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interleukin-4 promotes microglial polarization toward a neuroprotective phenotype after retinal ischemia/reperfusion injury

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Neural Regeneration Research 2022年第12期17卷 2755-2760页

作者： Di Chen Cheng Peng Xu-Ming Ding Yue Wu Chang-Juan Zeng Li Xu Wen-Yi Guo Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology ShanghaiChina

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.

关键词： glaucoma hyper-intraocular pressure in vivo interleukin-4 intravitreal injection M2 microglia neurodegeneration neuroprotective effect retinal ganglion cell retinal ischemia-reperfusion

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interleukin-4 affects microglial autophagic flux

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Neural Regeneration Research 2019年第9期14卷 1594-1602页

作者： Run-Hong Tang Rui-Qun Qi Hua-Yan Liu Department of Neurology the First Hospital of China Medical UniversityShenyangLiaoning ProvinceChina Department of Dermatology Key Laboratory of Immunodermatologythe First Hospital of China Medical UniversityShenyangLiaoning ProvinceChina

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.

关键词： nerve regeneration Alzheimer’s disease interleukin-4 amyloid-β microglial autophagy microglial polarization microglia M1 phenotype M2 phenotype peptide degradation neural regeneration

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The Akt/glycogen synthase kinase-3β pathway participates in the neuroprotective effect of interleukin-4 against cerebral ischemia/reperfusion injury

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Neural Regeneration Research 2020年第9期15卷 1716-1723页

作者： Mei Li Wen-Wei Gao Lian Liu Yue Gao Ya-Feng Wang Bo Zhao Xiao-Xing Xiong Department of Anesthesiology Renmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina Department of Critical Care Medicine Renmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina Department of Personnel Renmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina Department of Neurosurgery Renmin Hospital of Wuhan UniversityWuhanHubei ProvinceChina

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.

关键词： Akt/glycogen synthase kinase-3βpathway apoptosis autophagy cerebral ischemia/reperfusion injury infarct volume interleukin-4 neuroprotection oxidative stress

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Recombinant adeno-associated virus-mediated inhibiting of interleukin-4 expression in rat model of asthma

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Chinese Medical Journal 2006年第3期119卷 223-225页

作者： CAO Yong XIONG Wei-ning XU Yong-jian ZHANG Zhen-xiang GAO Bao-an DU Chun-ling LU Jun-yu YE Tao Department of Respiratory Medicine Tongji Hospital TongjiMedical College Huazhong University of Science and TechnologyWuhan 430030 China

Asthma is a chronic disease characterized by ,reversible airway obstruction, airway hyperresponsiveness, and inflammation of airways, Th2 cells, one sort of CD4＋ T lymphocytes, are currently considered to play an important role in the chronic airway inflammation of asthma, Meanwhile, a number of laboratories have clearly established the importance of the Th2-dedved cytokine interleukin-4 （IL-4） in mediating the airway inflammatory response, Anti-IL-4 therapy might be beneficial in treatment of chronic asthma.

关键词： adeno-associated virus interleukin-4 asthma

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Association between the polymorphisms of interleukin-4, the interleukin-4 receptor gene and asthma

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Chinese Medical Journal 2013年第15期126卷 2943-2951页

作者： ZHU Ning GONG Yi CHEN Xiao-dong ZHANG Jing LONG Feng HE Jian XIA Jing-wen DONG Liang Fudan Univ Allergy Res Lab Inst Resp Dis Shanghai 200040 Peoples R China Fudan Univ Dept Resp Dis Huashan Hosp Shanghai 200040 Peoples R China

Background interleukin-4 （IL4） is one of the most important cytokines involved in a variety of allergic disorders, particularly, asthma. A number of genetic epidemiological studies have identified an association between the gene polymorphisms of IL4 and interleukin-4 receptor （IL4R） and asthma in different populations. However, these studies have been inconsistent and inconclusive. The aim of this study was to investigate the association between the single nucleotide polymorphism （SNP） of IL-4, IL-4R and asthma risk in case-controlled studies using meta-analysis. Method A genetic model-free approach was used to perform the meta-analysis. Asthma （atopy status nondefined）, nonatopic and atopic asthma subgroups were separately analyzed. Next, the ethnic subgroup was analyzed. Heterogeneity and publication bias were also explored. Results Only two polymorphisms of IL4 （rs2243250 and rs2070874） and four polymorphisms of IL4R （rs1801275, rs1805011, rs1805010, and rs1805015） were included in the meta-analysis. Polymorphisms rs2243250 and rs2070874 of IL-4 and rs1801275 and rs1805011 of IL4R were associated with asthma. The overall odds ratio （OR） of rs2243250 in the CC versus TT＋TC genotypes was 0.84 （95% CI： 0.75-0.94）, and the Z-test for the overall effect was 3.0 （P=0.003）. We obtained significant results from this polymorphism in the Caucasian ethnicity and adult groups. However, the overall OR of rs1801275 for the GG＋AG versus AA genotype was 1.16 （95% CI： 1.00-1.35）, and the Z-test for the overall effect was 1.87 （P=0.06）. Moreover, significant results were only obtained from the sub-group analysis in Asians （P=0.02）. In the rs1805011 polymorphism of IL4R, the overall OR for the CC ＋AC versus AA genotypes was 0.39 （95% CI： 0.16-0.95）, and the Z-test for the overall effect was 2.08 （P=0.04）. Conclusions Both the IL4 and IL4R polymorphisms were associated with asthma. The rs2243250 polymorphism of IL4 was more important in the white and adult groups. Individuals who carried the C allele for rs2070874 of the IL4 gene

关键词： interleukin-4 interleuMn-4 receptor asthma gene polymorphism case-controlled study meta-analysis

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The Relationship between Polymorphisms of interleukin-4 Gene and Silicosis

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Biomedical and Environmental Sciences 2011年第6期24卷 678-682页

作者： FANG Guo Feng FAN Xue Yun SHEN Fu Hai Department of Occupational and Environmental Health School of Public Health Hebei United UniversityTangshan 063000 Hebei China

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 ofAA, 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%, 12.6%, 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.

关键词： Silicosis interleukin-4 Polymorphism Susceptibility

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Effect of Inhaled Budesonide on interleukin-4 and interleukin-6 in Exhaled Breath Condensate of Asthmatic Patients

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Chinese Medical Journal 2016年第7期129卷 819-823页

作者： Chun-Hua Chi Ji-Ping Liao Yan-Ni Zhao Xue-Ying Li Guang-Fa Wang Department of Respiratory and Critical Care Medicine Peking University First Hospital geijing 100034 China Department of Medical Statistics Peking University First Hospital Beijing 100034 China

Background： Studies of interleukin （IL）-4 and IL-6 in the exhaled breath condensate （EBC） of asthmatic patients are limited. This study was to determine the effect of inhaled corticosteroid （ICS） treatment on IL-4 and IL-6 in the EBC ＆asthmatic patients. Methods： In a prospective, open-label study, budesonide 200 μg twice daily by dry powder inhaler was administered to 23 adult patients with uncontrolled asthma （mean age 42.7 years） for 12 weeks. Changes in asthma scores, lung function parameters （forced expiratory volume in 1 s [FEV1], peak expiratory flow [PEF], forced expiratory flow at 50% of forced vital capacity [FEFs0], forced expiratory flow at 75% of forced vital capacity, maximum mid-expiratory flow rate） and the concentrations of IL-4 and IL-6 in EBC were measured. Results： Both asthma scores and lung function parameters were significantly improved by ICS treatment. The mean IL-4 concentration in the EBC was decreased gradually, from 1.92 ± 0.56 pmol/L before treatment to 1.60 ± 0.36 pmolJL after 8 weeks of treatment （P 〈 0.05） and 1.54 ± 0.81 pmol/L after 12 weeks of treatment （P 〈 0.01）. However, the IL-6 concentration was not significantly decreased. The change in the IL-4 concentration was correlated with improvements in mean FEVt, PEF and FEFso values （correlation coefficients -0.468, -0.478, and -0.426, respectively）. Conclusions： The concentration of IL-4 in the EBC of asthmatic patients decreased gradually with ICS treatment. Measurement of IL-4 in EBC could be useful to monitor airway inflammation in asthmatics.

关键词： Asthma Exhaled Breath Condensate Inhaled Corticosteroids interleukin-4 interleukin-6

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Association between Promoter Polymorphisms of interleukin-4 Gene and Allergic Rhinitis Risk: a Meta-analysis

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2014年第3期34卷 306-313页

作者：李志鹏尹丽丽王慧刘立思 Department of Otorhinolaryngology-Head and Neck Surgery Tongji Hospital Tongji Medical College Huazhong University of Sci-ence and Technology

Summary： 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 soitvcare 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 aller- gic rhinitis.

关键词： interleukin-4 polymorphisms allergic rhinitis meta-analysis

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Interactions of thymic stromal lymphopoietin with interleukin-4 in adaptive immunity during Aspergillus fumigatus keratitis

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International Journal of Ophthalmology(English edition) 2021年第10期14卷 1473-1483页

作者： Chen Chen Chen-Yang Dai Fang Han Jia-Yin Wu Lin Sun Xin-Yi Wu Department of Ophthalmology Clinical Medical College of Shandong UniversityJinan 250012Shandong ProvinceChina Department of Ophthalmology Qilu Hospital of Shandong UniversityJinan 250012Shandong ProvinceChina Key Laboratory of Cardiovascular Remodeling and Function Research Shandong UniversityJinan 250012Shandong ProvinceChina

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.

关键词： Aspergillus fumigatus keratitis thymic stromal lymphopoietin Th2 immune response interleukin-4

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Effect of Ligustrazine Injection on Levels of interleukin-4 and Interferon-γin Patients with Bronchial Asthma

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Chinese Journal of Integrative Medicine 2008年第3期14卷 217-220页

作者：车晓文张颖王晖王伟 Department of Respiratory Medicine Second Hospital of Shandong University

Objective： To explore the effect of ligustrazine injection （LI） on serum levels of interleukin-4 （IL-4） and interferon- -γ （IFN- -γ ） in patients with bronchial asthma and determine the mechanism of action of LI in preventing and treating asthma. Methods： Sixty-eight patients with mild or moderate bronchial asthma were assigned to two groups equally according to their sequence number, odd or even. The conventional treatment was administered to both groups, and LI was given to the treatment group by ultrasonic spray inhalation twice a day but not to the control group. The therapeutic course for all was 2 weeks. Further, 30 healthy subjects who had no history of smoking were enrolled as the normal control group. The clinical condition scores, frequency of attacks and dosage of Terbutaline inhaled were scored and recorded on the first day of hospitalization （before treatment） and after treatment. At the same time, the indexes of lung function, including forced expiratory volume in one second （FEV1）, forced expiratory volume in one second to forced vital capacity ratio （FEV1%） and the peak expiratory flow （PEF） were determined before treatment. The levels of IL-4 and IFN--γ in peripheral blood were detected by ELISA before and after treatment, and compared with that of the healthy control group. Results： After treatment, the clinical condition scores were found to be lower, indexes of lung function were elevated, but serum level of IL-4 and ratio of IL-4/IFN-γwere reduced in both groups, showing significant differences as compared to those before treatment （P〈0.05）. However, the changes in all the indexes were more significant in the treatment group than in the control group, also showing statistical significance （P〈0.05）. No significant difference was revealed when IFN--γ levels were compared before and after treatment in both groups, though a lowering trend could be seen, significant difference could not be found in the comparison of IFN--γ levels between groups after treatment （P〉0.05）. Conclusion： LI shows good c

关键词： ligustrazine injection asthma lung function TH1/Th2 disequilibrium interleukin-4 interferon- -γ

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