Advances in research on IL-18 in the pathogenesis of allergic airway diseases / 西安交通大学学报(医学版)

The prevalence of allergic airway diseases has been increasing in recent years. Interleukin-18 (IL-18) plays an imperative role in allergic airway diseases by binding to IL-18Rα, thereby initiating the downstream proinflammatory pathway. IL-18 also binds to IL-18BP, thus inhibiting its binding to IL-18Rα. Therefore, further understanding of the role of IL-18 and its action mechanisms in allergic airway diseases is important for the treatment of allergic airway diseases, and for the development of IL-18-related biological agents.

A preliminary study on Candida albicans-induced pyroptosis of murine bone marrow-derived macrophages / 中华皮肤科杂志

Objective:To investigate the effect of Candida albicans ( C. albicans) on pyroptosis of murine bone marrow-derived macrophages (BMDMs) . Methods:Live-cell imaging was used to observe morphologic changes of in vitro C. albicans-infected BMDMs (multiplicity of infection [MOI] = 50) so as to evaluate whether pyroptosis occurred. Cultured BMDMs were divided into a control group and a C. albicans group, which were treated with phosphate-buffered saline and C. albicans suspensions respectively for 6 hours; then, real-time fluorescence-based quantitative PCR was performed to determine the mRNA expression of NOD-like receptor pyrin domain containing 3 (NLRP3), interleukin (IL) -1β and IL-18, and Western blot analysis to determine the protein expression and cleavage levels of NLRP3, caspase-1 and gasdermin D (GSDMD). BMDMs were cultured with C. albicans suspensions for different durations (0, 10, 15, 20, and 25 hours), and enzyme-linked immunosorbent assay was conducted to detect secretion levels of IL-1β and IL-18. Cultured wild-type BMDMs and GSDMD-knockout BMDMs were treated with C. albicans suspensions for 15 minutes, and then rates of phagocytosis of C. albicans by wild-type BMDMs and GSDMD-knockout BMDMs were estimated by flow cytometry; after 6-hour treatment with C. albicans, flow cytometry and lactate dehydrogenase (LDH) release assay were performed to assess mortality rates of wild-type BMDMs and GSDMD-knockout BMDMs. In addition, some wild-type BMDMs and GSDMD-knockout BMDMs were separately divided into blank control group, control group, maximum enzyme activity-sample control group, IL-1β alone group, C. albicans alone group, and IL-1β + C. albicans group, and cell mortality rates were detected by the LDH release assay after treatment with IL-1β and/or C. albicans. Statistical analysis was carried out by using unpaired t test, Kruskal-Wallis test, analysis of variance, and other statistical methods. Results:After in vitro treatment with C. albicans, swelling and ballooning with large bubbles blowing from the plasma membrane occurred in BMDMs, suggesting the occurrence of cell pyroptosis; compared with the control group, the C. albicans group showed significantly increased mRNA expression levels of NLRP3 and IL-1β after 6-hour treatment with C. albicans ( t = 13.02, 17.51, respectively, P = or < 0.001), but no significant change in the IL-18 mRNA expression level ( P = 0.486), and Western blot analysis showed that C. albicans could increase the expression of NLRP3 inflammasomes, as well as cleaved caspase-1 and GSDMD. After the treatment with C. albicans for different durations (0, 10, 15, 20, and 25 hours), the secretion level of IL-1β by BMDMs gradually increased over time ( H = 12.90, P = 0.012), while the secretion level of IL-18 did not significantly change ( F = 0.48, P = 0.753), and the secretion level of IL-1β was significantly lower in the GSDMD-knockout BMDM group than in the wild-type BMDM group ( F = 24.22, P = 0.008). After 15-minute in vitro treatment with C. albicans, the phagocytosis rate of C. albicans was significantly lower in the GSDMD-knockout BMDM group (50.3% ± 1.10%) than in the wild-type BMDM group (58.53% ± 1.19%, t = 5.09, P = 0.007) ; after 6-hour treatment with C. albicans, the cell mortality rate was significantly higher in the GSDMD-knockout BMDM group than in the wild-type BMDM group (flow cytometry: 38.40% ± 0.50% vs. 34.37% ± 0.52%, t = 4.72, P = 0.009; LDH release assay: 22.52% ± 0.18% vs. 12.48% ± 0.15%, t = 42.36, P < 0.001) ; the cell mortality rates of wild-type BMDMs and GSDMD-knockout BMDMs both significantly decreased in the IL-1β + C. albicans groups compared with the C. albicans groups (both P < 0.001) . Conclusion:Pyroptosis could be induced in murine BMDMs after C. albicans infection, which promotes the release of IL-1β and may reduce the mortality rate of macrophages by improving their immune activity.

Effects of aerosol therapy with budesonide suspension combined with compound ipratropium bromide on partial pressure of carbon dioxide and tumor necrosis factor α in children with bronchiolitis / 中国基层医药

Objective:To investigate the effects of aerosol therapy with budesonide suspension combined with compound ipratropium bromide on partial pressure of carbon dioxide (PaCO 2) and tumor necrosis factor α (TNF-α) in children with bronchiolitis. Methods:A total of 124 children with bronchiolitis admitted to Gujiao Central Hospital from January 2019 to December 2021 were included in this study. These children were randomly divided into two groups using the coin-tossing method. The control group ( n = 62) was treated with routine symptomatic treatment, and the study group ( n = 62) was treated with aerosol therapy of budesonide suspension combined with compound ipratropium bromide based on routine symptomatic treatment. The time at which clinical symptoms disappear, clinical efficacy, inflammatory reaction, and blood gas index were determined in each group. Results:After treatment, the time at which asthma, cough, pulmonary rales, and fever in the study group were (2.28 ± 0.71) days, (3.30 ± 0.82) days, (5.25 ± 1.03) days, and (19.01 ± 2.65) hours, respectively, which were significantly shorter than (2.71 ± 0.89) days, (3.81 ± 0.98) days, (5.72 ± 1.37) days, and (20.76 ± 3.12) hours in the control group ( t = 2.97, 3.14, 2.15, 3.36, all P < 0.05). Total response rate and PaO 2 in the study group were 91.94% and (83.94 ± 4.02) mmHg, respectively, which were significantly higher than 77.42% and (81.25 ± 5.53) mmHg in the control group ( χ2 = 5.03, t = 3.09, both P < 0.05). Interleukin-18, interleukin-33, TNF-α, and PaCO 2 in the study group were (141.03 ± 34.69) ng/L, (143.87 ± 38.43) ng/L, (75.49 ± 18.43) ng/L, and (41.85 ± 3.31) mmHg, respectively, which were significantly lower than (158.64 ± 47.92) ng/L, (162.75 ± 50.32) ng/L, (83.22 ± 21.75) ng/L, and (43.58 ± 4.46) mmHg in the control group ( t = -2.34, -2.34, -3.23, -2.45, all P < 0.05). Conclusion:Aerosol therapy with budesonide suspension combined with compound ipratropium bromide based on routine symptomatic treatment is more effective on bronchiolitis than routine symptomatic treatment alone. The combined therapy can effectively decrease PaCO 2 and TNF-α levels.

Preliminary study of the role of IL-18/IL-18BP in mediating cytotoxic ability of NK-92MI cells against endothelial cells from GTKO porcine models / 器官移植

Objective To evaluate the role and potential mechanism of interleukin (IL)-18/IL-18 binding protein (BP) in mediating the killing effect of natural killer (NK)-92MI cells upon endothelial cells from α-1, 3- galactosyltransferase gene-knockout (GTKO) porcine models. Methods NK-92MI cells were divided into the NK, NK+IL-18, NK+GTKO, IL-18+NK+GTKO and IL-18+IL-18BP+NK+GTKO groups. The messenger ribonucleic acid (mRNA) levels of inflammation-related genes in NK-92MI cells were detected by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The killing effect of NK-92MI cells on endothelial cells from GTKO porcine models was evaluated by lactate dehydrogenase (LDH) assay. The apoptosis of endothelial cells from GTKO porcine models was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. The expression levels of proteins with killing effect and apoptosis-related proteins were determined by Western blot. Results Compared with the NK, NK+IL-18 and NK+GTKO groups, the expression levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-8, IL-3, IL-6 and granulocyte-macrophage colony stimulating factor (GM-CSF) mRNA were up-regulated in NK-92MI cells in the IL-18+NK+GTKO group, and the differences were statistically significant (all P < 0.05). Compared with the IL-18+NK+GTKO group, the expression levels of IFN-γ, TNF-α, IL-8, IL-3, IL-6 and GM-CSF mRNA were down-regulated in NK-92MI cells in the IL-18+IL-18BP+NK+GTKO group, and the differences were statistically significant (all P < 0.05). Compared with the NK+GTKO group, the expression levels of perforin, granzyme B and IFN-γ proteins in NK-92MI cells were up-regulated, the killing rate of NK-92MI cells against endothelial cells from GTKO porcine models was enhanced, the apoptosis rate of endothelial cells from GTKO porcine models was increased, and the ratios of B cell lymphoma-2 (Bcl-2)-associated X protein (Bax)/Bcl-2 and cleaved Caspase-3/Caspase-3 in endothelial cells from GTKO porcine models were elevated in the IL-18+NK+GTKO group, and the differences were statistically significant (all P < 0.05). Compared with the IL-18+NK+GTKO group, the expression levels of perforin, granzyme B and IFN-γ proteins were down-regulated, the killing rate of NK-92MI cells against endothelial cells from GTKO porcine models was decreased, the apoptosis rate of endothelial cells from GTKO porcine models was decreased, and the ratios of Bax/Bcl-2 and cleaved Caspase-3/Caspase-3 in endothelial cells from GTKO porcine models were declined in the IL-18+IL-18BP+NK+GTKO group, and the differences were statistically significant (all P < 0.05). Conclusions IL-18BP may block the expression of inflammation-related genes in NK-92MI cells induced by IL-18 and the killing effect of NK-92MI cells on endothelial cells from GTKO porcine models.

Long Noncoding RNA AF131217.1 Regulated Coronary Slow Flow-Induced Inflammation Affecting Coronary Slow Flow via KLF4

Abstract Introduction: This study investigated the correlation between the levels of long noncoding ribonucleic acids (lncRNAs) AF131217.1 and coronary slow flow (CSF). Methods: A total of 22 patients in the high-sensitivity C-reactive protein (hsCRP) group diagnosed with CSF from January 2018 to December 2018 were enrolled in this study. Coronary flow velocity was determined using the thrombolysis in myocardial infarction frame count (TFC) method. Results: LncRNA AF131217.1 expression in the CSF model was activated. Mean TFC was positively correlated with lncRNA AF131217.1 levels and hsCRP levels. LncRNA AF131217.1 induced inflammation factor levels in the in vitro model. Micro ribonucleic acid (miR)-128-3p is a target spot of lncRNA AF131217.1 on the inflammation in vitro model via Kruppel-like factor (KLF) 4. MiR-128-3p reduced inflammation factor levels (tumor necrosis factor alpha, interleukin [IL]-6, IL-1β, and IL-18). Conclusion: Thus, lncRNA AF131217.1 promoted inflammation in the regulated CSF via KLF4 by miR-128-3p.

Elevated levels of interleukin-18 are associated with several indices of general and visceral adiposity and insulin resistance in women with polycystic ovary syndrome

ABSTRACT Objective: Our aim was to analyze levels of proinflammatory biomarker interleukin-18 (IL-18) in healthy controls and patients with polycystic ovary syndrome (PCOS) focusing on its association with obesity, clinical, hormonal, and metabolic characteristics. Subjects and methods: Fifty-eight patients with PCOS were enrolled in the study fulfilling the Rotterdam criteria and were matched for age, body mass index (BMI), and ethnicity with 30 healthy controls. Detailed anthropometric measurements, clinical investigations, hormonal and biochemical tests were obtained between the 3rd and 5th day of a menstrual cycle. A subanalysis of the PCOS group was performed separating patients into several groups according to a waist-to-height ratio (WHtR), insulin resistance (IR), and free androgen index (FAI). Serum IL-18 levels were measured using the ELISA method. Results: Levels of IL-18 were similar between PCOS patients and controls. IL-18 was higher in overweight/obese women compared to normal-weight women when analyzing all participants together and separately PCOS or controls group (p < 0.001, p < 0.001, p = 0.01, respectively). Additionally, IL-18 levels were higher in high-WHtR and IR subgroups compared to low-WHtR (p < 0.001) and non-IR PCOS women (p < 0.001). PCOS women with high FAI had greater serum IL-18 levels than normal-FAI patients (p = 0.002). Levels of IL-18 correlated positively with most of the anthropometric and metabolic parameters. In multiple linear regression, age, waist circumference, and fasting insulin were independently related factors with IL-18. Conclusion: Elevated levels of IL-18 were related to several indices of general and visceral adiposity and insulin resistance in PCOS.

Interventional effect of asiaticosdide on rats exposed to silica dust / 中华劳动卫生职业病杂志

Objective: To investigate the effect of asiaticoside for fibrosis in lung tissues of rats exposed to silica and to explore its possible mechanism. Methods: 144 SD male rats were randomly divided into control group, model group, positive drug control group, asiaticoside high-dose group, medium-dose group and low-dose group, each group included 24 rats. Rats in the control group were perfused with 1.0 ml of normal saline, and the other groups were given 1.0 ml 50 mg/ml SiO(2) suspension. Gavage of herbal was given from the next day after model establishment, once a day. Rats in the positive drug control group were administration with 30 mg/kg tetrandrine and rats in the low-dose group, medium-dose group and high-dose group were given 20 mg/kg, 40 mg/kg and 60 mg/kg asiaticoside for fibrosis respectively. Rats in the control group and the model group were given 0.9% normal saline. The rats were sacrificed in on the 14th, 28th and 56th day after intragastric administration and collect the lung tissues to detect the content of hydroxyproline, TGF-β(1) and IL-18, observe the pathological changes of the lung tissues by HE and Masson staining and determine the expressions of Col-I, a-SMA, TGF-β in lung tissues by Western Blot. Results: On the 14th day, 28th day and 56th day after model establishment, the lung tissues of rats in the model group showed obvious inflammatory response and accumulation of collagen fibers, and the degree of inflammation and fibrosis increased with time. The intervention of asiaticoside could effectively inhibit the pathological changes of lung tissues. The contents of hydroxyproline, IL-18 and TGF-β1 in lung tissues of model group were higher than those in the control group (P<0.05) , while the level of hydroxyproline, IL-18 and TGF-β1 in asiaticoside groups were significantly decreased, and the difference was statistically signicant (P<0.05) . Compared with the control group, the expression levels of Col-I, TGF-β1and α-SMA in lung tissue of model group were increased (P<0.05) , while the expression level of Col-I, TGF-β1 and α-SMA were decreased after the intervention of asiaticoside, and the difference was statistically signicant (P<0.05) . Conclusion: Asiaticoside can inhibit the increase of Col-I, TGF-β1 and α-SMA content in the SiO(2)-induced lung tissues of rats, reduce the release of TGF-β1 and IL-18 inflammatory factors in lung tissue, and then inhibit the synthesis and deposition of extracellular matrix in rat lung tissue, and improve silicosis fibrosis.

High glucose promotes the release of IL-1β and IL-18 from placental trophoblast by activating NLRP3 inflammasome / 中华内分泌代谢杂志

Objective:To investigate the effect of high glucose on the release of interleukin (IL)-1β and IL-18 in placental trophoblast by activating NLRP3 inflammasome.Methods:Gestational diabetes mellitus(GDM) placentas and control placentas were collected and the expression levels of NLRP3 and Caspase-1 were determined. Human placental trophoblast HTR-8/SVneo were cultured and divided into control group(5.5 mmol/L glucose), high glucose group(25 mmol/L glucose), DMSO+ high glucose group, and Ac-YVAD-cmk(NLRP3 inflammasome inhibitor)+ high glucose group. The expression levels of NLRP3 and Caspase-1 in cells as well as the contents of IL-1β and IL-18 in the medium were determined.Results:The expression levels of NLRP3 and Caspase-1 in GDM placenta were higher than those in control placenta( P<0.05) and positively correlated with homeostasis model assessment of insulin resistant index(HOMA-IR) and fasting insulin. The expression levels of NLRP3 and Caspase-1 in HTR-8/SVneo cells and the secretion levels of IL-1β and IL-18 in high glucose group were higher than those in control group( P<0.05). Ac-YVAD-cmk significantly suppressed high glucose-stimulated IL-1β and IL-18 secretion( P<0.05). Conclusion:High glucose promotes the release of IL-1β and IL-18 from placental trophoblast via activating NLRP3 inflammasome.

Clinical significance of combined detection of serum immunoglobulin and interleukin-18 in patients with viral hepatitis B / 中国基层医药

Objective:To detect serum immunoglobulin and interleukin-18 (IL-18) levels in patients with viral hepatitis B and investigate the clinical significance of combined detection of serum immunoglobulin and IL-18 levels.Methods:A total of 102 patients with viral hepatitis B who received treatment in Jinan 2 nd People's Hospital from September 2019 to September 2020 were included in the observation group. An additional 99 patients who concurrently underwent physical examination were included in the control group. Serum immunoglobulin and IL-18 levels were detected in each group and they were compared between the two groups. Changes in serum immunoglobulin and IL-18 levels detected after treatment relative to before treatment were analyzed in the observation group. Results:Serum levels of immunoglobulin A, immunoglobulin G, immunoglobulin M, and IL-18 in the observation group were (2.68 ± 0.74) g/L, (15.24 ± 4.17) g/L, (2.59 ± 1.03) g/L, (2.53 ± 0.21) ng/mL, respectively, which were significantly higher than those in the control group [(1.76 ± 0.63) g/L, (11.58 ± 3.46) g/L, (1.38 ± 0.49) g/L, (1.68 ± 0.34) g/L, respectively, t = 9.45, 6.74, 10.54, 21.36, all P < 0.01). In the observation group, serum levels of immunoglobulin A, immunoglobulin G, immunoglobulin M, and IL-18 were (2.03 ± 0.51) g/L, (13.12 ± 3.25) g/L, (1.93 ± 0.47) g/L, (1.74 ± 0.15) μg/L after treatment, which were significantly lower than those before the treatment [(2.68 ± 0.74) g/L, (15.24 ± 4.17) g/L, (2.59 ± 1.03) g/L, (2.53 ± 0.21) μg/L , t = 7.26, 4.02, 10.54, 5.87, all P < 0.01). Conclusion:Serum immunoglobulin and IL-18 levels in combination can reflect the condition of viral hepatitis B patients and provide scientific reference for clinical treatment. The research results are scientific and innovative and are worthy of promotion.

NLRP3 inflammasome and its role in age-related macular degeneration / 中华实验眼科杂志

Age-related macular degeneration (AMD), the leading cause of central vision loss among people aged 50 years and older, is one of the major eye diseases causing blindness in the world.Clinically, advanced AMD is divided into two types, non-exudative AMD with manifestation of geographic atrophy and exudative AMD with manifestation of choroidal neovascularization.The pathogenesis of AMD is complex, and the para-inflammation is recognized as an important risk factor.Nucleotide-binding oligomerization domain like receptors 3 (NLRP3) inflammasome is a cytoplasmic pattern recognition receptor and is expressed in several kings of cells, including retinal pigment epithelium (RPE) cells, microglial cells, Müller glia cells and retinal vascular endothelial cells.Recent studies have suggested that NLRP3 inflammasome plays an important role in the pathophysiology of both non-exudative and exudative AMD.The role of the NLRP3 inflammasome and its effector cytokines interleukin (IL)-1β and IL-18 in AMD were reviewed in this article to provide guidance on future prevention and therapy of AMD.

Value of urine IL-8, NGAL and KIM-1 for the early diagnosis of acute kidney injury in patients with ureteroscopic lithotripsy related urosepsis / 中华创伤杂志(英文版)

PURPOSE@#To investigate the clinical value of urine interleukin-18 (IL-8), neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) for the early diagnosis of acute kidney injury (AKI) in patients with ureteroscopic lithotripsy (URL) related urosepsis.@*METHODS@#A retrospective study was carried out in 157 patients with urosepsis after URL. The patients were divided into AKI group and non-AKI group according to the Kidigo guideline and urine IL-8, NGAL and KIM-1 levels were detected by enzyme-linked immunosorbent assay at 0, 4, 12, 24 and 48 h after the surgery. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic value of these three biomarkers for postoperative AKI.@*RESULTS@#The level of urine IL-8, NGAL and KIM-1 in AKI group was significantly higher than that in non-AKI group at 4, 12, 24 and 48 h (p < 0.01). The ROC analysis showed the combined detection of urine IL-8, NGAL and KIM-1 at 12 h had a larger area under curve (AUC) than a single marker (0.997, 95% CI: 0.991-0.998), and the sensitivity and specificity were 98.2% and 96.7%, respectively. Pearson correlation analysis showed that the levels of urine NGAL at 4, 12, 24 and 48 h in AKI patients were positively correlated with the levels of urine KIM-1 and IL-18 (p < 0.01).@*CONCLUSION@#AKI could be quickly recognized by the elevated level of urine IL-8, NGAL and KIM-1 in patients with URL-related urosepsis. Combined detection of the three urine biomarkers at 12 h after surgery had a better diagnostic performance, which may be an important reference for the early diagnosis of AKI.

Effects and significance of continuous hemoperfusion on patients with diquat poisoning / 中华危重病急救医学

Objective:To investigate the effect of continuous hemoperfusion (HP) on the levels of soluble CD14 isoform (sCD14-st) and neutrophil gelatinase-associated lipocalin (NGAL) on patients with diquat (DQ) poisoning and its significance.Methods:A total of 86 patients with acute DQ poisoning admitted to the department of emergency medicine, Harrison International Peace Hospital Affiliated to Hebei Medical University from May 2018 to August 2021 were enrolled and divided into the intermittent HP group (40 cases) and the continuous HP group (46 cases) according to the random number table method. All patients received basic treatment and continuous veno-venous hemofiltration (CVVH) within 24 hours after admission. On this basis, the intermittent HP group received HP treatment within 2 hours, lasting 2 hours each time for every 8 hours, 3 times in all; the continuous HP group received continued HP treatment until there was no DQ component in urine samples. Serum NGAL levels were detected in all patients before treatment and at 3 hours, 12 hours, 24 hours, 2 days, 3 days, 5 days, and 7 days after treatment. At the same time, serum sCD14-st, blood lactate (Lac), arterial partial pressure of oxygen (PaO 2), serum creatinine (SCr), MB isoenzyme of creatine kinase (CK-MB) and interleukin-18 (IL-18) levels were detected before treatment and at 24 hours, 3 days, and 7 days after treatment. Kaplan-Meier survival curve was drawn to analyze the 28-day survival of patients. Results:Before treatment, there was no significant difference in serum NGAL, sCD14-st, Lac, PaO 2, SCr, CK-MB and IL-18 levels between the two groups. With the prolongation of treatment, the serum levels of NGAL, sCD14-st, Lac, SCr, CK-MB and IL-18 in the intermittent HP group increased at first and then decreased. Serum levels of NGAL, sCD14-st, CK-MB and IL-18 reached their peaks at 24 hours after treatment, and the Lac and SCr levels reached their peaks at 3 days after treatment. In addition, the levels of the above indexes at each time point in the continuous HP group were all significantly lower than those in the intermittent HP group [after 24 hours of treatment: NGAL (μg/L) was 345.90±30.75 vs. 404.24±38.79, sCD14-st (ng/L) was 1 941.88±298.02 vs. 2 656.35±347.93, CK-MB (U/L) was 30.67±9.11 vs. 43.28±8.06, IL-18 (ng/L) was 139.49±16.29 vs. 177.98±27.85; 3 days of treatment: Lac (mmol/L) was 2.98±0.26 vs. 3.72±0.49, SCr (μmol/L) was 125.01±24.24 vs. 156.74±28.88; all P < 0.05]. However, there was no significant difference in PaO 2 levels between the two groups at each time point after treatment. The Kaplan-Meier survival curve showed that the 28-day mortality of patients in the continuous HP group was significantly lower than that in the intermittent HP group [26.09% (12/46) vs. 52.50% (21/40); Log-Rank test: χ2 = 7.288, P = 0.007]. Conclusion:Continuous HP could effectively reduce serum sCD14-st, NGAL levels and 28-day mortality in patients with DQ poisoning, with good curative effect.

Regulatory effect of interleukin-18 on natural killer cell activity in patients with alopecia areata / 中华皮肤科杂志

Objective:To investigate changes of natural killer (NK) cell subsets and interleukin-18 (IL-18) level in peripheral blood of patients with alopecia areata, and to assess the regulatory effect of IL-18 on NK cell activity.Methods:A total of 67 patients with alopecia areata (alopecia areata group) and 25 healthy volunteers (control group) were collected from Shanxi Provincial People′s Hospital between December 2019 and January 2021. Peripheral blood mononuclear cells (PBMCs) and plasma were isolated. The percentage of NK cell subsets was investigated by flow cytometry, and plasma IL-18 level was measured by enzyme-linked immunosorbent assay. PBMCs were stimulated with recombinant human IL-18, and co-culture systems of PBMCs with 721.221 cells, K562 cells and P815-Ab cells were established separately. NK cell function was assessed by determining the percentage of CD107a-expressing NK cells and fluorescence intensity of CD16 + NK cells. Comparisons between groups were performed using t test or paired t test. Results:Compared with the control group, the alopecia areata group showed significantly decreased percentage of CD56 +CD16 - NK cells (8.12% ± 3.14% vs. 10.78% ± 4.08%, t = 3.33, P = 0.001) , but significantly increased percentage of CD56 +CD16 + NK cells (46.08% ± 15.21% vs. 32.14% ± 10.45%, t = 4.22, P < 0.001) , and there was no significant difference in the percentage of CD56 -CD16 + NK cells between the alopecia areata group and control group (28.81% ± 8.65% vs. 27.09% ± 7.62%, t = 0.88, P = 0.383) . The plasma IL-18 level was significantly higher in the alopecia areata group than in the control group (112.0 ± 23.72 pg/ml vs. 99.34 ± 15.15 pg/ml, t = 2.48, P = 0.015) . After co-culture with 721.221 cells, K562 cells and P815-Ab cells, the percentage of CD107a-expressing NK cells was significantly higher in NK cells from the alopecia areata group (9.53% ± 1.70%, 5.15% ± 1.35%, 6.50% ± 1.64%, respectively) than in those from the control group (5.00% ± 1.17%, 4.40% ± 1.09%, 5.13% ± 1.36%, respectively, all P < 0.05) . After the stimulation with P815-Ab cells, the alopecia areata group showed significantly decreased fluorescence intensity of CD16 + NK cells (151.10% ± 59.30%) compared with the control group (221.90% ± 93.56%, t = 4.31, P < 0.001) . After IL-18 stimulation, the percentage of CD107a-expressing NK cells significantly increased in the co-culture system of NK cells with 721.221 cells compared with the unstimulated co-culture system (14.47% ± 2.67% vs. 9.93% ± 1.94%, t = 6.00, P < 0.001) , while there was no significant difference between the IL-8-stimulated co-culture system of NK cells with K562 cells or P815-Ab cells and the unstimulated co-culture systems (both P > 0.05) . Conclusion:IL-18 could enhance NK cell activity in patients with alopecia areata, likely by promoting natural cytotoxicity receptor-mediated cytotoxicity.

Investigation of serum vaspin, visfatin, chemerin and IL-18 levels in migraine patients / Investigação dos níveis séricos de vaspina, visfatina, quemerina e IL-18 em pacientes com migrânea

Abstract Background: Migraines are headaches caused by changes in the trigeminovascular metabolic pathway. Migraine headache attacks are associated with neurovascular inflammation, but their pathophysiological mechanisms have not been fully explained. Objective: To investigate the relationship between serum vaspin, visfatin, chemerin and interleukin-18 (IL-18) levels and the frequency of attacks in migraine headache. Methods: Three groups were established: migraine with aura (n = 50), migraine without aura (n = 50) and control group (n = 50). The migraine diagnosis was made in accordance with the International Classification of Headache Disorders-III beta diagnostic criteria. The analyses on serum vaspin, visfatin, chemerin and IL-18 levels were performed using the enzyme-linked immunosorbent assay method. Results: The serum vaspin, visfatin, chemerin and IL-18 levels were found to be significantly higher in the migraine patients than in the control group (p < 0.01). No statistically significant differences in serum vaspin, visfatin, chemerin and IL-18 levels were found among the migraine patients during attacks or in the interictal period (p>0.05). The serum visfatin and chemerin levels of the migraine patients were positively correlated with their serum IL-18 levels (p < 0.01), while their serum chemerin and visfatin levels were positively correlated with their serum vaspin levels (p < 0.05). Conclusions: This study showed that these biomarkers may be related to migraine pathogenesis. Nonetheless, we believe that more comprehensive studies are needed in order to further understand the role of vaspin, visfatin, chemerin and IL-18 levels in the pathophysiology of migraine headaches.

Resumo Introdução: A migrânea é causada por alterações nas vias metabólicas do sistema trigeminovascular. Crises de migrânea estão associadas à inflamação neurovascular, mas seus mecanismos patofisiológicos ainda não são totalmente explicados. Objetivo: Investigar a relação entre níveis séricos de vaspina, visfatina, quemerina e interleucina-18 (IL-18) e a frequência de crises de migrânea. Métodos: Três grupos foram formados: migrânea com aura (n = 50), migrânea sem aura (n = 50) e grupo controle (n = 50). A migrânea foi diagnosticada de acordo com os critérios da Classificação Internacional das Cefaleias (ICHD-III). As análises dos níveis séricos de vaspina, visfatina, quemerina e IL-18 foram realizadas utilizando-se o método imunoenzimático (ELISA). Resultados: Os níveis séricos de vaspina, visfatina, quemerina e interleucina-18 (IL-18) foram significativamente mais elevados em pacientes com migrânea do que no grupo controle (p < 0.01). Nenhuma diferença estatisticamente significativa foi observada nos níveis séricos de vaspina, visfatina, quemerina e interleucina-18 (IL-18) entre os pacientes com migrânea durante crises ou no período interictal (p>0,05). Os níveis séricos de visfatina e quemerina em pacientes com migrânea se correlacionaram positivamente com os níveis séricos de IL-18 (p < 0,01), ao passo que os níveis séricos de quemerina e visfatina se correlacionaram positivamente com os níveis séricos de vaspina (p < 0,05). Conclusões: Este estudo demonstrou que estes biomarcadores podem estar relacionados à patogênese da migrânea. Contudo, acreditamos que estudos mais abrangentes são necessários a fim de melhor compreendermos o papel dos níveis de vaspina, visfatina, quemerina e IL-18 na fisiopatologia da migrânea.

Análise clínico-patológica e qualitativa da expressão de mediadores inflamatórios teciduais no líquen plano oral / Clinicopathological and qualitative analysis of the expression of tissue inflammatory mediators in oral lichen planus

O líquen plano oral (LPO) é uma condição imuno-inflamatória mucocutânea crônica que ainda possui etiologia e patogênese desconhecidas. Estudos mostrando a participação de citocinas no LPO, em especial, interleucinas (IL)-6, IL-17 e IL-18, são escassos, assim como a correlação das características clínicas e histológicas das lesões de LPO com a presença destes mediadores inflamatórios. Todas as lesões de LPO e de lesões liquenoides orais (LLO) foram revisadas a partir do arquivo do laboratório de Patologia Bucal da Faculdade de Odontologia da Universidade do Estado do Rio de Janeiro e as características clínico-patológicas dos casos foram analisadas. Foram selecionados 40 casos de LPO para realização adicional de reações imuno-histoquímicas para IL-6, IL-17 e IL-18. A amostra total foi composta por 221 casos e mostrou que o LPO apresentou predileção por mulheres adultas, mais frequentemente acometidas pelo padrão reticular e com lesões localizadas predominantemente na mucosa jugal. Os 40 casos selecionados para a avaliação imuno-histoquímica incluíram pacientes com média de idade de 53 anos, sem predileção por gênero, e com lesões localizadas preferencialmente na mucosa jugal (85%), na gengiva/mucosa alveolar (47%) e na língua (42%). Quanto ao padrão clínico, 14 pacientes (35%) mostravam lesões exclusivamente reticulares e 26 (65%) mostravam lesões reticulares associadas a lesões atrófico-erosivas. Sintomas foram relatados por 53% dos pacientes e incluíram principalmente ardência e desconforto local. A análise histológica mostrou que o epitélio das lesões mostrava espessura normal, atrófica ou hiperplásica em, respectivamente, 17 (43%), 9 (22%) e 14 (35%) casos. A presença de hiperqueratose foi observada em 21 casos (53%) e exocitose de linfócitos T CD4+ e T CD8+ estava presente em, respectivamente, 17 (42%) e 30 (75%) casos. A análise imuno-histoquímica revelou que a IL-6 foi, de forma geral, a mais expressa, tanto no epitélio, quanto no conjuntivo. A expressão de IL-17 se mostrou intensa no tecido conjuntivo, em 40% dos casos. A IL-18 mostrou intensidade mais frequente leve/moderada tanto no epitélio (40%), quanto no tecido conjuntivo (45%). A presença de exocitose mostrou relação com a maior expressão das ILs e a expressão de IL-17 foi maior no epitélio mostrando hiperqueratose. Os resultados do presente estudo mostraram que as características clínicas das lesões de LPO e de LLO são distintas e podem ser utilizadas para diferenciação entre as duas entidades. Os achados histológicos e imunohistoquímicos sugerem que as ILs estudadas mostram-se mais presentes quando há exocitose linfócitos T CD4+ e T CD8+ e que sua expressão pode ter relação com as alterações epiteliais encontradas no LPO, participando da patogênese e da modulação da expressão da doença.

Oral lichen planus (OLP) is a chronic immunoinflammatory mucocutaneous condition of unknown etiology and pathogenesis. Studies focusing on the presence of cytokines in OLP, especially interleukin (IL)-6, IL-17 and IL-18, are scarce, as well as the correlation of clinical and histological characteristics with the presence of inflammatory mediators. All lesions diagnosed as OLP and oral lichenoid lesions (OLL) were reviewed from the files of the Oral Pathology laboratory, Dental School, Rio de Janeiro State University, and their clinicopathological characteristics were analyzed. Forty cases diagnosed as OLP were selected for additional immunohistochemical reactions directed against IL-6, IL-17 e IL-18. The total sample was composed by 221 cases and showed that OLP presented a predilection for adult females, mostly affected by lesions with the reticular pattern and located in the buccal mucosa. The 40 cases selected for the immunohistochemical reactions included patients with a mean age of 53 years, with no gender predilection, and with lesions located mostly in the buccal mucosa (85%), gingiva/alveolar mucosa (47%) and tongue (42%). The clinical pattern showed reticular lesions in 14 patients (35%) and reticular and atrophic/erosive lesions in 26 patients (65%). Symptoms were reported by 53% of the patients and included mostly burning sensation and local discomfort. Histological analysis showed that the epithelial thickness was normal, atrophic, or hyperplastic in, respectively, 17 (43%), 9 (22%) and 14 (35%) cases. The presence of hyperkeratosis was observed in 21 cases (53%), and exocytosis of T CD4+ and T CD8+ lymphocytes was present in, respectively, 17 (42%) and 30 (75%) cases. Immunohistochemical analysis showed that, in general, IL-6 was the most expressed IL both in epithelium and connective tissue. IL-17 expression was considered intense in the connective tissue from 40% of the cases. IL-18 expression was considered mostly mild/moderate both in epithelium (40% of the cases) and connective tissue (45% of the cases). The presence of exocytosis was associated with a higher expression of the ILs and expression of IL-17 was higher in epithelium showing hyperkeratosis. The results from the present study showed that the clinical characteristics of OLP and OLL are distinct and can be useful in differentiating these two diagnostic entities. The histological and immunohistochemical features suggest that the studied ILs are more expressed when there is exocytosis of both T CD4+ and T CD8+ lymphocytes. Expression of the ILs can be associated with the epithelial alterations encountered in OLP, participating in the pathogenesis and modulating the expression of the disease.

Interleukin-18 and post-stroke depression / 国际脑血管病杂志

Post-stroke depression (PSD) can seriously affect the outcome and quality of life of patients with stroke. However, due to the lower diagnostic rate, a large number of patients with PSD have not been treated in time and have a poor outcome. Therefore, only early detection, early diagnosis and early treatment of PSD can improve the prognosis and quality of life of patients with stroke. In recent years, a large number of studies on serum biomarkers have tried to find objective indicators related to PSD. Among them, interleukin-18 is associated with the pathogenesis of stroke and PSD, which may be attributed to its polymorphism and constitutive expression in the brain, especially the role of serum level changes in the risk stratification and outcome of acute ischemic stroke. This article reviews the role of interleukin-18 in the pathogenesis of PSD.

Research progress on the correlation between interleukin-18 and chronic periodontitis / 口腔疾病防治

@#Chronic periodontitis is an infectious disease caused by plaque as the initiating factor. Clinically, it manifests as irreversible loss of hard tissue, leading to the destruction of surrounding periodontal tissue, including the deep periodontal pocket, loss of attachment, and finally, tooth loss. Interleukin-18 (IL-18) can promote inflammation and regulate immune function and plays an important role in mediating the host immune response and inflammatory response. An increase in IL-18 in vivo can induce the production of interferon and inflammatory factors, such as interleukin, tumor necrosis factor and matrix metalloproteinase, thus mediating the dual reaction of immunity and inflammation. These inflammatory factors are involved in the occurrence and development of chronic periodontitis. Many clinical studies have shown that the levels of IL-18 in serum, saliva, gingival crevicular fluid and gingival tissue samples of patients with chronic periodontitis may be positively correlated with the severity of periodontitis; however, as a candidate gene, IL-18 is involved in the susceptibility polymorphism of periodontitis. Understanding how to quantify the level of IL-18 in clinical studies and apply it to diagnostic tools and new sites identified by new methods (genome-wide association studies and omics research) will also deepen our understanding of the pathogenesis of IL-18 in chronic periodontitis and provide new ideas for future precision medicine and the formulation of personalized programs. In this paper, the structure, biological function and association between IL-18 and periodontitis are reviewed.

Clinical application of biomarkers in DCD donor kidney perfusate for predicting delayed graft function after renal transplantation / 器官移植

Objective To explore the feasibility of biomarkers in static cold storage (SCS) perfusate of donor kidney from donation after cardiac death (DCD) for predicting delayed graft function (DGF) after renal transplantation. Methods Clinical data of 64 recipients and 47 donors undergoing DCD renal transplantation were retrospectively analyzed. All recipients were divided into the DGF group (n=7) and immediate graft function (IGF) group (n=57) according to the incidence of postoperative DGF in the recipients. The levels of neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), interleukin -18(IL-18) and kidney injury molecule-1 (KIM-1) in the SCS perfusate were statistically compared between two groups, and the correlation with DGF was analyzed. The predictive value of each biomarker in the occurrence of DGF in recipients after renal transplantation was analyzed. Results The incidence of DGF in the recipients undergoing DCD renal transplantation was 11% (7/64). The NGAL level in the donor kidney perfusate of the DGF group was significantly higher than that in the IGF group (P=0.009). The NGAL level in the donor kidney perfusate was positively correlated with the incidence of DGF in recipients after renal transplantation (r=0.430, P < 0.001). The receiver operating characteristic (ROC) curve analysis showed that the increased levels of NGAL and KIM-1 in the perfusate yielded certain predictive value for DGF in recipients after renal transplantation (both P < 0.05). The area under the curve (AUC) of combined detection of NGAL and KIM-1 for predicting DGF in recipients after renal transplantation was 0.932 [95% confidence interval (CI) 0.850-1.000]. The sensitivity was calculated as 1.000 and 0.754 for the specificity (P < 0.05). Conclusions The NGAL level in the SCS perfusate of DCD donor kidney is associated with the occurrence of DGF in recipients after renal transplantation. Combined detection of NGAL and KIM-1 levels in the perfusate may accurately predict the occurrence of DGF in recipients after renal transplantation.

Significance of expression of AIM2, IL / 中南大学学报(医学版)

OBJECTIVES@#Inflammation especially the overexpression of inflammasome and inflammatory cytokines, is one of the important reasons that affect the occurrence and development of acute cerebral infarction, including the initiation of cerebral infarction, the progress and recovery of post-infarction injury. This study aims to explore expressions of absent in melanoma 2 (AIM2), interleukin-1β (IL-1β), and interleukin-18 (IL-18) in plasma of patients with acute cerebral infarction and its significance.@*METHODS@#A total of 85 patients with acute cerebral infarction were enrolled in the cerebral infarction group. They were assigned into mild, moderate, and severe groups according to the severity of neurological deficits. They were assigned into small, middle, and large cerebral infarction groups according to the area of cerebral infarction. They were assigned into a good prognosis group and a poor prognosis group according to the Modified Rankin Scale (mRS) score on the 90th day after the onset. A total of 85 healthy controls were selected as a control group. The levels of AIM2, IL-1β, and IL-18 in plasma of the cerebral group and the control group were detected by enzyme-linked immunosorbent assay (ELISA).@*RESULTS@#The levels of plasma AIM2, IL-1β, and IL-18 in the cerebral infarction group were significantly higher than those in the control group (all @*CONCLUSIONS@#Expressions of AIM2, IL-1β, and IL-18 are up-regulated in the plasma of patients with acute cerebral infarction, and they are closely related to the severity of neurological deficit, cerebral infarction area, and prognosis in patients with acute cerebral infarction, suggesting that AIM2, IL-1β, and IL-18 may play an important role in the occurrence and development of acute cerebral infarction.

Alterações Precoces nas Interleucinas Circulantes e no Risco Inflamatório Residual após Infarto Agudo do Miocárdio / Early Changes in Circulating Interleukins and Residual Inflammatory Risk After Acute Myocardial Infarction

Resumo Fundamento Pacientes com infarto agudo do miocárdio podem apresentar uma grande área infartada e disfunção ventricular mesmo com trombólise e revascularização precoces. Objetivo Investigar o comportamento das citocinas circulantes em pacientes com infarto agudo do miocárdio com supradesnivelamento do segmento ST (IAMCSST) e a relação delas com a função ventricular. Métodos No estudo BATTLE-AMI (Avaliação dos Linfócitos Tipos B e T no Infarto Agudo do Miocárdio), os pacientes com IAMCSST foram tratados com uma estratégia farmacoinvasiva. Os níveis de citocinas (IL-1β, IL-4, IL-6, IL-10 e IL-18) no plasma foram testados através de ensaio de imunoadsorção enzimática (ELISA) no início do estudo e após 30 dias. A massa infartada e a fração de ejeção ventricular esquerda (FEVE) foram examinadas por ressonância magnética cardíaca 3-T. Valores de p menores que 0,05 foram considerados significativos. Resultados Na comparação com o início do estudo, níveis mais baixos foram detectados para IL-1β (p = 0,028) e IL-18 (p < 0,0001) após 30 dias do IAMCSST, enquanto níveis mais altos foram observados para IL-4 (p = 0,001) e IL-10 (p < 0,0001) no mesmo momento. Em contrapartida, nenhuma mudança foi detectada nos níveis de IL-6 (p = 0,63). Os níveis da proteína C-reativa de alta sensibilidade e de IL-6 se correlacionaram no início do estudo (rho = 0,45, p < 0,0001) e 30 dias após o IAMCSST (rho = 0,29, p = 0,009). No início do estudo, a correlação entre os níveis de IL-6 e FEVE também foi observada (rho = -0,50, p = 0,004). Conclusões Durante o primeiro mês pós-infarto agudo do miocárdio, observamos uma melhora significativa no balanço das citocinas pró e anti-inflamatórias, exceto da IL-6. Esses achados sugerem risco inflamatório residual. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

Abstract Background Patients with acute myocardial infarction may have a large infarcted area and ventricular dysfunction despite early thrombolysis and revascularization. Objective To investigate the behavior of circulating cytokines in patients with ST-segment elevation myocardial infarction (STEMI) and their relationship with ventricular function. Methods In the BATTLE-AMI (B and T Types of Lymphocytes Evaluation in Acute Myocardial Infarction) trial, patients with STEMI were treated with a pharmacoinvasive strategy. The plasma levels of cytokines (IL-1 β , IL-4, IL-6, IL-10, and IL-18) were tested using enzyme-linked immunosorbent assay (ELISA) at baseline and after 30 days. Infarcted mass and left ventricular ejection fraction (LVEF) were examined by 3-T cardiac magnetic resonance imaging. All p-values < 0.05 were considered statistically significant. Results Compared to baseline, lower levels were detected for IL-1 β (p = 0.028) and IL-18 (p < 0.0001) 30 days after STEMI, whereas higher levels were observed for IL-4 (p = 0.001) and IL-10 (p < 0.0001) at that time point. Conversely, no changes were detected for IL-6 levels (p = 0.63). The levels of high-sensitivity C-reactive protein and IL-6 correlated at baseline (rho = 0.45, p < 0.0001) and 30 days after STEMI (rho = 0.29, p = 0.009). At baseline, correlation between IL-6 levels and LVEF was also observed (rho = -0.50, p = 0.004). Conclusions During the first month post-MI, we observed a marked improvement in the balance of pro- and anti-inflammatory cytokines, except for IL-6. These findings suggest residual inflammatory risk. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)