa was subcutaneously injected for ten days. During Dexa injection period, FO, GABA, lactate, or GABA+Lactate were also administered, and grip strength test and muscle harvesting were performed on the day of the last Dexa injection. We compared the attenuation effect of FO with GABA, lactate, and GABA+lactate treatment. Nrf2 and HO-1 expressions were increased by Dexa but decreased by FO; SOD activity and glutathione levels were decreased by Dexa but increased by FO; NADPH oxidase activity was increased by Dexa but decreased by FO; NF-κB, IL-6, and TNF-α activities were increased by Dexa were decreased by FO; Cbl-b expression was increased by Dexa but restored by FO; IGF-1 expression was decreased by Dexa but increased by FO; FoxO3, Atrogin-1, and MuRF1 expressions were increased by Dexa but decreased by FO. The gastrocnemius thickness and weight were decreased by Dexa but increased by FO. The cross-sectional area of muscle fiber and grip strength were decreased by Dexa but increased by FO. In conclusion, FO decreased Dexa-induced oxidative stress through the upregulation of Nrf2/HO-1. Decreased oxidative stress led to decreased Cbl-b, FoxO3, atrogin1, and MuRF1, which attenuated muscle atrophy.

In vivo and in vitro studies of Danzhi Jiangtang capsules against diabetic cardiomyopathy via TLR4/MyD88/NF-κB signaling pathway

ObjectivesDanzhi Jiangtang capsule (DJC) is widely used for preventing and treating diabetic cardiomyopathy (DCM). However, the underlying mechanisms of the anti-inflammatory and antiapoptotic activities are unclear. MethodsIn the in vivo diabetic cardiomyopathy rat model, cardiac function was measured through echocardiography, histological changes in the myocardium were visualized using HE staining, and cardiomyocyte apoptosis was detected using TUNEL. The serum levels of anti-inflammatory cytokines were detected using ELISA. Finally, TLR4, MyD88, and NF-κB mRNA expressions were analyzed using RT-qPCR. In the in vitro experiments, the apoptosis rate of the H9c2 cells was detected using FCM; moreover, TLR4, MyD88 and NF-κB mRNA expressions were measured using RT-qPCR and related protein levels were investigated using Western blotting. ResultsIn vivo, DJC effectively improved cardiac function, alleviated the pathological changes, and reduced the apoptosis rate. Moreover, DJC reduced TNF-α, IL-1β, and IL-6 activities, with significant inhibition of the TLR4, MyD88 and NF-κB p65 mRNA expression. Moreover, in vitro, DJC effectively inhibited high-glucose-induced H9c2 apoptosis-an effect similar to that for TAK242. Finally, both the DJC and TAK242 considerably reduced TLR4, MyD88, NF-κB, Bax, and caspase-3 protein expression but increased that of BCL-2. ConclusionsDJC prevented the overactivation of the TLR4/MyD88/NF-κB signaling pathway and regulate cardiomyocyte apoptosis against DCM.

Comparative study on five kinds of cytokines in the tissues of Chinese giant salamander (Andrias davidianus) of different developmental stages

By using of the double antibody sandwich method of ELISA, the activities of five cytokines including IL-2, IL-4, IFN-α, IFN-β and TNF-α from the blood serum, liver, intestine and spleen at two developmental stages of Chinese giant salamander (Andrias davidianus) were determined to analyze the distribution of the cytokines. The result indicated that five cytokines were found in these four tissues, while their activities were different in different tissues and different ages. The highest activity of IL-2 and IL-4 was all present in blood serum of two different ages. The activity of IFN-α was the highest in blood serum of 1-year-old and in spleen of 2-year-old, respectively. The activity of IFN-β was also highest in blood serum of two different ages. The activity of TNF-α was highest in liver of two different ages. Thus, this study provides convincing reference for blood serum and liver as the most important distribution area of Chinese giant salamander.

Selective IL-1 activity on CD8+ T cells empowers antitumor immunity and synergizes with neovasculature-targeted TNF for full tumor eradication

BackgroundClinical success of therapeutic cancer vaccines depends on the ability to mount strong and durable antitumor T cell responses. To achieve this, potent cellular adjuvants are highly needed. Interleukin-1β (IL-1β)...

Endotoxin Mass Concentration in Plasma Is Associated With Mortality in a Multicentric Cohort of Peritonitis-Induced Shock.

Objectives: To investigate the association of plasma LPS mass with mortality and inflammation in patients with peritonitis-induced septic shock (SS).Design: Longitudinal endotoxin and inflammatory parameters in a multicentric cohort of SS.Patients: Protocolized post-operative parameters of 187 SS patients collected at T1 (12 h max post-surgery) and T4 (24 h after T1).Intervention: Post-hoc analysis of ABDOMIX trial.Measurements and Results: Plasma concentration of LPS mass as determined by HPLC-MS/MS analysis of 3-hydroxymyristate, activity of phospholipid transfer protein (PLTP), lipids, lipoproteins, IL-6, and IL-10. Cohort was divided in low (LLPS) and high (HLPS) LPS levels. The predictive value for mortality was tested by multivariate analysis. HLPS and LLPS had similar SAPSII (58 [48.5; 67]) and SOFA (8 [6.5; 9]), but HLPS showed higher death and LPS to PLTP ratio (p < 0.01). LPS was stable in HLPS, but it increased in LLPS with a greater decrease in IL-6 (p < 0.01). Dead patients had a higher T1 LPS (p = 0.02), IL-6 (<0.01), IL-10 (=0.01), and day 3 SOFA score (p = 0.01) than survivors. In the group of SAPSII > median, the risk of death in HLPS (38%) was higher than in LLPS (24%; p < 0.01). The 28-day death was associated only with SAPSII (OR 1.06 [1.02; 1.09]) and HLPS (OR 2.47 [1; 6.11]) in the multivariate model. In HLPS group, high PLTP was associated with lower plasma levels of IL-6 (p = 0.02) and IL-10 (p = 0.05).Conclusions: Combination of high LPS mass concentration and high SAPS II is associated with elevated mortality in peritonitis-induced SS patients.

The effect of coffee consumption on glucose homeostasis and redox-inflammatory responses in high-fat diet-induced obese rats

Coffee effects on glucose homeostasis in obesity remain controversial. We investigated whether coffee mitigates the negative effects on glucose metabolism induced by a high-fat diet and the interrelationships with redox-inflammatory responses. Rats were treated with: control (CT-); coffee (CT+) 3.9 g of freeze-dried coffee/kg of diet; high-fat (HF-); or high-fat + coffee 3.9 g of freeze-dried coffee/kg of diet (HF+) diet. The high-fat diet increased weight gain, feed efficiency, HOMA β, muscle and hepatic glycogen, intestinal CAT and SOD activity, hepatic protein (CARB) and lipid oxidation (MDA), muscle Prkaa1 mRNA and IL6 levels, and decreased food intake, hepatic GR, GPX and SOD activities, intestinal CARB, intestinal Slc2a2 and Slc5a1 and hepatic Prkaa1 and Prkaa2 mRNA levels, hepatic glucose-6-phosphatase and muscle hexokinase (HK) activities, compared to the control diet. The high-fat diet with coffee increased hepatic GST activity and TNF and decreased IL6 and intestinal glucosidase activity compared with the high-fat diet. The coffee diet increased muscle glycogen, hepatic CARB and PEPCK activity, and decreased hepatic GR and SOD activities and intestinal CARB, compared with the control diet. Coffee increased insulin levels, HOMA IR/β, FRAP, muscle Prkaa1 mRNA levels and hepatic and muscle phosphofructokinase-1, and it decreased intestinal CAT, hepatic Slc2a2 mRNA levels and muscle HK activity, regardless of the diet type. In conclusion, chronic coffee consumption improves antioxidant and anti-inflammatory responses, but does not ameliorate glucose homeostasis in a high-fat diet-induced obesity model. In addition, coffee consumption increases insulin secretion and promotes muscle glycogen synthesis in rats maintained on a control diet.

Tryptophan (W) at position 37 of murine IL-12/IL-23 p40 is mandatory for binding to IL-12Rβ1 and subsequent signal transduction

Interleukin (IL)-12 and IL-23 are composite cytokines consisting of p35/p40 and p19/p40, respectively, which signal via the common IL-12 receptor β1 (IL-12Rβ1) and the cytokine-specific receptors IL-12Rβ2 and IL-23R. Previous data showed that the p40 component interacts with IL-12Rβ1, whereas p19 and p35 subunits solely bind to IL-23R and IL-12Rβ2, resulting in tetrameric signaling complexes. In the absence of p19 and p35, p40 forms homodimers and may induce signaling via IL-12Rβ1 homodimers. The critical amino acids of p19 and p35 required for binding to IL-23R and IL-12Rβ2 are known, and two regions of p40 critical for binding to IL-12Rβ1 have recently been identified. In order to characterize the involvement of the N-terminal region of p40 in binding to IL-12Rβ1, we generated deletion variants of the p40-p19 fusion cytokine. We found that an N-terminal deletion variant missing amino acids M23 to P39 failed to induce IL-23-dependent signaling and did not bind to IL-12Rβ1, whereas binding to IL-23R was maintained. Amino acid replacements showed that p40W37K largely abolished IL-23-induced signal transduction and binding to IL-12Rβ1, but not binding to IL-23R. Combining p40W37K with D36K and T38K mutations eliminated the biological activity of IL-23. Finally, homodimeric p40D36K/W37K/T38K did not interact with IL-12Rβ1, indicating binding of homodimeric p40 to IL-12Rβ1 is comparable to the interaction of IL-23/IL-12 and IL-12Rβ1. In summary, we have defined D36, W37, and T38 as hotspot amino acids for the interaction of IL-12/IL-23 p40 with IL-12Rβ1. Structural insights into cytokine–cytokine receptor binding are important to develop novel therapeutic strategies.

Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation.

Metformin is an anti-diabetic drug and has anticancer effects on various cancers. Several studies have suggested that metformin reduces cell proliferation and stimulates cell-cycle arrest and apoptosis. However, the definitive molecular mechanism of metformin in the pathophysiological signaling in endometrial tumorigenesis and metastasis is not clearly understood. In this study, we examined the effects of metformin on the cell viability and apoptosis of human cervical HeLa and endometrial HEC-1-A and KLE cancer cells. Metformin suppressed cell growth in a dose-dependent manner and dramatically evoked apoptosis in HeLa cervical cancer cells, while apoptotic cell death and growth inhibition were not observed in endometrial (HEC-1-A, KLE) cell lines. Accordingly, the p27 and p21 promoter activities were enhanced while Bcl-2 and IL-6 activities were significantly reduced by metformin treatment. Metformin diminished the phosphorylation of mTOR, p70S6K and 4E-BP1 by accelerating adenosine monophosphate-activated kinase (AMPK) in HeLa cancer cells, but it did not affect other cell lines. To determine why the anti-proliferative effects are observed only in HeLa cells, we examined the expression level of liver kinase B1 (LKB1) since metformin and LKB1 share the same signalling system, and we found that the LKB1 gene is not expressed only in HeLa cancer cells. Consistently, the overexpression of LKB1 in HeLa cancer cells prevented metformin-triggered apoptosis while LKB1 knockdown significantly increased apoptosis in HEC-1-A and KLE cancer cells. Taken together, these findings indicate an underlying biological/physiological molecular function specifically for metformin-triggered apoptosis dependent on the presence of the LKB1 gene in tumorigenesis.

Molecular Mechanism of the Anti-Inflammatory Action of Heparin.

Our objective is to reveal the molecular mechanism of the anti-inflammatory action of low-molecular-weight heparin (LMWH) based on its influence on the activity of two key cytokines, IFNγ and IL-6. The mechanism of heparin binding to IFNγ and IL-6 and the resulting inhibition of their activity were studied by means of extensive molecular-dynamics simulations. The effect of LMWH on IFNγ signalling inside stimulated WISH cells was investigated by measuring its antiproliferative activity and the translocation of phosphorylated STAT1 in the nucleus. We found that LMWH binds with high affinity to IFNγ and is able to fully inhibit the interaction with its cellular receptor. It also influences the biological activity of IL-6 by binding to either IL-6 or IL-6/IL-6Rα, thus preventing the formation of the IL-6/IL-6Rα/gp130 signalling complex. These findings shed light on the molecular mechanism of the anti-inflammatory action of LMWH and underpin its ability to influence favourably conditions characterised by overexpression of these two cytokines. Such conditions are not only associated with autoimmune diseases, but also with inflammatory processes, in particular with COVID-19. Our results put forward heparin as a promising means for the prevention and suppression of severe CRS and encourage further investigations on its applicability as an anti-inflammatory agent.

NLRX1 can counteract innate immune response induced by an external stimulus favoring HBV infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells.

This study is aimed at the determination of the effect of the immune-regulatory factor NLRX1 on the antiviral activity of hepatocytes against an external stimuli favoring hepatitis B virus infection, and to explore its mechanism of action. A HepG2-NTCP model was established using the LV003 lentivirus. Cells were transfected using an overexpression vector and NLRX1 siRNA to achieve overexpression and interference of NLRX1 expression (OV-NLRX1, si-NLRX1). Levels of HBsAg and HBcAg were determined using Western blotting analysis and immunohistochemical analysis. The levels of hepatitis B virus DNA and hepatitis B virus cccDNA were determined by real-time quantitative polymerase chain reaction. The expression and transcriptional activity of IFN-α, IFN-β, and IL-6 were measured using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and promoter-luciferase reporter plasmids. Co-immunoprecipitation was used to determine the effect of NLRX1 on the interaction between MAVS and RIG-1. Western blotting was used to obtain the phosphorylation of essential proteins in the MAVS-RLRs signaling pathways. NLRX1 promoted HepG2-NTCP cell hepatitis B virus infection. Compared to the control group, the levels of HBsAg, HBcAg, hepatitis B virus cccDNA, and hepatitis B virus DNA increased in the OV-NLRX1 group and decreased in the si-NLRX1. Co-immunoprecipitation results showed that NLRX1 competitively inhibited the interaction between MAVS and RIG-1, and inhibited the phosphorylation of p65, IRF3, and IRF7. Additionally, NLRX1 reduced the transcription activity and expression levels of the final products: IFN-α, IFN-β, and IL-6. NLRX1 can counteract innate immune response induced by an external stimuli favoring hepatitis B virus infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells. Inhibition of the MAVS-RLR-mediated signaling pathways leads to a decline in the expression levels of I-IFN and IL-6.

Mitigation of ILβ-1, ILβ-6, TNF-α, and markers of apoptosis by ursolic acid against cisplatin-induced oxidative stress and nephrotoxicity in rats.

Ursolic acid (UA) is a natural pentacyclic triterpenoid that is known for its benefits under several pathological conditions. Cisplatin (CP) is among the most preferred chemotherapeutic agents; however, its nephrotoxicity limits its clinical utility. This study was aimed to determine the role of UA in the reduction of CP-induced nephrotoxicity and mitigation of pro-inflammatory cytokines and apoptosis in a rat model. Male Wistar rats were randomized into vehicle control, CP (7.5 mg/kg), UA 10 mg/kg, and CP with UA 5 and 10 mg/kg groups. Kidney and blood samples were collected for assessment of renal function, measurement of pro-inflammatory cytokines, apoptosis markers, antioxidant activity, and tissue histology. CP significantly increased the levels of serum Cr, BUN, and uric acid; it also induced histological damage reflecting the pathophysiology observed during nephrotoxicity. CP has also shown its pro-oxidant activity in kidney tissue because CP decreased the levels of GSH, SOD, and CAT; it increased the lipid peroxidation as measured by MDA content. In addition, CP significantly upregulated the activity of pro-inflammatory cytokines and expression of apoptotic markers, that is, there were increased levels of IL-1β, IL-6, TNF-α, caspase-3, and caspase-9. Two weeks of continuous treatment of UA showed significant recovery against CP-induced nephrotoxicity; UA decreased the levels of Cr, BUN, and uric acid and ameliorated histological damage. UA also downregulated the activities of IL-1β, IL-6, and TNF-α as well as expression of caspase-3 and caspase-9. Furthermore, CP-induced oxidative stress that was antagonized by UA-the levels of GSH, SOD, and CAT were significantly increased while MDA content was decreased. UA has a protective effect against CP-induced nephrotoxicity, which may be due to its antioxidant activity and mitigation of ILβ-1, ILβ-6, TNF-α, and markers of apoptosis.

Follicular dendritic cells restrict interleukin-4 availability in germinal centers and foster memory B cell generation

B cells within germinal centers (GCs) enter cycles of antibody affinity maturation or exit the GC as memory cells or plasma cells. Here, we examined the contribution of interleukin (IL)-4 on B cell fate decisions in the GC. Single-cell RNA-sequencing identified a subset of light zone GC B cells expressing high IL-4 receptor-a (IL4Ra) and CD23 and lacking a Myc-associated signature. These cells could differentiate into pre-memory cells. B cell-specific deletion of IL4Ra or STAT6 favored the pre-memory cell trajectory, and provision of exogenous IL-4 in a wild-type context reduced pre-memory cell frequencies. IL-4 acted during antigen-specific interactions but also influenced bystander cells. Deletion of IL4Ra from follicular dendritic cells (FDCs) increased the availability of IL-4 in the GC, impaired the selection of affinity-matured B cells, and reduced memory cell generation. We propose that GC FDCs establish a niche that limits bystander IL-4 activity, focusing IL-4 action on B cells undergoing selection and enhancing memory cell differentiation.

Nephroprotective effect of naringin in methotrexate induced renal toxicity in male rats

The current work aims to study the nephroprotective potential of naringin (NG), a flavanone derived from citrus fruits, in methotrexate (MTX)-induced renal toxicity. Thirty male rats were divided into five groups; control group (IP saline), MTX group (IP single dose, 20 mg/kg), and three groups co-treated with MTX and naringin (IP daily dose; 20, 40, and 80 mg/kg, respectively). Kidney tissues were used to investigate renal function, oxidative stress, lipid peroxidation, and caspase-3 activity. Biochemical cytokine analysis was performed in addition to ultrastructural examinations of kidney tissue. When compared to the MTX-treated rats, MTX+NG significantly reduced the levels of urea, creatinine, MDA, NO, TNFα, IL-6, and caspase-3 activity. A significant increase in the levels of the antioxidant enzymes and GSH were also noted. Additionally, naringin ameliorated the apparent ultrastructural changes observed in the glomeruli and renal tubules of MTX-intoxicated rats. Noticeable structural improvements of glomerular lesions, proximal, and distal convoluted tubular epithelium were observed in MTX+NG treated animals, including podocytes with regular foot processes, perfectly organized filtration barrier, no signs of GBM thickening, organized brush border, and normal architecture of microvilli. Naringin (80 mg/kg) had the maximum amelioration effect. To the best of our knowledge, this is the first study to investigate the ultrastructural manifestations of naringin and/or MTX on the kidney of rats. Taken all, naringin has a potent therapeutic effect and can be used in adjuvant therapy to prevent MTX-induced nephrotoxicity. Nevertheless, the molecular mechanism underlying the nephroprotective capacity of naringin needs further investigation.

IL6 Signaling in Cancer: Not Always Bad News.

Understanding the molecular mechanisms that underpin the pleiotropic effects of IL6 in disease are critical to better inform when this cytokine should be therapeutically targeted to provide the most benefit to patients. This is particularly important for cancer and other pathologic conditions strongly linked to chronic inflammation. Shriki and colleagues provide mechanistic evidence that IL6 protects against chronic liver injury and its ensuing tumor development, thereby challenging the prevailing paradigm that IL6 always acts as a tumor-promoting cytokine. These observations contribute to an emerging view of dichotomous and complex activities of IL6 in solid malignancies and will help understand which patients under which circumstances receive the most benefit from therapies that interfere with IL6 signaling.See related article by Shriki et al., p. 4766.

Soluble CD127 potentiates IL-7 activity in vivo in healthy mice.

IntroductionSoluble forms of cytokine receptors can be involved in the endogenous regulation of cytokine activity. Soluble interleukin 7 receptor α (sCD127) naturally binds IL‐7, therefore there is interest in its potential application as an immunotherapeutic agent to regulate IL‐7. With the hypothesis that sCD127 enhances IL‐7 activity, thus promoting T‐cell proliferation in vivo, we sought to assess the effect of sCD127, IL‐7 or IL‐7 + sCD127 treatment on CD4+ and CD8+ T‐cells in the blood and spleen of mice.MethodsPeripheral blood mononuclear cells and splenocytes were prepared, and analyzed for T‐cell number, phenotype and proliferation (Ki67+) by flow cytometry.ResultsIL‐7 treatment induced T‐cell proliferation, increased T‐cell number, and triggered T‐cell differentiation each of which was enhanced with the addition of sCD127. IL‐7 + sCD127 treatment significantly increased spleen weight over that seen with IL‐7 treatment alone. More pronounced proliferation and a greater increase in cell number was observed in CD8+ T‐cells relative to the effect on CD4+ T‐cells.ConclusionsThese findings suggest that the addition of sCD127 enhances IL‐7‐mediated T‐cell proliferation and suggests a potential therapeutic use for sCD127.

Vinpocetine Suppresses Inflammatory and Oxidative Machineries in Acute Model of Inflammation—Pivotal Role of COX-2 Signaling

The presence of inflammation is one of the key factors in the onset and progression of various medical disorders and diseases, making it a crucial challenge for treatment. The purpose of this study is to evaluate antioxidant and anti-inflammatory effects of Vinpocetine, using acute models of inflammation; Xylene-, Carrageenan (CGN)-induced inflammation and acetic acid-induced vascular- permeability in mice were used. We also employed molecular docking approach to verify the underlying mechanism of anti-inflammatory activity of Vinpocetine. In a current investigation, Vinpocetine showed anti-inflammatory and antioxidant effects on Xylene- and CGN-induced inflammation in a dose-dependent manner. Vinpocetine reduced inflammatory edema and restored antioxidant tissue balance, probably via suppression of IL-1β, IL-6, TNF-α, MDA and MPO activity, and also through increased non-enzymatic antioxidant (GSH) levels in paw tissue. Histopathological examination showed that Vinpocetine restored normal skin architecture with significant inhibition of tissue edema, congestion, and cellular infiltration in CGN-challenged paw. Mechanistically, Vinpocetine showed downregulation the expression of COX-2 protein, in western blot assessment, that was associated with significant decrease in the level of prostaglandin E 2 (PGE2) levels; a major metabolic product of COX-2 enzyme. Interestingly, Silico study showed that Vinpocetine has strong affinity to COX-2, similar to diclofenac, suggested possible mechanism of downregulation of COX-2 expression. Therefore, Vinpocetine showed antioxidant and anti-inflammatory responses might, in part, due to inhibition of COX-2/PGE 2 pathway.