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.

Factors Influencing the efficacy of Plasma Exchange in the Treatment of Immune Thrombocytopenic Purpura / 中国实验血液学杂志

OBJECTIVE@#To observe the efficacy of plasma exchange in the treatment of patients with immune thrombocytopenic purpura (ITP), and to analyze the factors influencing the efficacy of plasma exchange in the treatment of ITP.@*METHODS@#The medical records of 39 ITP patients who were treated effectively by plasma exchange in Huai'an First People's Hospital from January 2013 to January 2021 were retrospectively analyzed, and they were set as the effective group. In addition, the medical records of 39 ITP patients who were treated ineffective by plasma exchange during the same period in our hospital were collected, and they were set as the ineffective group. The general data such as sex and age of patients and laboratory indicators on admission were collected and recorded. The possible influencing factors were included, and Logistic regression analysis was used to examine the influencing factors of efficacy of plasma exchange in the treatment of ITP.@*RESULTS@#The serum levels of IL-6, IL-18 and B lymphocyte activating factor (BAFF) on admission in the ineffective group were significantly higher than those in the effective group, and the proportions of Helicobacter pylori (HP) infection and splenomegaly were significantly higher than those in the effective group (P<0.05). There was no statistical significantly difference in sex, age and other data between the two groups (P>0.05). After single factor analysis, multiple regression model was established, which showed that splenomegaly, HP infection and the over expression of serum IL-6, IL-18 and BAFF on admission might be the influencing factors of ineffective treatment of ITP by plasma exchange (OR>1, P<0.05).@*CONCLUSION@#The over expression of serum IL-6, IL-18, BAFF, splenomegaly and HP infection on admission may be the influencing factors resulting in the ineffective treatment of plasma exchange in ITP.

Schisandrin B Inhibits NLRP3 Inflammasome Pathway and Attenuates Early Brain Injury in Rats of Subarachnoid Hemorrhage / 中国结合医学杂志

OBJECTIVE@#To determine whether Schisandrin B (Sch B) attenuates early brain injury (EBI) in rats with subarachnoid hemorrhage (SAH).@*METHODS@#Sprague-Dawley rats were divided into sham (sham operation), SAH, SAH+vehicle, and SAH+Sch B groups using a random number table. Rats underwent SAH by endovascular perforation and received Sch B (100 mg/kg) or normal saline after 2 and 12 h of SAH. SAH grading, neurological scores, brain water content, Evan's blue extravasation, and terminal transferase-mediated dUTP nick end-labeling (TUNEL) staining were carried out 24 h after SAH. Immunofluorescent staining was performed to detect the expressions of ionized calcium binding adapter molecule 1 (Iba-1) and myeloperoxidase (MPO) in the rat brain, while the expressions of B-cell lymphoma 2 (Bcl-2), Bax, Caspase-3, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated specklike protein containing the caspase-1 activator domain (ASC), Caspase-1, interleukin (IL)-1β, and IL-18 in the rat brains were detected by Western blot.@*RESULTS@#Compared with the SAH group, Sch B significantly improved the neurological function, reduced brain water content, Evan's blue content, and apoptotic cells number in the brain of rats (P<0.05 or P<0.01). Moreover, Sch B decreased SAH-induced expressions of Iba-1 and MPO (P<0.01). SAH caused the elevated expressions of Bax, Caspase-3, NLRP3, ASC, Caspase-1, IL-1β, and IL-18 in the rat brain (P<0.01), all of which were inhibited by Sch B (P<0.01). In addition, Sch B increased the Bcl-2 expression (P<0.01).@*CONCLUSION@#Sch B attenuated SAH-induced EBI, which might be associated with the inhibition of neuroinflammation, neuronal apoptosis, and the NLRP3 inflammatory signaling pathway.

Interference of P2X4 receptor expression in tumor-associated macrophages suppresses migration and invasion of glioma cells / 南方医科大学学报

OBJECTIVE@#To investigate the effect of interference of P2X4 receptor expression in tumor-associated macrophages (TAMs) on invasion and migration of glioma cells.@*METHODS@#C57BL/6 mouse models bearing gliomas in the caudate nucleus were examined for glioma pathology with HE staining and expressions of Iba-1 and P2X4 receptor with immunofluorescence assay. RAW264.7 cells were induced into TAMs using conditioned medium from GL261 cells, and the changes in mRNA expressions of macrophage polarization-related markers and the mRNA and protein expressions of P2X4 receptor were detected with RT-qPCR and Western blotting. The effect of siRNA-mediated P2X4 interference on IL-1β and IL-18 mRNA and protein expressions in the TAMs was detected with RT-qPCR and Western blotting. GL261 cells were cultured in the conditioned medium from the transfected TAMs, and the invasion and migration abilities of the cells were assessed with Transwell invasion and migration experiment.@*RESULTS@#The glioma tissues from the tumor-bearing mice showed a significantly greater number of Iba-1-positive cells, where an obviously increased P2X4 receptor expression was detected (P=0.001), than the brain tissues of the control mice (P < 0.001). The M2 macrophage markers (Arg-1 and IL-10) and M1 macrophage markers (iNOS and TNF-α) were both significantly up-regulated in the TAMs derived from RAW264.7 cells (all P < 0.01), but the up-regulation of the M2 macrophage markers was more prominent; the expression levels of P2X4 receptor protein and mRNA were both increased in the TAMs (P < 0.05). Interference of P2X4 receptor expression significantly lowered the mRNA(P < 0.01)and protein (P < 0.01, P < 0.05)expression levels of IL-1β and IL-18 in the TAMs and obviously inhibited the ability of the TAMs to promote invasion and migration of the glioma cells (P < 0.05).@*CONCLUSION@#Interference of P2X4 receptor in the TAMs suppresses the migration and invasion of glioma cells possibly by lowering the expressions of IL-1β and IL-18.

Effects of MCC950 on nerve injury in rats with intracerebral hemorrhage / 中国应用生理学杂志

Objective: To investigate the effects of the pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950 on nerve injury in rats with intracerebral hemorrhage(ICH). Methods: Seventy-two SD rats were randomly divided into three groups (n=24): Sham group, ICH group and MCC950 group. ICH group and MCC950 group rats were injected with autogenous non-anticoagulant blood to establish ICH model, and then the rats in MCC950 group were intraperitoneally injected with MCC950 at the dose of 10 mg/kg(2 mg/ml) for 3 days after ICH model was established. Seventy-two hours after the establishment of the model, the forelimb placement test, the corner test and mNSS score were performed to observe the neurological function of the rats with ICH. The volume of hematoma was observed in fresh brain tissue sections. HE staining was used to observe the pathological changes of brain tissue. The dry-wet weight ratio was calculated to evaluate the changes of brain tissue edema. The degeneration of neurons was observed by FJC staining. The neuronal apoptosis was observed by TUNEL staining. The protein expression and activation levels of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD were determined by Western blot. Results: Compared with sham group, the percentage of successful placement of left forelimb and left turn was decreased significantly (P＜0.01, P＜0.05), mNSS score was increased significantly (P＜0.01) in ICH group. Hematoma volume was increased significantly, the number of microglial cells around the hematoma was increased, the number of neurons was decreased, nerve cell swelled, some cells showed pyknotic necrosis, and the staining was deepened. The water content of the right base was increased significantly (P＜0.05). The number of FJC positive and TUNEL positive cells around the hematoma was increased significantly (P＜0.05). The levels of NLRP3, ASC, caspase-1, pro-caspase-1, caspase-1/pro-caspase-1 ratio, GSDMD-N, GSDMD, GSDMD-N/GSDMD ratio, IL-1β and IL-18 were increased significantly (P＜0.01, P＜ 0.05). Compared with ICH group, the percentage of successful placement of left forelimb and left turn was increased significantly in MCC950 group (P＜0.05), while the mNSS score and the volume of hematoma were decreased significantly (P＜0.01), the swelling degree of nerve cells around the hematoma was reduced significantly, and the number of pyrotic necrotic cells was decreased. The water content of the right base was decreased significantly (P＜0.05), and the number of FJC positive and TUNEL positive cells around the hematoma was decreased significantly (P＜0.05). The levels of NLRP3, ASC, caspase-1, pro-caspase-1, caspase-1/pro-caspase-1 ratio, GSDMD-N, GSDMD, GSDMD-N/GSDMD ratio, IL-1β and IL-18 were decreased significantly (P＜0.05). Conclusion: MCC950 can ameliorate nerve injury after ICH by inhibiting NLRP3 inflammasome mediated inflammation and pyroptosis.

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.

Mechanism of Shenling Baizhu Powder on treatment of ulcerative colitis based on NLRP3 inflammatory / 中国中药杂志

This study deciphered the mechanism of Shenling Baizhu Powder in treatment of mouse model of ulcerative colitis(UC) via NOD-like receptor thermoprotein domain 3(NLRP3) signaling pathway. After three days of adaptive feeding, 70 SPF-grade BALB/c mice were randomized into 7 groups: normal group, model group(dextran sodium sulfate, DSS), mesalazine group(DSS + 5-aminosalicylic acid, 5-ASA), NLRP3 inhibitor group(DSS + MCC950), and high-, medium-, and low-dose Shenling Baizhu Powder groups(DSS + high-, medium-, and low-dose Shenling Baizhu Powder), with 10 mice per group. The normal group had free access to double distilled water, and the remaining groups had free access to DSS-containing water to establish the acute UC model. Intragastric administration was started at the same time as modeling for one week. During the experiment, the general mental state and disease activity of each group of mice were recorded and scored. After the experiment, colon and serum samples were collected. The pathological changes in colon tissue were observed through hematoxylin-eosin(HE) staining. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the levels of interleukin-18(IL-18) and myeloperoxidase(MPO) in colon tissue and interleukin-1β(IL-1β) in serum. Immunofluorescence(IF) and immunohistochemistry(IHC) methods were employed to examine the expression of NLRP3 and IL-18 in colon tissue. Western blot was employed to measure the protein levels of NLRP3, apoptosis-associated speck-like protein(ASC), cystein-aspartate protease 1(caspase-1), and downstream inflammatory cytokines in colon tissue. Compared with the normal group, the modeling of UC increased the disease activity index(DAI), colon pathological injury score, IL-1β level in serum, and IL-18 and MPO levels in colon tissue(P<0.05, P<0.01). Furthermore, the modeling caused obvious pathological changes and up-regulated the expression of NLRP3, caspase-1, ASC, pro-IL-1β, cleaved-IL-1β, pro-IL-18, and cleaved-IL-18 in the colon(P<0.01). Compared with the model group, the administration of corresponding drugs decreased the DAI, pathological injury score, IL-1β level in serum, and IL-18 and MPO levels in colon tissue, and down-regulated the protein levels of NLRP3, caspase-1, ASC, pro-IL-1β, cleaved-IL-1β, pro-IL-18, and cleaved-IL-18 in the colon(P<0.05, P<0.01). According to the results of previous study and this study, we concluded that Shenling Baizhu Powder can alleviate the inflammatory response and intestinal damage of DSS-induced UC by regulating the expression of the proteins and inflammatory cytokines associated with NLRP3 signaling pathway.

Protective effects of Lycium ruthenicum Murr. juice on alcoholic liver injury in rats / 中国应用生理学杂志

Objective: To study the protective effects of Lycium ruthenicum Murr. juice on alcoholic liver injury in rats and explore the regulatory mechanism of toll-like receptors 4 (TLR4)/p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway in this process. Methods: Sixty male SD rats were randomly divided into control group (C), model group (M), low-dose Lycium ruthenicum Murr. juice group (LLM), medium-dose Lycium ruthenicum Murr. juice group (MLM) and high-dose Lycium ruthenicum Murr. juice group (HLM), 12 rats in each group. The group M, LLM, MLM and HLM were treated with 20 ml/kg (8 g/(kg·d)) ethanol (400 g/L) intragastrically and the gavage was divided into two sessions, group C was treated with an equal volume of distilled water at the same time point. Four hours before the first alcohol gavage session, rats in each dose group of Lycium ruthenicum Murr. juice were administered with 2.4, 4.8, 9.6 ml/(kg·d) Lycium ruthenicum Murr. juice respectively, and the other groups were given equal volume of distilled water at the corresponding time points. Four weeks later, the rats were sacrificed 24 hours after the end of the last experiment, blood and liver were collected. The liver index was calculated. The morphology of the liver was observed by HE staining. The expressions of hepatic TLR4, p38 MAPK and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) were detected by immunohistochemistry. The activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by colorimetry. The levels of hepatic tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-10 (IL-10) and interleukin-18 (IL-18) were detected by enzyme linked immunosorbent assay. Results: Compared with group C, the alcoholic liver injury model was established successfully in Group M. Compared with group M, related indicators in each dose group of Lycium ruthenicum Murr. juice were improved, the improvement of hepatic morphology in group HLM was the most significant, the liver index, the levels of serum ALT, AST and hepatic TLR4, p38 MAPK/p-p38 MAPK ratio, TNF-α, IL-1β, IL-18 were decreased (P＜ 0.05 or P＜0.01), while the level of hepatic IL-10 was increased (P＜0.01). Comparison among the dose groups of Lycium ruthenicum Murr. juice, the levels of liver index, serum AST and hepatic TLR4, p38 MAPK/p-p38 MAPK ratio, TNF-α, IL-18 in HLM were lower than those in LLM (P＜0.05 or P＜0.01); the level of hepatic IL-10 in HLM was higher than that in LLM and MLM (P＜0.05 or P＜0.01); the other indicators in each dose group had no statistical difference (P＞0.05). Conclusion: Lycium ruthenicum Murr. juice can improve the inflammatory stress by regulating TLR4/p38 MAPK signaling pathway, relieve alcoholic liver injury in rats, and the effect of high-dose group is better than the others.

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.

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.

Mechanism of Huanglian Wendan Decoction in improving impaired glucose tolerance based on skeletal muscle NLRP3/caspase-1/IL-1β, IL-18 pathway / 中国中药杂志

This study investigated the mechanism of improving impaired glucose tolerance(IGT) of rats by Huanglian Wendan Decoction from the perspective of the skeletal muscle Nod-like receptor protein 3(NLRP3)/cysteinyl aspartate specific proteinase-1(caspase-1)/interleukin-1β(IL-1β), interleukin-18(IL-18) pathway. Healthy male SD rats were fed with the diet containing 45% fat for 20 weeks, accompanied by a high-temperature and high-humidity environment and an inactive lifestyle, for the establishment of the IGT rat model. The rats were divided into the blank control group, model control group, metformin hydrochloride group(positive drug group, 0.05 g·kg~(-1)·d~(-1)) and Huanglian Wendan Decoction group(7.8 g·kg~(-1)·d~(-1)). After continuous intragastric administration for 4 weeks, the obesity and glycemic indexes of all the rats were measured. The fasting serum insulin(FINS) level was determined by ELISA, with the insulin sensitivity index(ISI) and insulin resistance index(IRI) calculated. The mRNA and protein expression le-vels of nuclear factor kappaB(NF-κB), NLRP3, caspase-1, IL-1β and IL-18 in skeletal muscle tissue were detected by real-time polymerase chain reaction(PCR), Western blot and immunofluorescence. Compared with the blank control group, the model control group witnessed significantly increased mRNA and protein expression of NF-κB, NLRP3, caspase-1, IL-1β and IL-18. As revealed by the comparison with the model control group, Huanglian Wendan Decoction could effectively regulate the obesity status, reduce body weight, correct the abnormal levels of 2-hour plasma glucose(2 hPG), insulin resistance index(IRI), insulin sensitivity index(ISI), and lower the mRNA and protein expression of NF-κB, NLRP3, caspase-1, IL-1β and IL-18 in the skeletal muscle tissue of IGT rats. Combined with previous studies, the above results showed that the occurrence and development of IGT was closely related to inflammatory response and the classic pyroptosis pathway in skeletal muscle, such as NLRP3/caspase-1/IL-1β, IL-18. It is inferred that the mechanism of Huanglian Wendan Decoction was to alleviate insulin resistance(IR) and then reverse the course of IGT lies in the regulation of the abnormal insulin receptor signaling pathway based on the NLRP3 inflammasome pathway.

Papel da Interleucina 18 e da Proteína Precursora do Trombo na Doença Arterial Coronariana / Role of Interleukin-18 and the Thrombus Precursor Protein in Coronary Artery Disease

Resumo Fundamento A insuficiência coronariana constitui a principal causa de morte no mundo, e a identificação de pacientes de maior risco para doença arterial coronariana (DAC) constitui um desafio. Objetivos Testar os biomarcadores interleucina 18 (IL-18) e proteína precursora do trombo (TpP), envolvidos na aterogênese, para auxílio na avaliação precoce de DAC. Métodos Coorte transversal de 119 pacientes, estratificados em três grupos: Grupo I - síndrome coronariana aguda (39); Grupo II - DAC crônica (40); e Grupo III - controle, sem lesão coronariana, mas podendo apresentar fatores de risco para DAC (40). Análise estatística através do programa estatístico SPSS (Statistical Package for the Social Sciences) para Windows versão 17.0 de 2008. Fixou-se em 0,05 ou 5% (p<0,05) nível de significância e intervalo de confiança de 95%. Teste do qui-quadrado (χ2). Análise de variância (ANOVA), Teste de Tukey. Resultados Idade média, 60,36±9,64 anos; prevalência do sexo feminino no Grupo III (65,0% p=0,002), porém sem significado estatístico para os valores médios de IL-18 e TpP. Os valores médios de IL-18 e TpP mostravam-se aumentados no Grupo I, quando comparados aos valores dos demais grupos: IL-18 = 1325,44±1860,13 ng/dL, p=0,002; TpP = 35,86±28,36 µg/mL, p<0,001. Na comparação dois a dois, observou-se que o Grupo I apresentou valor médio de IL-18 e TpP maior que o do Grupo II (IL-18 = 353,81±273,65 ng/dL; TpP = 25,66±12,17 µg/mL) e o do Grupo III (IL-18 = 633,25±993,93 ng/dL; TpP=18,00±8,45 µg/mL). Conclusão Na vigência de DAC aguda, houve elevação desses biomarcadores, sugerindo relação com o processo de instabilidade da placa aterosclerótica, mas não com a fase crônica. (Arq Bras Cardiol. 2020; 114(4):692-698)

Abstract Background Coronary failure is the leading cause of death worldwide and identifying patients at higher risk for coronary artery disease (CAD) is a challenge. Objectives To test the biomarkers interleukin 18 (IL-18) and thrombus precursor protein (TpP), involved in atherogenesis, to aid in the early assessment of CAD. Methods This was a cross-sectional cohort of 119 patients, stratified into three groups: Group I - acute coronary syndrome (39); Group II - chronic CAD (40) and Group III - control, without coronary lesion, but who might have risk factors for CAD (40). Statistical analysis was performed using the statistical program SPSS (Statistical Package for the Social Sciences) for Windows ,version 17.0 of 2008. The significance level was set at 0.05 or 5% (p <0.05), with a 95% confidence interval. Chi-square test (χ2), Analysis of variance (ANOVA), and Tukey's test were used. Results The mean age was 60.36 ± 9.64 years; there was a prevalence of females in Group III (65.0% p = 0.002), but without statistical significance for the means of IL-18 and TpP. The means of IL-18 and TpP were increased in Group I when compared to the other groups; IL-18 = 1325.44 ± 1860.13 ng/dL, p = 0.002; TpP = 35.86 ± 28.36 µg / mL, p <0.001). When compared two-by-two, it was observed that Group I had higher mean IL-18 and TpP values than Group II (IL-18 = 353.81 ± 273.65 ng / dL; TpP = 25.66 ± 12, 17 µg / mL) and Group III (IL-18 = 633.25 ± 993.93 ng / dL; TpP = 18.00 ± 8.45 µg / mL). Conclusion There was an increase in these biomarkers in acute CAD, suggesting a relationship with the atherosclerotic plaque instability process, but not with the chronic phase. (Arq Bras Cardiol. 2020; 114(4):692-698)

Uso de interferon para el tratamiento de pacientes con COVID-19 / Use of interferon for the treatment of patients with COVID-19

INTRODUCCIÓN: Al momento se tienen propuestas de tratamiento para el COVID-19, en las que se incluye el uso de interferón (Lu 2020; Li and De Clercq 2020). Dentro del espectro de los medicamentos catalogados como interferón (IFN) tenemos IFN alfa o IFN alfa pegilado, IFN alfa 2a, IFN alfa 2b, IFN beta, IFN beta 1a, IFN beta 1b, e IFN gamma (Friedman 2008). De manera anecdótica, ante los brotes de MERS y SARS producidos en años previos, se investigó el uso de IFN como medida terapéutica (Sainz et al. 2004; Scagnolari et al. 2004). Sin embargo, dichos estudios corresponden a estudios in-vitro. En el estudio in vitro de Sainz y col. 2004 (Sainz et al. 2004), se encontró que sinérgicamente IFN beta e IFN gamma inhiben el crecimiento de los cultivos en placa del SARS-CoV, virus que causó el brote del 2003 en China; en el estudio in vitro de Scagnolari y col. 2005 (Scagnolari et al. 2004), se encontró que los IFN presentaban capacidad para inhibir el crecimiento en placa del SARS-CoV (principalmente de IFN beta e IFN gamma). Por otra parte, en una revisión sistemáticade Morra y col 2018 (Morra et al. 2018), donde se estudió el uso de IFN para el tratamiento de MERS-CoV, responsable del brote en Arabia Saudita en el 2012, en sus diferentes presentaciones (incluyendo IFN alfa-2a, IFN alfa-2b, e IFN beta-1a) en combinación con ribavirina, se encontró que no hubo diferencias significativas en desenlaces clínicos cuando se le comparó con otra terapia de soporte. Se observó que se suele utilizar IFN (IFN alfa-2a, IFN alfa-2b, e IFN beta1a) en combinación con ribavirina. En otro estudio tipo revisión sistemática de Momattin y col. 2019 (Momattin, Al-Ali, and Al-Tawfiq 2019), encontraron que no existe consenso para el tratamiento de MERS-CoV pues los estudios fueron heterogéneos y los resultados no concluyentes. En dicho estudio se utilizó IFN 1b en combinación con ribavirina. Debemos resaltar que existe una escasez de evidencia respecto al uso de interferón en COVID19, y la mayoría de la evidencia proviene de estudios in-vitro. GUÍAS DE PRÁCTICA CLÍNICA: La Guía de Medicina Integrativa de China Oriental para el manejo del nuevo coronavirus 2019, provee de información clínica y epidemiológica sobre el COVID 19. Dentro de las alternativas terapéuticas que se encuentran en investigación, menciona al interferón y la evidencia que proviene de estudios de ciencias básicas que encontraron que este medicamento puede frenar la replicación in-vitro del SARS-CoV (Sainz y col. 2004) (Scagnolari y col. 2005). El estudio de Sainz y col. del 2014 encontró que sinérgicamente IFN beta e IFN gamma inhiben el crecimiento de los cultivos en placa del SARS-CoV. El estudio de Scagnolari y col. del 2005, encontró que los IFN presentaban capacidad para inhibir el crecimiento en placa del SARS-CoV (principalmente de IFN beta e IFN gamma). La GPC no presenta recomendaciones respecto al uso de IFN (en ninguna presentación), solo indica que se encuentra en etapa experimental para el uso de pacientes con COVID-19. ESTUDIO SERIE DE CASOS: Lo que se presenta aqui es la experiencia de manejo de pacientes, quienes recibieron múltiples esquemas de tratamiento incluido el IFN. Por tanto, no podemos concluir que los resultados encontrados se deben al uso de IFN. Además, la metodología de una serie de casos no es la ideal para establecer que los pacientes mejoraron por el uso de IFN. Es necesario realizar ensayos clínicos para determinar como influye el IFN en el manejo clínico de pacientes con COVID19. ENSAYOS CLÍNICOS EN CURSO O NO PUBLICADOS REGISTRADOS EN CLINICALTRIALS.GOV: Ensayo clínico no publicado, en fase de reclutamiento de pacientes. NCT04254874 Abidol hydrochloride vs Abidol Hydrochloride combinado con atomización de Interferon PegIFN-α-2b, fase 4, en pacientes con neumonía viral COVID19. Patrocinador Tongji Hospital. A ser realizado en Wuhan, Hubei, China. Fecha estimada de término de estudio: 1ero de julio del 2020. Ensayo clínico no publicado, aún no inicia fase de reclutamiento de pacientes NCT04293887. Uso de interferón alfa-1b en pacientes con infección por COVID19, fase 1, patrocinador Tongji Hospital. Fecha estimada de término de estudio: 30 de junio del 2020. Ensayo clínico no publicado, aún no inicia reclutamiento de pacientes. NCT04275388. Inyección de Xiyanping vs Lopinavir / ritonavir, nebulización de interferon alfa, no aplica fase, en pacientes con neumonía viral COVID19. Patrocinador Jiangxi Qingfeng Pharmaceutical Co. Ltd. Fecha estimada de término de estudio: 14 de diciembre del 2021. Ensayo clínico no publicado, en fase de reclutamiento de pacientes NCT04276688. Lopinavir/ritonavir, ribavirina e interferón beta-1b, fase 2, patrocinador The University of Hong Kong. Fecha estimada de término de estudio: 31 de julio del 2022. EXPERIENCIA RECOGIDA DE HOSPITALES EN EL MUNDO: Debido a que la enfermedad por COVID19 inició en diciembre del 2019, algunos hospitales han recomendado el uso de IFN bajo las siguientes modalidades: España (Sociedad Española de Farmacia Hospitalaria al 18 de marzo 2020): (Sociedad Española de Farmacia Hospitalaria 2020). Se utiliza hasta que caiga la fiebre y no más de 14 días: Estados Unidos (Guía de manejo de COVID19 del Massachusetts Medical Hospital al 17 de marzo 2020): (Massachusetts General Hospital 2020). CONCLUSIONES: A la fecha, 24 de marzo del 2020, aun no se encuentran ensayos clínicos publicados con resultados de eficacia y seguridad respecto al uso del IFN en pacientes con COVID19, infectadas con el virus SARS-CoV-2. Como hecho anecdótico se toma la experiencia de uso de IFN en infecciones causadas por los virus SARS-CoV y MERS-CoV en años previos, los cuales comparten parte importante de su componente genético con el SARS-CoV-2. Encontramos resultados en estudios in-vitro donde el IFN mostró cierta capacidad de inhibir el crecimiento de los virus mencionados. Las recomendaciones de la GPC de Chan y col. (2020), se basa en estudios invitro realizados en el 2004 (Sainz et al. 2004; Scagnolari et al. 2004). La guía de Chan y col. (2020) indica que el uso de IFN en cualquiera de sus presentaciones no se encuentra recomendado para pacientes con infección por COVID-19 y su uso solo es experimental. Por otro lado, la GPC de National Health Commission & Stare Administration of Traditional Chinese Medicine recomienda incluir el uso de IFN-alfa pero no menciona la Encontramos una serie de casos en China (Wan et al. 2020) con 135 pacientes con COVID19 a quienes se le administró IFN más lopinavir/ritonavir, en combinación con antibióticos y corticoides. Alrededor del mes de seguimiento, 11.1% (n=15) de pacientes fueron dados de alta, la tasa de mortalidad a los 28 días de seguimiento fue de 2.5%. Este estudio constituye un primer aporte a la literatura científica sobre el manejo de pacientes con COVID19. Debido a que todos los pacientes del estudio recibieron IFN en combinación con lopinavir/ritonavir, no se puede discriminar si el efecto del IFN es favorable o no para pacientes con COVID19. Es necesario realizar ensayos clínicos para determinar cómo influye el IFN en el manejo clínico de pacientes con COVID19. fuente de donde se obtiene la evidencia para recomendar el uso de IFN. Encontramos que se están llevando a cabo varios ensayos clínicos (EC) respecto al uso de IFN para pacientes con COVID19. Los ensayos clínicos más próximos para finalizar son en julio del 2020. La intervención de interés en la experiencia en hospitales (Sociedad Española de Farmacia Hospitalaria 2020) (Massachusetts General Hospital 2020), por lo general, es dual. Es decir, combina la acción de un tipo de IFN junto a otro antiviral, que por lo general es ribavirina. Otros tipos de antivirales con los cuales se combina al IFN son los esteroides, lopinavir/ritonavir, o micofenolato mofetil. Encontramos guías de sociedades/hospitales internacionales donde actualmente tienen picos muy altos de pacientes con COVID19. Dichas guías incluyen en su algoritmo terapéutico al IFN en diferentes formas (IFN alfa-2b nebulizada e IFN beta-1b inyectable). Sin embargo, no existe ningún ensayo clínico a la fecha que respalde su uso, salvo la experiencia de manejo de pacientes en China. Por ello, son necesarios los resultados de los ensayos clínicos en curso. Por lo expuesto, al momento, no se encuentra que IFN en ninguna de sus presentaciones (IFN alfa o IFN alfa pegilado, IFN alfa 2a, IFN alfa 2b, IFN beta, IFN beta 1a, IFN beta 1b, o IFN gamma), tenga evidencia clínica que respalde una recomendación a favor como una alternativa de tratamiento para pacientes con COVID19. Se necesita de los resultados de los EC que se están realizando para conocer tanto su eficacia como su seguridad en pacientes con COVID19.

Effect of acupuncture on NLRP3 inflammatory corpuscle in rats with intracerebral hemorrhage / 中国针灸

OBJECTIVE@#To observe the effect of acupuncture at "Baihui" (GV 20) through "Qubin" (GB 7) on NLRP3 inflammatory corpuscle in rats with intracerebral hemorrhage (ICH), and to explore the action mechanism of acupuncture on promoting the recovery of neural function in rats with ICH.@*METHODS@#Forty SPF six-week-old male SD rats were randomly divided into a sham operation group, a model group, a non-acupoint group and an acupuncture group, 10 rats in each group. The rats in the model group, non-acupoint group and acupuncture group were intervened with autologous blood injection to prepare ICH model, while the rats in the sham operation group were only intervened with operation but not injection with autologous blood. About 3 hours after the establishment of the model, the rats in the acupuncture group were intervened with acupuncture at "Baihui" (GV 20) through "Qubin" (GB 7), once every 12 hours, for 7 days; the rats in the non-acupoint group were intervened with acupuncture at the non-acupoint [parallel to the "Baihui" (GV 20), 1 cm next to the midline] on the affected side, and other treatment was the same as the acupuncture group. At the end of the intervention, the composite nerve function score of each group was evaluated; the histomorphology of the hemorrhage penumbra was observed by HE staining; the expression of NLRP3 inflammatory corpuscle in the brain was detected by immunohistochemistry; the relative protein expression levels of NLRP3, interleukin-1β (IL-1β) and interleukin-18 (IL-18) in brain were detected by the method of Western blot.@*RESULTS@#Seven days into intervention, compared with the sham operation group, each item score and total score of composite nerve function in the model group were significantly reduced (<0.01, <0.05). There was edema and karyopyknosis in brain neuron as well as necrocytosis and inflammatory cell infiltration in the model group. Compared with the model group and the non-acupoint group, the total score of composite nerve function and the scores of symmetrical movement of limbs (LS) and proprioception of tentacles (VP) in the acupuncture group were increased (<0.01, <0.05), and the cell necrosis and inflammatory cell infiltration were relieved. Compared with the sham operation group, NLRP3 inflammatory corpuscle expression and the relative protein expression levels of NLRP3, IL-1β and IL-18 in brain tissue in the model group were increased (<0.01); compared with the model group and the non-acupoint group, NLRP3 inflammatory corpuscle expression and the relative protein expression levels of NLRP3, IL-1β and IL-18 in brain tissue in the acupuncture group were reduced (<0.01).@*CONCLUSION@#Acupuncture at "Baihui" (GV 20) through "Qubin" (GB 7) could downregulate the expression of NLRP3, IL-1β and IL-18 in the brain tissue of ICH rats, inhibit the inflammatory response, and promote the recovery of neural function.

Elastase-Positive Neutrophils Are Associated With Refractoriness of Chronic Rhinosinusitis With Nasal Polyps in an Asian Population

PURPOSE: Various immune cells, including eosinophils and neutrophils, are known to contribute to the development of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the current understanding of the role of neutrophils in the development of CRSwNP still remains unclear. Therefore, we investigated risk factors for refractoriness of CRSwNP in an Asian population. METHODS: Protein levels of 17 neutrophil-related mediators in nasal polyps (NPs) were determined by multiplex immunoassay, and exploratory factor analysis using principal component analysis was performed. Immunofluorescence analysis was conducted to detect human neutrophil elastase (HNE) or myeloperoxidase (MPO)-positive cells. Tissue eosinophilic nasal polyp (ENP) and tissue neutrophilia (Neu(high)) were defined as greater than 70 eosinophils and 20 HNE-positive cells, otherwise was classified into non-eosinophilic nasal polyp (NENP) and absence of tissue neutrophilia (Neu(low)). RESULTS: In terms of disease control status, NENP-Neu(low) patients showed the higher rate of disease control than NENP-Neu(high) and ENP-Neu(high) patients. Linear by linear association demonstrated the trend in refractoriness from NENP-Neu(low) to NENP-Neu(high) or ENP-Neu(low) to ENP-Neu(high). When multiple logistic regression was performed, tissue neutrophilia (hazard ratio, 4.38; 95% confidence interval, 1.76-10.85) was found as the strongest risk factor for CRSwNP refractoriness. Additionally, exploratory factor analysis revealed that interleukin (IL)-18, interferon-γ, IL-1Ra, tumor necrosis factor-α, oncostatin M, and MPO were associated with good disease control status, whereas IL-36α and IL-1α were associated with refractory disease control status. In subgroup analysis, HNE-positive cells and IL-36α were significantly upregulated in the refractory group (P = 0.0132 and P = 0.0395, respectively), whereas MPO and IL-18 showed higher expression in the controlled group (P = 0.0002 and P = 0.0009, respectively). Moreover, immunofluorescence analysis revealed that IL-36R⁺HNE⁺-double positive cells were significantly increased in the refractory group compared to the control group. We also found that the ratio of HNE-positive cells to α1 anti-trypsin was increased in the refractory group. CONCLUSIONS: Tissue neutrophilia had an influence on treatment outcomes in the Asian CRSwNP patients. HNE-positive cells and IL-36α may be biomarkers for predicting refractoriness in Asians with CRSwNP. Additionally, imbalances in HNE and α1 anti-trypsin may be associated with pathophysiology of neutrophilic chronic rhinosinusitis.

Correlation of interleukin-18 gene polymorphism with the susceptibility of condyloma acuminatum in Chinese population

ABSTRACT Host immunogenetic setting is involved in the regulation of human papillomavirus (HPV) infection and development of condyloma acuminatum (CA). We investigated the correlation of two common single nucleotide polymorphisms (SNPs) (−607C/A and −137G/C) of IL-18 with the susceptibility of CA in a large Chinese cohort. Out of 408 CA patients analyzed, 300 had HPV infection transmitted through sexual contact (SC) and 108 through non-sexual contact (NSC). In addition, 360 healthy volunteers were enrolled as controls. SNPs at positions −607C/A and −137G/C in IL-18 promoter were analyzed. Comparing CA patients to healthy controls, no dominant relevance was found between the IL-18 promoter −607 C/A or −137G/C polymorphisms and the CA disease either identified genotypically (p > 0.05) or by allelically (p > 0.05). However, the IL-18 promoter −137G/C polymorphism genotype and allele frequencies in the NSC CA group, but not between in the SC group, were significantly higher than in the controls. There was no dominant relevance between IL-18-607C/A polymorphism genotype and allele frequencies among SC, NSC CA patients, and controls. Our study demonstrates that polymorphism −137G/C in IL-18 promoter is significantly correlated with risk of CA in NSC patients.

Interleukin-18 exacerbates skin inflammation and affects microabscesses and scale formation in a mouse model of imiquimod-induced psoriasis / 中华医学杂志(英文版)

BACKGROUND@#As a potent pro-inflammatory cytokine of the interleukin (IL)-1 family, IL-18 was elevated in early active and progressive plaque-type psoriatic lesions and that serum or plasma levels of IL-18 correlated with the Psoriasis Area and Severity Index (PASI). Although results from previous studies have established that IL-18 may aggravate psoriatic inflammation, the mechanisms of this process remain unknown. In this study, IL-18 knock out (KO) mice and wild-type (WT) mice were used to investigate the effects of IL-18 within a mouse model of psoriasis.@*METHODS@#WT and IL-18 KO mice were divided into four groups, including imiquimod (IMQ)-treated IL-18 KO group (n = 11) and WT group (n = 13) as well as their respectively gene-matched control mice (receiving vaseline; n = 12). PASI scores were used to evaluate psoriatic lesions in IMQ-treated mice. Pathological features and dermal cellular infiltration were investigated by hematoxylin and eosin staining. The levels of psoriasis-related cytokines including IL-23, IL-17, IL-12, IL-1β, IFNγ, IL-15, IL-27, and IL-4 were tested by real-time polymerase chain reaction (PCR). The protein level of IL-1β, IL-27, CXCL1, and Ly6 g were investigated by immunohistochemistry (IHC).@*RESULTS@#Acanthosis (98.46 ± 14.12 vs. 222.68 ± 71.10 μm, P < 0.01) and dermal cell infiltration (572.25 ± 47.45 vs. 762.47 ± 59.59 cells/field, P < 0.01) were significantly milder in IMQ-induced IL-18 KO mice compared with that in WT mice. IMQ-induced IL-18 KO mice manifested larger areas of Munro microabscesses (11,467.83 ± 5112.09 vs. 4093.19 ± 2591.88 μm, P < 0.01) and scales (100,935.24 ± 41,167.77 vs. 41,604.41 ± 14,184.10 μm, P < 0.01) as compared with WT mice. In skin lesions of IL-18 KO mice, the expressions of IL-1β, IL-4, and IL-27 were all significantly upregulated but IL-17 was decreased. Histologically, strong positive signals of Ly6g were observed within the epidermis of IL-18 KO mice but expressions of CXCL1 were decreased.@*CONCLUSIONS@#IL-18 may exacerbate prominent inflammation and influence pathological features in IMQ-induced mouse model of psoriasis. IL-18 may upregulate pro-inflammatory cytokines and reduce protective cytokines, thus aggravating psoriatic inflammation. In addition, IL-18 may be involved in the formation of Munro microabscesses and scales.