Interleukin-4(IL-4) has a protective effect against cerebral ischemia/reperfusion injury. Animal experiments have shown that IL-4 improves the short-and long-term prognosis of neurological function. The Akt(also calle...Interleukin-4(IL-4) has a protective effect against cerebral ischemia/reperfusion injury. Animal experiments have shown that IL-4 improves the short-and long-term prognosis of neurological function. The Akt(also called protein kinase B, PKB)/glycogen synthase kinase-3β(Akt/GSK-3β) signaling pathway is involved in oxidative stress, the inflammatory response, apoptosis, and autophagy. However, it is not yet clear whether the Akt/GSK-3β pathway participates in the neuroprotective effect of IL-4 against cerebral ischemia/reperfusion injury. In the present study, we established a cerebral ischemia/reperfusion mouse model by middle cerebral artery occlusion for 60 minutes followed by a 24-hour reperfusion. An IL-4/anti-IL-4 complex(10 μg) was intraperitoneally administered 30 minutes before surgery. We found that administration of IL-4 significantly alleviated the neurological deficits, oxidative stress, cell apoptosis, and autophagy and reduced infarct volume of the mice with cerebral ischemia/reperfusion injury 24 hours after reperfusion. Simultaneously, IL-4 activated Akt/GSK-3β signaling pathway. However, an Akt inhibitor LY294002, which was injected at 15 nmol/kg via the tail vein, attenuated the protective effects of IL-4. These findings indicate that IL-4 has a protective effect on cerebral ischemia/reperfusion injury by mitigating oxidative stress, reducing apoptosis, and inhibiting excessive autophagy, and that this mechanism may be related to activation of the Akt/GSK-3β pathway. This animal study was approved by the Animal Ethics Committee of Renmin Hospital of Wuhan University, China(approval No. WDRY2017-K037) on March 9, 2017.展开更多
Glaucoma results from irreversible loss of retinal ganglion cells(RGCs)through an unclear mechanism.Microglial polarization and neuroinflammation play an important role in retinal degeneration.Our study aimed to explo...Glaucoma results from irreversible loss of retinal ganglion cells(RGCs)through an unclear mechanism.Microglial polarization and neuroinflammation play an important role in retinal degeneration.Our study aimed to explore the function of microglial polarization during glaucoma progression and identify a strategy to alleviate retinal neuroinflammation.Retinal ischemia/reperfusion injury was induced in C57BL/6 mice.In a separate cohort of animals,interleukin(IL)-4(50 ng/mL,2μL per injection)or vehicle was intravitreally injected after retinal ischemia/reperfusion injury.RGC loss was assessed by counting cells that were positive for the RGC marker RNA binding protein,mRNA processing factor in retinal flat mounts.The expression of classically activated(M1)and alternatively activated(M2)microglial markers were assessed by quantitative reverse transcription-polymerase chain reaction,immunofluorescence,and western blotting.The results showed that progressive RGC loss was accompanied by a continuous decrease in M2 microglia during the late phase of the 28-day period after retinal ischemia/reperfusion injury.IL-4 was undetectable in the retina at all time points,and intravitreal IL-4 administration markedly improved M2 microglial marker expression and ameliorated RGC loss in the late phase post-retinal ischemia/reperfusion injury.In summary,we observed that IL-4 treatment maintained a high number of M2 microglia after RIR and promoted RGC survival.展开更多
Interleukin-4 plays an important protective role in Alzheimer’s disease by regulating microglial phenotype,phagocytosis of amyloid-β,and secretion of anti-inflammatory and neurotrophic cytokines.Recently,increasing ...Interleukin-4 plays an important protective role in Alzheimer’s disease by regulating microglial phenotype,phagocytosis of amyloid-β,and secretion of anti-inflammatory and neurotrophic cytokines.Recently,increasing evidence has suggested that autophagy regulates innate immunity by affecting M1/M2 polarization of microglia/macrophages.However,the role of interleukin-4 in microglial autophagy is unknown.In view of this,BV2 microglia were treated with 0,10,20 or 50 ng/mL interleukin-4 for 24,48,or 72 hours.Subsequently,light chain 3-II and p62 protein expression levels were detected by western blot assay.BV2 microglia were incubated with interleukin-4(20 ng/mL,experimental group),3-methyladenine(500μM,autophagy inhibitor,negative control group),rapamycin(100 nM,autophagy inductor,positive control group),3-methyladenine+interleukin-4(rescue group),or without treatment for 24 hours,and then exposed to amyloid-β(1μM,model group)or vehicle control(control)for 24 hours.LC3-II and p62 protein expression levels were again detected by western blot assay.In addition,expression levels of multiple markers of M1 and M2 phenotype were assessed by real-time fluorescence quantitative polymerase chain reaction,while intracellular and supernatant amyloid-βprotein levels were measured by enzyme-linked immunosorbent assay.Our results showed that interleukin-4 induced microglial autophagic flux,most significantly at 20 ng/mL for 48 hours.Interleukin-4 pretreated microglia inhibited blockade of amyloid-β-induced autophagic flux,and promoted amyloid-βuptake and degradation partly through autophagic flux,but inhibited switching of amyloid-β-induced M1 phenotype independent on autophagic flux.These results indicate that interleukin-4 pretreated microglia increases uptake and degradation of amyloid-βin a process partly mediated by autophagy,which may play a protective role against Alzheimer’s disease.展开更多
Summary: To investigate the effects of intrinsic nitric oxide (NO) on the expression of interleukin-4 (IL-4) mRNA and interferon-γ (IFN-γ) mRNA in the airway inflammation of asthma, the rat models of asthmatic infla...Summary: To investigate the effects of intrinsic nitric oxide (NO) on the expression of interleukin-4 (IL-4) mRNA and interferon-γ (IFN-γ) mRNA in the airway inflammation of asthma, the rat models of asthmatic inflammation were established by sensitizing and then challenging the animals with ovalbumin. The 24 animals were randomly divided into control group, sensitized group, sensitized and L-Arg-treated group as well as L-NAME-treated group equally. By using in situ hybridization combined with compute physiological quantitative imaging analysis techniques, the influence of intrinsic NO on the expression of IL-4 mRNA and IFN-Y mRNA in the airway inflammatory cells was observed. In situ hybridization study demonstrated that IL-4 mRNA expres- sion was obviously increased as compared with that in the control group, mainly distributed in the inflammatory cells in the submucous of airways in the sensitized group. The increase of intensity of IL-4 mRNA expression was positively correlated with the numbers of eosinophil (Eos) and lymphocyte (both with P<0. 05) in the sensitized group. There was no statistically difference IFN- γ expression between the control group and the sensitized group. Imaging analysis showed that L- NAME could inhibit the expression of IL-4 mRNA (P<0. 05) and increase the expression of IFNY mRNA (P<0. 05), while L-Arg could increase the expression of IL-4 mRNA in inflammatory cells (P<0. 05). It was indicated that a suitable levels of intrinsic NO can influence the expression of IL-4 mRNA of Th2 lymphocytes and the expression of IFN-γ mRNA of Th1 lymphocytes and in turn, promote the development of asthmatic airway inflammation.展开更多
AIM:To investigate the potential interactions of thymic stromal lymphopoietin(TSLP)with interleukin-4(IL-4)in adaptive immunity during fungal keratitis(FK).METHODS:An FK mouse model was induced with Aspergillus fumiga...AIM:To investigate the potential interactions of thymic stromal lymphopoietin(TSLP)with interleukin-4(IL-4)in adaptive immunity during fungal keratitis(FK).METHODS:An FK mouse model was induced with Aspergillus fumigatus(AF)hyphal infection.Mice were divided into several groups:untreated,phosphate buffer saline(PBS),infected with AF,and pretreated with a scrambled siRNA,a TSLP-specific siRNA(TSLP siRNA),murine recombinant TSLP(rTSLP),immunoglobulin G(IgG),murine recombinant IFN(rIFN-γ),murine recombinant IL-4(rI L-4),rIL-13,murine recombinant IL-17A(rIL-17A),and murine recombinant IL-17F(rIL-17F)groups.Quantitative realtime reverse transcription-polymerase chain reaction(qRTPCR)and enzyme-linked immunosorbent assay(ELISA)or Western blot were performed to determine mRNA and protein levels in the inflamed cornea.Cytokine locations were observed by immunofluoresence staining after AF hyphal infection.RESULTS:Compared to those in the untreated group,TSLP and T helper type 1(Th1)cytokine levels in the AF group were upregulated at 24 h post infection(hpi),and those of T helper type 2(Th2)and T helper type 17(Th17)cytokines were increased at 5 d post infection(dpi).Th2 cytokine levels were decreased in the TSLP siRNA-pretreated group and increased in the rTSLP-pretreated group compared with the AF group.The TSLP level was increased in the rIL-4-pretreated group,but there were no significant changes among the other groups.Immunofluorescence staining showed cytokine locations after AF hyphal infection.CONCLUSION:TSLP induces a Th2 immune response and promots Th2 T cell differentiation in vivo.IL-4 promotes TSLP secretion.Therefore,TSLP with IL-4 regulates adaptive immunity in FK.展开更多
The relationship of interleukin-4(IL-4) C-33T and C-590T(C-589T) gene polymorphisms with allergic rhinitis was analyzed. Data about the case control studies of IL-4 gene promoter polymorphisms [C-33T and C-590T(C-589T...The relationship of interleukin-4(IL-4) C-33T and C-590T(C-589T) gene polymorphisms with allergic rhinitis was analyzed. Data about the case control studies of IL-4 gene promoter polymorphisms [C-33T and C-590T(C-589T)] and their association with allergic diseases and correlation between serum IL-4 levels and allergic rhinitis were retrieved. The Stata 12.0 statistical software was applied to analyze the correlation between IL-4 gene polymorphisms and allergic rhinitis. The meta-analysis result of TT/CC genotype of-590(-589) polymorphism showed a significant association with allergic diseases [OR=1.93, 95% CI(1.61–2.31), P=0.00]. Meta-analysis of the TT+TC versus CC genotype of IL-4 C-33/T polymorphism revealed significant associations with allergic diseases [OR=3.23, 95% CI(1.13–9.25), P=0.03]. Meanwhile, there was a significant correlation between serum IL-4 levels and allergic rhinitis [OR=2.52, 95% CI=(1.80–3.23), P=0.00]. IL-4 gene-590 TT genotype may increase the risk of allergic rhinitis and the T allele mutation of-33 might be correlated with allergic rhinitis.展开更多
Objective To explore the relationship between polymorphisms of interleukin‐4 (IL‐4) gene (‐33,+45,intron3,+429,+448) and the susceptibility of silicosis.Methods A case‐control study was carried out.101 silicosis p...Objective To explore the relationship between polymorphisms of interleukin‐4 (IL‐4) gene (‐33,+45,intron3,+429,+448) and the susceptibility of silicosis.Methods A case‐control study was carried out.101 silicosis patients were selected as cases.As strictly matching,121 of non silicosis workers were selected as the controls.The polymophisms of IL‐4 (five locus) were detected by the method of polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) techniques.Results The GA genotype in the IL‐4+429 locus and the CC genotype in the IL‐4+448 locus were found.The frequencies of AA,GG and AG of IL‐4+45 locus in the cases were 55.4%,10.9%,and 33.7% and in the controls were 62.0%,11.6%,and 26.4%.The differences between cases and controls were not significant.The frequencies of B1B1,B2B2,and B1B2 of intron3 VNTR locus in the cases were 73.3%,1.0%,and 25.7% and in the controls were 68.6%,1.7%,and 29.8%.The differences were not significant.The frequencies of TT,CC,and CT in ‐33 locus in the cases were 55.4%,11.9%,and 32.7% and in the controls were 69.4%,4.1%,and 26.4%.The differences were significant (P=0.034).Conclusion The relationship between genetic polymorphism of IL‐4‐33 site and silicosis has been found and‐33TT is a protective genotype for silicosis.展开更多
In order to investigate the role of interleukin 4 in experimental murine systemic Candidiasis, we created the intact and dexamethasone induced immunosuppressed murine systemic Candidiasis models. In these models, two ...In order to investigate the role of interleukin 4 in experimental murine systemic Candidiasis, we created the intact and dexamethasone induced immunosuppressed murine systemic Candidiasis models. In these models, two site ELISA and RT PCR were applied to determine the level of IL 4 protein and mRNA expression in spleens respectively, clone forming units of infected kidneys were determined with the plating dilution method, and mean survival time of the mice was recorded. The results showed that, when compared with the controls, protein level of IL 4 increased in both intact mice infected with lethal doses of yeast (day 3, P <0.05; day 7, P <0 001) and immunosuppressed mice infected with sublethal doses of yeast (day 3, P >0.05; day 7, P <0.05). Furthermore, the level of IL 4 was higher on day 7 than on day 3 after infection ( P <0 001 and P <0.05 respectively in two groups). The tendency of IL 4mRNA expression was similar with that of IL 4 protein. As for fungal loads in kidneys, CFUs were significantly higher on day 7 than on day 3 after infection . Mice in both groups succumbed to infection within several days. It was suggested that IL 4 might play a promoting role in the development of murine systemic Candidiasis.展开更多
BACKGROUND: Neuropeptide Y (NPY) may influence differentiation of Th cells. It is assumed that the immunological pathology of experimental allergic encephalomyelitis (EAE) is related to abnormal differentiation of Th ...BACKGROUND: Neuropeptide Y (NPY) may influence differentiation of Th cells. It is assumed that the immunological pathology of experimental allergic encephalomyelitis (EAE) is related to abnormal differentiation of Th cells OBJECTIVE: To investigate the effect of NPY on white matter demyelination, the serum levels interleukin-4 (IL-4) and gamma-interferon (IFN-γ), as well as EAE pathogenesis in an EAE guinea pig model following NPY injection into the lateral cerebral ventricle. DESIGN, TIME AND SETTING: A randomized controlled animal study, which was performed in the Infection Immunity Animal Laboratory, Affiliated Hospital of Luzhou Medical College, China, from October 2005 to April 2006. MATERIALS: Thirty healthy female guinea pigs of 8–12 weeks of age, and 10 healthy female rats of three months of age were used. NPY was provided by Sigma Company, USA. NPY kit was provided by Beijing Huaying Biotechnology Institute, China. METHODS: Thirty guinea pigs were randomly divided into three groups: normal control group, EAE model group, and NPY intervention group (n =10 per group). Normal control group and EAE model group: Saline (10 μL, once) was injected into the lateral cerebral ventricle. After one week, the same volume of Freund’s adjuvant complete was either injected subcutaneously into two post-palms or EAE was modeled. NPY intervention group: EAE was modeled after one week and NPY was injected (10 μL of 6 nmol NPY, once) into the lateral cerebral ventricle. Myelin basic protein (MBP) antigen made from rat spinal cord homogenate and Freund’s adjuvant complete were injected subcutaneously into both post-palms (0.2 mL per palm) to establish the EAE model. MAIN OUTCOME MEASURES: White matter demyelination of the cerebrum, cerebellum, brain stem, and spinal cord were observed by light microscopy after HE staining. Levels of serum IFN-γ and IL-4 were detected by the double antibody sandwich ABC-ELISA technique. NPY content was detected by radioimmunoassay. RESULTS: Pathological alterations in the NPY intervention groups were reduced compared to those in the EAE model group, suggesting a reduction and remission of white matter demyelination with NPY treatment. When compared to the model group, the serum IL-4 level was increased in the NPY intervention group during the high-frequent EAE stage (P < 0.01), but the serum IFN-γ level was decreased (P < 0.01). Furthermore, the EAE latency was prolonged (P < 0.01), the neurological scores were decreased in the high-frequent EAE stage (P < 0.01), and the death rate was decreased (P < 0.05). NPY content and the serum IL-4 level at the peak stage were positively correlated with those in the latent phase (r =0.863-0.900, P < 0.01), but negatively correlated with neurological scores at the peak stage (r= -0.068 to –0.863, P < 0.05–0.01). The IFN-γ level at the peak stage was negatively correlated to that in the latent phase (r = -0.683–0.650, P < 0.05), but positively correlated to neurological scores at the peak stage (r =0.975, 0.845, P < 0.05). CONCLUSION: NPY injection into the lateral cerebral ventricle can promote the secretion of IL-4, inhibit the production of IFN-γ, relieve white matter demyelination, and inhibit EAE attack in an experimental model of EAE.展开更多
Objective:To perform a systematic review and meta analysis on the association of C-589T and C-590T polymorphisms of IL-4 with asthma and to estimate allele frequencies, the magnitude of the gene effect as well as the ...Objective:To perform a systematic review and meta analysis on the association of C-589T and C-590T polymorphisms of IL-4 with asthma and to estimate allele frequencies, the magnitude of the gene effect as well as the possible mode of inheritance. Methods: A genetic model-free approach was used to perform a meta analysis. Heterogeneity, sensitivity analysis and publication bias were also explored. Results: Our meta analysis summarized the evidence to date regarding the association of C-589T and C-590T polymorphisms in the promoter region of IL-4 gene with asthma. For C-590T, the results showed a significant recessive genetic model, and the CC genotype was about 24% less likely to have asthma than the genotype CT and TT. Although there was evidence suggesting a recessive genetic model for C-589T, the recessive model was not statistically significant. Conclusion: This meta analysis suggests that there may be an important effect of single nucleotide polymorphisms (SNPs) in the promoter region of IL-4 gene on the pathogenesis of asthma.展开更多
To observe the effects of the micronutrients on oxidative and autoimmune destruction of islets so as to prevent a person from the onset and development of type 1 Diabetes Mellitus(T1DM),the interleukin-4 and interleuk...To observe the effects of the micronutrients on oxidative and autoimmune destruction of islets so as to prevent a person from the onset and development of type 1 Diabetes Mellitus(T1DM),the interleukin-4 and interleukin-10 expressions of lymphocytes in peripheral blood and spleen of T1DM rats were determined by flow cytometry.GSH-Px activity and MDA level in the rats' pancreas were measured using biochemical methods.The insulin contents in serum and β cell insulin secret storage were tested by RIA and IHC,respectively.There was an increase in the percentages of IL-4 and IL-10 positive lymphocytes in the peripheral blood and spleen of the groups of rats supplemented with various combinations of micronutrients(p<0.01 and p<0.05,respectively);the blood glucose concentration decreased(p<0.05);both the functional β cell in islets and the insulin content in pancreatic tissue increased(p<0.05 and p<0.01);the GSH-Px activity and MDA level of pancreas in the rats enhanced and decreased respectively(p<0.01 and p<0.05).The results suggest that micronutrients may alleviate the islet lesions by upregulating the expressions of IL-4 and IL-10 and lowering oxidative stress in diabetic rats.展开更多
AIM: To investigate the inhibitory effect of heparin-derived oligosaccharides (Oligs) on secretion of interleukin-4 (IL-4) and interleukin-5 (IL-5) from human peripheral blood T lymphocytes (PBTLs).METHODS: Oligs were...AIM: To investigate the inhibitory effect of heparin-derived oligosaccharides (Oligs) on secretion of interleukin-4 (IL-4) and interleukin-5 (IL-5) from human peripheral blood T lymphocytes (PBTLs).METHODS: Oligs were prepared by three different heparin depolymerization methods and separated by gel filtration chromatography. PBTLs from ten adult patients with allergic eosinophilic gastroenteritis were treated with phytahematoagglutinin (PHA) and Oligs. The supernatants from the cell culture of PBTLs were harvested and subjected to the determination of IL-4 and IL-5 contents by ELISA method.RESULTS: At the concentration of 5μg/mL, Oligs with different Mr had different effects on the secretion of IL-4 and IL-5. The tetrasaccharide with Mr of 1 142, produced by depolymerizing heparin with hydrogen peroxide, had the strongest inhibitory effect on the secretion of IL-4. It decreased the IL-4 content from 375.6±39.2 ng/L (PHA group) to 12.5±5.7 ng/L (P<0.01). The hexasaccharide with Mr of I 806, produced by depolymerizing heparin with βelimination method, had the strongest inhibitory effect on the secretion of IL-5. It decreased the IL-5 content from 289.2±33.4 ng/L (PHA group) to 22.0±5.2 ng/L (P<0.01).CONCLUSION: The inhibitory activity of Oligs on the secretion of IL-4 and IL-5 from human PBTLs closely depends on their molecular structure, and there may be an essential structure to act as an inhibitor. The most effective inhibitors of IL-4 and IL-5 secretion are tetrasaccharides and hexasaccharides, respectively.展开更多
Our previous salivary study had demonstrated an apparent T helper 2(Th2)-predominance in saliva of oral lichen planus(OLP) patients and suggested a potential of salivary interleukin-4(IL-4) as a biomarker for monitori...Our previous salivary study had demonstrated an apparent T helper 2(Th2)-predominance in saliva of oral lichen planus(OLP) patients and suggested a potential of salivary interleukin-4(IL-4) as a biomarker for monitoring disease severity. To further determine the consistency of Th1/Th2 bias of OLP, this study investigated the expression profile of interferon-c(IFN-c) and IL-4 in serum and the relationship of the serum levels of these cytokines with their saliva partners. Sixty ethnic Chinese patients with OLP(40 of the erythematous/ulcerative form and 20 of the reticular form) were recruited for this study, with 40 age–sex-matched healthy volunteers as control group. IFN-c and IL-4 levels in serum and paired saliva samples were screened by enzyme-linked immunosorbent assay. OLP patient showed a low-level IFN-c but high-level IL-4 expression profile in both serum and saliva, with a lower IFN-c/IL-4 ratio. Serum IL-4 level in the erythematous/ulcerative group was significantly higher than that in the reticular group. Serum levels of IFN-c and IL-4 were significantly and positively correlated with their saliva partners. These results provided more evidence for Th2 cytokinepredominant immune imbalance in OLP, as well as the potential of IL-4 as the biomarker for monitoring severity of OLP.展开更多
Imminent abortion needs more serious attention since it remains a big problem in Indonesia considering its epidemiology, morbidity, mortality,?and prognosis. In fact, some cases can still be prevented.?The objective o...Imminent abortion needs more serious attention since it remains a big problem in Indonesia considering its epidemiology, morbidity, mortality,?and prognosis. In fact, some cases can still be prevented.?The objective of this study was to determine pathogenesis, diagnosis,?and prognosis of imminent abortion through the role of antioxidant vitamin C in the interaction of superoxide dismutase (SOD), interferon-γ?(IFN-γ), interleukin-4 (IL-4), vascular cells adhesion molecule-1?(VCAM-1), and decidual spiral artery resistance index (DSA RI).?This study took 10 months from March to December 2007 at Obstetrics and Gynecology Department of Medical Faculty of?Padjadjaran?University/Hasan Sadikin Hospital, Bandung. Sixty pregnant women who met the inclusion and exclusion criteria were divided into two groups with the random clinical trial method, double-blind with?repeated measurements.?Data were analyzed statistically using t test, Mann-Whitney, Rank?Spearman, Wilcoxon, t paired, and diagnostic test.?The results of this study showed that the incidence of abortion in vitamin C group was 9 cases (30%) and placebo group was 13 cases (43.3%). There was a significant difference in SOD, IFN-γ, IL-4 and VCAM-1 level between groups of women with and without abortion (p < 0.001).?There was a significant difference of SOD level between women with abortion 655.8 (163.6) U/gHb and placebo group 824.5 (106.7) U/gHb after vitamin C administration (p = 0.008). The cutoff point of SOD?was?￡992 U/gHbwhich?showed quite high sensitivity, specificity, accuracy,?and significant difference (p < 0.001). The cutoff point abortion of DSA resistance index was ≥0.55 with 45% accuracy (p = 0.002). The highest change of IL-4 level was 60.7% in vitamin C group and VCAM-1 was?-2.2% (p < 0.05) after?vitamin C administration. There was a negative correlation in SOD changes toward IL-4 changes after vitamin C administration (r =?-0.523) (p = 0.003), a positive correlation between SOD changes and IL-4 changes (0.597) (p < 0.001), a negative correlation between SOD changes and VCAM-1 changes (r =?-0.737) (p < 0.001) and a negative correlation between SOD changes and DSA RI changes (r =?-0.208) (p = 0.022). There were significant changes in the increment of IL-4 and SOD level (p < 0.001) and a decline in IFN-γ, VCAM-1 and DSA RI (p < 0.001) before and after vitamin C administration. In conclusion, there?was a correlation between the?increase of SOD level with?the?decrease of INF-γ?level and?the?increase of IL-4 level in imminent abortion after vitamin C administration. There?was a correlation between?the?increase of SOD level with?the?decrease of DSA RI and?the?decrease of VCAM-1 level in imminent abortion after vitamin C administration. In abortion, there?was?a?decrease of SOD and IL-4 level,?as well as an?increase of IFN-γ, VCAM-1, and DSA RI level.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81901994(to BZ)and 81571147(to XXX)the Natural Science Foundation of Hubei Province,China,No.2019CFC847(to WWG)the Fundamental Research Funds for the Central Universities,China,No.2042018kf0149(to ML)
文摘Interleukin-4(IL-4) has a protective effect against cerebral ischemia/reperfusion injury. Animal experiments have shown that IL-4 improves the short-and long-term prognosis of neurological function. The Akt(also called protein kinase B, PKB)/glycogen synthase kinase-3β(Akt/GSK-3β) signaling pathway is involved in oxidative stress, the inflammatory response, apoptosis, and autophagy. However, it is not yet clear whether the Akt/GSK-3β pathway participates in the neuroprotective effect of IL-4 against cerebral ischemia/reperfusion injury. In the present study, we established a cerebral ischemia/reperfusion mouse model by middle cerebral artery occlusion for 60 minutes followed by a 24-hour reperfusion. An IL-4/anti-IL-4 complex(10 μg) was intraperitoneally administered 30 minutes before surgery. We found that administration of IL-4 significantly alleviated the neurological deficits, oxidative stress, cell apoptosis, and autophagy and reduced infarct volume of the mice with cerebral ischemia/reperfusion injury 24 hours after reperfusion. Simultaneously, IL-4 activated Akt/GSK-3β signaling pathway. However, an Akt inhibitor LY294002, which was injected at 15 nmol/kg via the tail vein, attenuated the protective effects of IL-4. These findings indicate that IL-4 has a protective effect on cerebral ischemia/reperfusion injury by mitigating oxidative stress, reducing apoptosis, and inhibiting excessive autophagy, and that this mechanism may be related to activation of the Akt/GSK-3β pathway. This animal study was approved by the Animal Ethics Committee of Renmin Hospital of Wuhan University, China(approval No. WDRY2017-K037) on March 9, 2017.
基金supported by the National Natural Science Foundation of China, No.81970796(to WYG)Clinical Research Program of the Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No.JYLJ201905(to WYG)Interdisciplinary Program of Shanghai Jiao Tong University, No.YG2019QNA18(to YW)
文摘Glaucoma results from irreversible loss of retinal ganglion cells(RGCs)through an unclear mechanism.Microglial polarization and neuroinflammation play an important role in retinal degeneration.Our study aimed to explore the function of microglial polarization during glaucoma progression and identify a strategy to alleviate retinal neuroinflammation.Retinal ischemia/reperfusion injury was induced in C57BL/6 mice.In a separate cohort of animals,interleukin(IL)-4(50 ng/mL,2μL per injection)or vehicle was intravitreally injected after retinal ischemia/reperfusion injury.RGC loss was assessed by counting cells that were positive for the RGC marker RNA binding protein,mRNA processing factor in retinal flat mounts.The expression of classically activated(M1)and alternatively activated(M2)microglial markers were assessed by quantitative reverse transcription-polymerase chain reaction,immunofluorescence,and western blotting.The results showed that progressive RGC loss was accompanied by a continuous decrease in M2 microglia during the late phase of the 28-day period after retinal ischemia/reperfusion injury.IL-4 was undetectable in the retina at all time points,and intravitreal IL-4 administration markedly improved M2 microglial marker expression and ameliorated RGC loss in the late phase post-retinal ischemia/reperfusion injury.In summary,we observed that IL-4 treatment maintained a high number of M2 microglia after RIR and promoted RGC survival.
基金supported by the Natural Science Foundation of Liaoning Province of China,No.20170541036(to HYL)
文摘Interleukin-4 plays an important protective role in Alzheimer’s disease by regulating microglial phenotype,phagocytosis of amyloid-β,and secretion of anti-inflammatory and neurotrophic cytokines.Recently,increasing evidence has suggested that autophagy regulates innate immunity by affecting M1/M2 polarization of microglia/macrophages.However,the role of interleukin-4 in microglial autophagy is unknown.In view of this,BV2 microglia were treated with 0,10,20 or 50 ng/mL interleukin-4 for 24,48,or 72 hours.Subsequently,light chain 3-II and p62 protein expression levels were detected by western blot assay.BV2 microglia were incubated with interleukin-4(20 ng/mL,experimental group),3-methyladenine(500μM,autophagy inhibitor,negative control group),rapamycin(100 nM,autophagy inductor,positive control group),3-methyladenine+interleukin-4(rescue group),or without treatment for 24 hours,and then exposed to amyloid-β(1μM,model group)or vehicle control(control)for 24 hours.LC3-II and p62 protein expression levels were again detected by western blot assay.In addition,expression levels of multiple markers of M1 and M2 phenotype were assessed by real-time fluorescence quantitative polymerase chain reaction,while intracellular and supernatant amyloid-βprotein levels were measured by enzyme-linked immunosorbent assay.Our results showed that interleukin-4 induced microglial autophagic flux,most significantly at 20 ng/mL for 48 hours.Interleukin-4 pretreated microglia inhibited blockade of amyloid-β-induced autophagic flux,and promoted amyloid-βuptake and degradation partly through autophagic flux,but inhibited switching of amyloid-β-induced M1 phenotype independent on autophagic flux.These results indicate that interleukin-4 pretreated microglia increases uptake and degradation of amyloid-βin a process partly mediated by autophagy,which may play a protective role against Alzheimer’s disease.
文摘Summary: To investigate the effects of intrinsic nitric oxide (NO) on the expression of interleukin-4 (IL-4) mRNA and interferon-γ (IFN-γ) mRNA in the airway inflammation of asthma, the rat models of asthmatic inflammation were established by sensitizing and then challenging the animals with ovalbumin. The 24 animals were randomly divided into control group, sensitized group, sensitized and L-Arg-treated group as well as L-NAME-treated group equally. By using in situ hybridization combined with compute physiological quantitative imaging analysis techniques, the influence of intrinsic NO on the expression of IL-4 mRNA and IFN-Y mRNA in the airway inflammatory cells was observed. In situ hybridization study demonstrated that IL-4 mRNA expres- sion was obviously increased as compared with that in the control group, mainly distributed in the inflammatory cells in the submucous of airways in the sensitized group. The increase of intensity of IL-4 mRNA expression was positively correlated with the numbers of eosinophil (Eos) and lymphocyte (both with P<0. 05) in the sensitized group. There was no statistically difference IFN- γ expression between the control group and the sensitized group. Imaging analysis showed that L- NAME could inhibit the expression of IL-4 mRNA (P<0. 05) and increase the expression of IFNY mRNA (P<0. 05), while L-Arg could increase the expression of IL-4 mRNA in inflammatory cells (P<0. 05). It was indicated that a suitable levels of intrinsic NO can influence the expression of IL-4 mRNA of Th2 lymphocytes and the expression of IFN-γ mRNA of Th1 lymphocytes and in turn, promote the development of asthmatic airway inflammation.
文摘AIM:To investigate the potential interactions of thymic stromal lymphopoietin(TSLP)with interleukin-4(IL-4)in adaptive immunity during fungal keratitis(FK).METHODS:An FK mouse model was induced with Aspergillus fumigatus(AF)hyphal infection.Mice were divided into several groups:untreated,phosphate buffer saline(PBS),infected with AF,and pretreated with a scrambled siRNA,a TSLP-specific siRNA(TSLP siRNA),murine recombinant TSLP(rTSLP),immunoglobulin G(IgG),murine recombinant IFN(rIFN-γ),murine recombinant IL-4(rI L-4),rIL-13,murine recombinant IL-17A(rIL-17A),and murine recombinant IL-17F(rIL-17F)groups.Quantitative realtime reverse transcription-polymerase chain reaction(qRTPCR)and enzyme-linked immunosorbent assay(ELISA)or Western blot were performed to determine mRNA and protein levels in the inflamed cornea.Cytokine locations were observed by immunofluoresence staining after AF hyphal infection.RESULTS:Compared to those in the untreated group,TSLP and T helper type 1(Th1)cytokine levels in the AF group were upregulated at 24 h post infection(hpi),and those of T helper type 2(Th2)and T helper type 17(Th17)cytokines were increased at 5 d post infection(dpi).Th2 cytokine levels were decreased in the TSLP siRNA-pretreated group and increased in the rTSLP-pretreated group compared with the AF group.The TSLP level was increased in the rIL-4-pretreated group,but there were no significant changes among the other groups.Immunofluorescence staining showed cytokine locations after AF hyphal infection.CONCLUSION:TSLP induces a Th2 immune response and promots Th2 T cell differentiation in vivo.IL-4 promotes TSLP secretion.Therefore,TSLP with IL-4 regulates adaptive immunity in FK.
文摘The relationship of interleukin-4(IL-4) C-33T and C-590T(C-589T) gene polymorphisms with allergic rhinitis was analyzed. Data about the case control studies of IL-4 gene promoter polymorphisms [C-33T and C-590T(C-589T)] and their association with allergic diseases and correlation between serum IL-4 levels and allergic rhinitis were retrieved. The Stata 12.0 statistical software was applied to analyze the correlation between IL-4 gene polymorphisms and allergic rhinitis. The meta-analysis result of TT/CC genotype of-590(-589) polymorphism showed a significant association with allergic diseases [OR=1.93, 95% CI(1.61–2.31), P=0.00]. Meta-analysis of the TT+TC versus CC genotype of IL-4 C-33/T polymorphism revealed significant associations with allergic diseases [OR=3.23, 95% CI(1.13–9.25), P=0.03]. Meanwhile, there was a significant correlation between serum IL-4 levels and allergic rhinitis [OR=2.52, 95% CI=(1.80–3.23), P=0.00]. IL-4 gene-590 TT genotype may increase the risk of allergic rhinitis and the T allele mutation of-33 might be correlated with allergic rhinitis.
基金supported by the Science and Technology Department of Hebei Province,09276195D
文摘Objective To explore the relationship between polymorphisms of interleukin‐4 (IL‐4) gene (‐33,+45,intron3,+429,+448) and the susceptibility of silicosis.Methods A case‐control study was carried out.101 silicosis patients were selected as cases.As strictly matching,121 of non silicosis workers were selected as the controls.The polymophisms of IL‐4 (five locus) were detected by the method of polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) techniques.Results The GA genotype in the IL‐4+429 locus and the CC genotype in the IL‐4+448 locus were found.The frequencies of AA,GG and AG of IL‐4+45 locus in the cases were 55.4%,10.9%,and 33.7% and in the controls were 62.0%,11.6%,and 26.4%.The differences between cases and controls were not significant.The frequencies of B1B1,B2B2,and B1B2 of intron3 VNTR locus in the cases were 73.3%,1.0%,and 25.7% and in the controls were 68.6%,1.7%,and 29.8%.The differences were not significant.The frequencies of TT,CC,and CT in ‐33 locus in the cases were 55.4%,11.9%,and 32.7% and in the controls were 69.4%,4.1%,and 26.4%.The differences were significant (P=0.034).Conclusion The relationship between genetic polymorphism of IL‐4‐33 site and silicosis has been found and‐33TT is a protective genotype for silicosis.
文摘In order to investigate the role of interleukin 4 in experimental murine systemic Candidiasis, we created the intact and dexamethasone induced immunosuppressed murine systemic Candidiasis models. In these models, two site ELISA and RT PCR were applied to determine the level of IL 4 protein and mRNA expression in spleens respectively, clone forming units of infected kidneys were determined with the plating dilution method, and mean survival time of the mice was recorded. The results showed that, when compared with the controls, protein level of IL 4 increased in both intact mice infected with lethal doses of yeast (day 3, P <0.05; day 7, P <0 001) and immunosuppressed mice infected with sublethal doses of yeast (day 3, P >0.05; day 7, P <0.05). Furthermore, the level of IL 4 was higher on day 7 than on day 3 after infection ( P <0 001 and P <0.05 respectively in two groups). The tendency of IL 4mRNA expression was similar with that of IL 4 protein. As for fungal loads in kidneys, CFUs were significantly higher on day 7 than on day 3 after infection . Mice in both groups succumbed to infection within several days. It was suggested that IL 4 might play a promoting role in the development of murine systemic Candidiasis.
文摘BACKGROUND: Neuropeptide Y (NPY) may influence differentiation of Th cells. It is assumed that the immunological pathology of experimental allergic encephalomyelitis (EAE) is related to abnormal differentiation of Th cells OBJECTIVE: To investigate the effect of NPY on white matter demyelination, the serum levels interleukin-4 (IL-4) and gamma-interferon (IFN-γ), as well as EAE pathogenesis in an EAE guinea pig model following NPY injection into the lateral cerebral ventricle. DESIGN, TIME AND SETTING: A randomized controlled animal study, which was performed in the Infection Immunity Animal Laboratory, Affiliated Hospital of Luzhou Medical College, China, from October 2005 to April 2006. MATERIALS: Thirty healthy female guinea pigs of 8–12 weeks of age, and 10 healthy female rats of three months of age were used. NPY was provided by Sigma Company, USA. NPY kit was provided by Beijing Huaying Biotechnology Institute, China. METHODS: Thirty guinea pigs were randomly divided into three groups: normal control group, EAE model group, and NPY intervention group (n =10 per group). Normal control group and EAE model group: Saline (10 μL, once) was injected into the lateral cerebral ventricle. After one week, the same volume of Freund’s adjuvant complete was either injected subcutaneously into two post-palms or EAE was modeled. NPY intervention group: EAE was modeled after one week and NPY was injected (10 μL of 6 nmol NPY, once) into the lateral cerebral ventricle. Myelin basic protein (MBP) antigen made from rat spinal cord homogenate and Freund’s adjuvant complete were injected subcutaneously into both post-palms (0.2 mL per palm) to establish the EAE model. MAIN OUTCOME MEASURES: White matter demyelination of the cerebrum, cerebellum, brain stem, and spinal cord were observed by light microscopy after HE staining. Levels of serum IFN-γ and IL-4 were detected by the double antibody sandwich ABC-ELISA technique. NPY content was detected by radioimmunoassay. RESULTS: Pathological alterations in the NPY intervention groups were reduced compared to those in the EAE model group, suggesting a reduction and remission of white matter demyelination with NPY treatment. When compared to the model group, the serum IL-4 level was increased in the NPY intervention group during the high-frequent EAE stage (P < 0.01), but the serum IFN-γ level was decreased (P < 0.01). Furthermore, the EAE latency was prolonged (P < 0.01), the neurological scores were decreased in the high-frequent EAE stage (P < 0.01), and the death rate was decreased (P < 0.05). NPY content and the serum IL-4 level at the peak stage were positively correlated with those in the latent phase (r =0.863-0.900, P < 0.01), but negatively correlated with neurological scores at the peak stage (r= -0.068 to –0.863, P < 0.05–0.01). The IFN-γ level at the peak stage was negatively correlated to that in the latent phase (r = -0.683–0.650, P < 0.05), but positively correlated to neurological scores at the peak stage (r =0.975, 0.845, P < 0.05). CONCLUSION: NPY injection into the lateral cerebral ventricle can promote the secretion of IL-4, inhibit the production of IFN-γ, relieve white matter demyelination, and inhibit EAE attack in an experimental model of EAE.
基金Supported by a grant from the Science Foundation of Third Military Medical University (No. XG200353)
文摘Objective:To perform a systematic review and meta analysis on the association of C-589T and C-590T polymorphisms of IL-4 with asthma and to estimate allele frequencies, the magnitude of the gene effect as well as the possible mode of inheritance. Methods: A genetic model-free approach was used to perform a meta analysis. Heterogeneity, sensitivity analysis and publication bias were also explored. Results: Our meta analysis summarized the evidence to date regarding the association of C-589T and C-590T polymorphisms in the promoter region of IL-4 gene with asthma. For C-590T, the results showed a significant recessive genetic model, and the CC genotype was about 24% less likely to have asthma than the genotype CT and TT. Although there was evidence suggesting a recessive genetic model for C-589T, the recessive model was not statistically significant. Conclusion: This meta analysis suggests that there may be an important effect of single nucleotide polymorphisms (SNPs) in the promoter region of IL-4 gene on the pathogenesis of asthma.
基金Supported Partly by the National Natural Science Foundation of China(No.39870667)the Program for Scientific ResearchFoundation of Jilin Province,China(No.2002-714)the Key Scientific Research Project from the Third Clinical College of Jilin University,China.
文摘To observe the effects of the micronutrients on oxidative and autoimmune destruction of islets so as to prevent a person from the onset and development of type 1 Diabetes Mellitus(T1DM),the interleukin-4 and interleukin-10 expressions of lymphocytes in peripheral blood and spleen of T1DM rats were determined by flow cytometry.GSH-Px activity and MDA level in the rats' pancreas were measured using biochemical methods.The insulin contents in serum and β cell insulin secret storage were tested by RIA and IHC,respectively.There was an increase in the percentages of IL-4 and IL-10 positive lymphocytes in the peripheral blood and spleen of the groups of rats supplemented with various combinations of micronutrients(p<0.01 and p<0.05,respectively);the blood glucose concentration decreased(p<0.05);both the functional β cell in islets and the insulin content in pancreatic tissue increased(p<0.05 and p<0.01);the GSH-Px activity and MDA level of pancreas in the rats enhanced and decreased respectively(p<0.01 and p<0.05).The results suggest that micronutrients may alleviate the islet lesions by upregulating the expressions of IL-4 and IL-10 and lowering oxidative stress in diabetic rats.
基金Supported by the National Natural Science Foundation of China,No.30370613 and the Major state Basic Research Development Program of China,2001CCA01600
文摘AIM: To investigate the inhibitory effect of heparin-derived oligosaccharides (Oligs) on secretion of interleukin-4 (IL-4) and interleukin-5 (IL-5) from human peripheral blood T lymphocytes (PBTLs).METHODS: Oligs were prepared by three different heparin depolymerization methods and separated by gel filtration chromatography. PBTLs from ten adult patients with allergic eosinophilic gastroenteritis were treated with phytahematoagglutinin (PHA) and Oligs. The supernatants from the cell culture of PBTLs were harvested and subjected to the determination of IL-4 and IL-5 contents by ELISA method.RESULTS: At the concentration of 5μg/mL, Oligs with different Mr had different effects on the secretion of IL-4 and IL-5. The tetrasaccharide with Mr of 1 142, produced by depolymerizing heparin with hydrogen peroxide, had the strongest inhibitory effect on the secretion of IL-4. It decreased the IL-4 content from 375.6±39.2 ng/L (PHA group) to 12.5±5.7 ng/L (P<0.01). The hexasaccharide with Mr of I 806, produced by depolymerizing heparin with βelimination method, had the strongest inhibitory effect on the secretion of IL-5. It decreased the IL-5 content from 289.2±33.4 ng/L (PHA group) to 22.0±5.2 ng/L (P<0.01).CONCLUSION: The inhibitory activity of Oligs on the secretion of IL-4 and IL-5 from human PBTLs closely depends on their molecular structure, and there may be an essential structure to act as an inhibitor. The most effective inhibitors of IL-4 and IL-5 secretion are tetrasaccharides and hexasaccharides, respectively.
基金supported by grants from the National Natural Science Foundation of China (No. 30930100, 81072218, 81200791, 81321002 and 81300882)the Doctoral Program of the Ministry of Education of China (No. 20110181110055 and 20120181120011)Natural Science Foundation of Chongqing (No. cstc2013jcyjA10042)
文摘Our previous salivary study had demonstrated an apparent T helper 2(Th2)-predominance in saliva of oral lichen planus(OLP) patients and suggested a potential of salivary interleukin-4(IL-4) as a biomarker for monitoring disease severity. To further determine the consistency of Th1/Th2 bias of OLP, this study investigated the expression profile of interferon-c(IFN-c) and IL-4 in serum and the relationship of the serum levels of these cytokines with their saliva partners. Sixty ethnic Chinese patients with OLP(40 of the erythematous/ulcerative form and 20 of the reticular form) were recruited for this study, with 40 age–sex-matched healthy volunteers as control group. IFN-c and IL-4 levels in serum and paired saliva samples were screened by enzyme-linked immunosorbent assay. OLP patient showed a low-level IFN-c but high-level IL-4 expression profile in both serum and saliva, with a lower IFN-c/IL-4 ratio. Serum IL-4 level in the erythematous/ulcerative group was significantly higher than that in the reticular group. Serum levels of IFN-c and IL-4 were significantly and positively correlated with their saliva partners. These results provided more evidence for Th2 cytokinepredominant immune imbalance in OLP, as well as the potential of IL-4 as the biomarker for monitoring severity of OLP.
文摘Imminent abortion needs more serious attention since it remains a big problem in Indonesia considering its epidemiology, morbidity, mortality,?and prognosis. In fact, some cases can still be prevented.?The objective of this study was to determine pathogenesis, diagnosis,?and prognosis of imminent abortion through the role of antioxidant vitamin C in the interaction of superoxide dismutase (SOD), interferon-γ?(IFN-γ), interleukin-4 (IL-4), vascular cells adhesion molecule-1?(VCAM-1), and decidual spiral artery resistance index (DSA RI).?This study took 10 months from March to December 2007 at Obstetrics and Gynecology Department of Medical Faculty of?Padjadjaran?University/Hasan Sadikin Hospital, Bandung. Sixty pregnant women who met the inclusion and exclusion criteria were divided into two groups with the random clinical trial method, double-blind with?repeated measurements.?Data were analyzed statistically using t test, Mann-Whitney, Rank?Spearman, Wilcoxon, t paired, and diagnostic test.?The results of this study showed that the incidence of abortion in vitamin C group was 9 cases (30%) and placebo group was 13 cases (43.3%). There was a significant difference in SOD, IFN-γ, IL-4 and VCAM-1 level between groups of women with and without abortion (p < 0.001).?There was a significant difference of SOD level between women with abortion 655.8 (163.6) U/gHb and placebo group 824.5 (106.7) U/gHb after vitamin C administration (p = 0.008). The cutoff point of SOD?was?￡992 U/gHbwhich?showed quite high sensitivity, specificity, accuracy,?and significant difference (p < 0.001). The cutoff point abortion of DSA resistance index was ≥0.55 with 45% accuracy (p = 0.002). The highest change of IL-4 level was 60.7% in vitamin C group and VCAM-1 was?-2.2% (p < 0.05) after?vitamin C administration. There was a negative correlation in SOD changes toward IL-4 changes after vitamin C administration (r =?-0.523) (p = 0.003), a positive correlation between SOD changes and IL-4 changes (0.597) (p < 0.001), a negative correlation between SOD changes and VCAM-1 changes (r =?-0.737) (p < 0.001) and a negative correlation between SOD changes and DSA RI changes (r =?-0.208) (p = 0.022). There were significant changes in the increment of IL-4 and SOD level (p < 0.001) and a decline in IFN-γ, VCAM-1 and DSA RI (p < 0.001) before and after vitamin C administration. In conclusion, there?was a correlation between the?increase of SOD level with?the?decrease of INF-γ?level and?the?increase of IL-4 level in imminent abortion after vitamin C administration. There?was a correlation between?the?increase of SOD level with?the?decrease of DSA RI and?the?decrease of VCAM-1 level in imminent abortion after vitamin C administration. In abortion, there?was?a?decrease of SOD and IL-4 level,?as well as an?increase of IFN-γ, VCAM-1, and DSA RI level.
