Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not complet...Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.展开更多
BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against...BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.展开更多
Background:Amyotrophic lateral sclerosis(ALS)is irreversible and fatal within 3-5 years,with limited options for treatment.It is imperative to develop a symptom-based treatment that may increase the survival of ALS pa...Background:Amyotrophic lateral sclerosis(ALS)is irreversible and fatal within 3-5 years,with limited options for treatment.It is imperative to develop a symptom-based treatment that may increase the survival of ALS patients and improve their quality of life.Inflammation status,especially elevated interleukin 1β(IL1β),has been reported to play a critical role in ALS progression.Our study determined that neutralizing circulating IL1βslows down the progression of ALS in an ALS mouse model.Methods:The ALS mouse model was developed by microinjection of lentivirus-carrying OPTN^(E478G)(optineurin,a mutation from ALS patients)into the intra-motor cortex of mice.Peripheral circulating IL1βwas neutralized by injecting anti-IL1βan-tibody into the tail vein.Enzyme-linked immunosorbent assay(ELISA)and real-time polymerase chain reaction(RT-PCR)were carried out to determine the protein and gene expression levels of IL1β.TUNEL assay was used to assess the neural cell death.Immunofluorescent staining of MAP2 and CASP3 was accomplished to evaluate neuronal cell apoptosis.Glial fibrillary acidic protein staining was performed to ana-lyze the number of astrocytes.Rotarod test,grip strength test,balance beam test,and footprint test were conducted to assess the locomotive function after anti-IL1βtreatment.Results:The model revealed that neuroinflammation contributes to ALS progression.ALS mice exhibited elevated neuroinflammation and IL1βsecretion.After anti-IL1βtreatment,ALS mice revealed decreased neural cell death and astrogliosis and gained improved muscle strength and motor ability.Conclusions:Blocking IL1βis a promising strategy to slow down the progression of ALS.展开更多
AIM: To evaluate the effects of positive regulation of recombinant human interleukin 1 receptor antagonist (rhIL-1Ra) on hepatic tissue recovery in acute liver injury in mice induced by carbon tetrachloride (CCl 4 ). ...AIM: To evaluate the effects of positive regulation of recombinant human interleukin 1 receptor antagonist (rhIL-1Ra) on hepatic tissue recovery in acute liver injury in mice induced by carbon tetrachloride (CCl 4 ). METHODS: Acute liver damage was induced by injecting 8-wk-old mice with CCl 4 1 mL/kg (1:3 dilution in corn oil) intraperitoneally (ip). Survival after liver failure was assessed by injecting 8-wk-old mice with a lethal dose of CCl 4 2.6 mL/kg (1:1 dilution in corn oil) ip. Mice were subcutaneously injected with 1 mg/kg recombinant human IL-1Ra twice a day after CCl 4 treatment for 5 d. Serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels were determined with a commercial assay kit. Serum IL-1β, IL-1Ra levels were measured by enzyme-linked immunosorbent assay kit. Quantitative real-time polymerase chain reaction was used to determine liver IL-1β, IL-1Ra and IL-6 expression during CCl 4-induced acute liver injury. Liver sections were stained with hematoxylin-eosin. A histology-injury grading system was used to evaluate the degree of necrosis after acute liver injury. Proliferating cell nuclear antigen (PCNA) staining was used to evaluate the role of rhIL-1Ra in promoting hepatocyte proliferation. RESULTS: Quantitative analysis showed a higher level of IL-6 mRNA expression and reduced serum AST and ALT levels in the livers of the rhIL-1Ra-treated group at the early phase of CCl 4-induced acute liver injury. Histological examination indicated a decrease in centrilobular necrotic areas in mice treated with rhIL-1Ra, and a novel role of rhIL-1Ra in promoting hepatocyte proliferation was also supported by an increase of PCNA staining. All these results, accompanied by a strong survival benefit in rhIL-1Ra-treated vs PBS-treated groups, demonstrated that rhIL-1Ra administration ameliorated the histological damage and accelerated the regeneration and recovery process of the liver. CONCLUSION: rhIL-1Ra could be further developed as a novel therapeutic agent for the treatment of acute liver injury because of its ability to reduce hepatocellular damage and facilitate liver regeneration.展开更多
Interleukin 1β(IL-1β), the first interleukin to be characterized, plays a key role in regulating the immune response. In this study, we determined the c DNA and genomic DNA sequences of the IL-1β gene from the la...Interleukin 1β(IL-1β), the first interleukin to be characterized, plays a key role in regulating the immune response. In this study, we determined the c DNA and genomic DNA sequences of the IL-1β gene from the large yellow croaker, Larimichthys crocea. Phylogenetic analysis indicated that the IL-1β(Lc IL-1β) gene was most closely related to that of European seabass(Dicentrarchus labrax), sharing 67.8% amino acid identity. In healthy large yellow croaker, Lc IL-1β transcription was detected in all tested tissues, with the highest level found in the head kidney. Upon Vibrio alginolyticus infection, Lc IL-1β transcription in all tested tissues was significantly upregulated. Intraperitoneal injection of recombinant Lc IL-1β(r Lc IL-1β) improved the survival rate and reduced the tissue bacterial load after V. alginolyticus infection. In addition, r Lc IL-1β induced monocytes/macrophages(MO/MΦ) chemotaxis and increased phagocytosis and bactericidal activity in vitro. These results suggest that Lc IL-1β plays an important role in the large yellow croaker immune response against V. alginolyticus.展开更多
To investigate the effect of calcitonin gene related peptide (CGRP) on bone resorption mediated by interleukin 1β(IL 1β) in vitro , the osteoclasts isolated from the long bones of newborn SD rats were co cul...To investigate the effect of calcitonin gene related peptide (CGRP) on bone resorption mediated by interleukin 1β(IL 1β) in vitro , the osteoclasts isolated from the long bones of newborn SD rats were co cultured with osteoblasts on ivory slices placed in 24 well plates . 24 h later, conditioned media containing CGRP and/or IL 1β were added to the wells respectively, and continued culturing for 48 h. After the cells were stripped off by ultrasonication, the ivory slices were stained in toludine blue. The number and the total area of resorption lacunae on each slice were measured by computer imaging analysis system. Our results showed that IL 1β significantly stimulated bone resorption, but CGRP inhibited the effect mediated by IL 1β in a dose dependent manner. It is suggested that CGRP may inhibit osteoclastic bone resorption through two ways: One is that CGRP functions directly on osteoclasts to block their activation; the other is that CGRP regulates the release of cytokines by osteoblasts and indirectly affects the function of osteoclasts.展开更多
目的 探讨白细胞介素1β(IL-1β)基因+3954T/ C 多态性与乳腺癌易患性之间的关系.方法乳腺癌组为符合纳入标准并病理学确诊的乳腺癌新发病例223例,对照组为体检中心常规体检的健康女性284例,采用静脉采血分析各项指标后进行统计学分...目的 探讨白细胞介素1β(IL-1β)基因+3954T/ C 多态性与乳腺癌易患性之间的关系.方法乳腺癌组为符合纳入标准并病理学确诊的乳腺癌新发病例223例,对照组为体检中心常规体检的健康女性284例,采用静脉采血分析各项指标后进行统计学分析.结果 IL-1β+3954(rs1143634)和IL-1RN基因及基因型的频率在乳腺癌组与对照组之间差异无统计学意义(P>0.05);在肿瘤增殖抗原(ki67)的乳腺癌组中,IL-1β+3954(rs1143634)位点的C,T转换明显增高[C:96.5%(301/312)比88.8%(119/134);T:3.5%(11/312)比11.2%(15/134),P<0.05];在雌激素受体阴性的乳腺癌患者T等位基因的比例增高,差异有统计学意义[23.0%(32/139)比4.5%(15/332),P<0.05].结论 IL-1β基因+3954T/ C多态性与乳腺癌的易感性无相关性,但在ki67高指数的乳腺癌组中,IL-1β+3954(rs1143634)位点的C-T转换明显增高,在雌激素受体阴性和人表皮生长因子受体2-的乳腺癌患者中A2的比例增高,SNP可能与乳腺癌的不同分子类型相关.展开更多
BACKGROUND: Interleukin 1β-converting enzyme (ICE) gene expression can induce neuronal apoptosis. However, the dynamic changes in ICE gene expression and its effects on neuronal apoptosis under cerebral ischemia/r...BACKGROUND: Interleukin 1β-converting enzyme (ICE) gene expression can induce neuronal apoptosis. However, the dynamic changes in ICE gene expression and its effects on neuronal apoptosis under cerebral ischemia/reperfusion conditions remain unclear. OBJECTIVE: To observe neuronal apoptosis and changes in ICE gene expression in the frontal cortex and hippocampus following ischemia/reperfusion injury. DESIGN, TIME AND SETTING: A randomized, controlled animal study was conducted at the Laboratory of Experimental Animal Center, the Second Hospital of Jilin University and Central Laboratory, the Second Hospital of Jilin University, China, from November 2008 to September 2009. MATERIALS: The ICE gene primer sequence (TaKaPa Co., Dalian, China), FACScan Flow cytometer (Becton Dickinson, Franklin Lakes, N J, USA), and Perkin Elmer GeneAmp PCR system 2400 (Perkin Elmer, Waltham, MA, USA) were used in this study. METHODS: A total of 45 healthy, adult, male, Kunming mice were randomly assigned to normal control (n = 5), sham surgery (n = 5), and model (n = 35) groups. The mice in the model group were equally and randomly subdivided into seven subgroups according to various reperfusion time points (1 hour, 1,3, 7, 14, 28, and 42 days). Animal models of ischemia/reperfusion injury were established by bilateral carotid artery ligation in the model group. The mice in the sham surgery group only received saline perfusion and surgery for carotid artery exposure. MAIN OUTCOME MEASURES: Neuronal apoptosis in the frontal cortex and hippocampus of mice was measured using flow cytometry. The time course of ICE mRNA levels in the frontal cortex and hippocampus were quantified using reverse transcription-polymerase chain reaction. RESULTS: Neuronal apoptosis in the frontal cortex and hippocampus peaked at 3 days following ischemia/reperfusion injury (P 〈 0.05). ICE mRNA expression increased in the frontal cortex at 1 day following ischemia/reperfusion injury (P 〈 0.05), decreased at 3 days, and then peaked at 14 days (P 〈 0.05). ICE mRNA expression increased in the hippocampus at 3 days following ischemia/reperfusion injury (P 〈 0.05), peaked at 7 days (P 〈 0.05), and then decreased gradually to normal levels at 28 days. CONCLUSION: Neuronal apoptosis peaked at 3 days following ischemia/reperfusion injury, and both apoptosis and ICE mRNA levels remained high for 2 weeks after injury. Early apoptosis may result from increased ICE mRNA expression.展开更多
Summary: To explore the mechanism of interleukin-1beta ( IL-1β) in the onset of seizure and the effect of IL-1β on the expression of adenylyl cyclase (AC) in rats with seizure induced by L-glutamate. Experimental ra...Summary: To explore the mechanism of interleukin-1beta ( IL-1β) in the onset of seizure and the effect of IL-1β on the expression of adenylyl cyclase (AC) in rats with seizure induced by L-glutamate. Experimental rats were first injected with IL-1β and then L-glutamate (a dose under the threshold) was injected into the right lateral ventricle. The rats were sacrificed 4 h after the onset of epileptic activity and examined for changes in behavior, immunohistochemistry and compared with those with seizure induced by L-glutamate alone. It was found that the expression of AC in hippocampal and neocortex of rats with seizure induced by IL-1β and L-glutamate were stronger than that of control group (P<0.05), without significant difference found between the L-glutamate group and IL-1β plus L-glutamate group in the expression of AC, the latent period and the severity of seizure. When IL-ra were given (i.c.v.) first, there was no epileptic activity and the expression of AC did not increase. There were no differences in the expression of AC of rats with IL-1ra and that of control rats. But when 2-methyl-2-(carboxycyclopropyl)glycine (MCCG) was given (i.c.v.) first, the strongest expression of AC, the shortest latent period and the the most serious seizure activities were observed. The results indicated that IL-1β could facilitate the onset of epilepsy induced by L-glutamate through IL-1R, metabotropic glutamate receptors might work with IL-1R and the increased expression of AC might be involved in the process.展开更多
To investigate the intracellular mechanism that interleukin 1β (IL 1β) facilitates epileptic seizure and neuronal damage, the effect of IL 1β alone or IL 1β plus glutamate (Glu) on the intracellular free calci...To investigate the intracellular mechanism that interleukin 1β (IL 1β) facilitates epileptic seizure and neuronal damage, the effect of IL 1β alone or IL 1β plus glutamate (Glu) on the intracellular free calcium ([Ca 2+ ] i) of single cultured hippocampal neuron was examined by using EPC 9 light electricity measurement system. The results showed that IL 1β of different concentrations (5×10 3 U/L, 10×10 3 U/L, 20×10 3 U/L, 30×10 3 U/L, 50×10 3 U/L, 100×10 3 U/L) failed to affect the neuronal [Ca 2+ ] i, but IL 1β could facilitate the augmentation of neuronal [Ca 2+ ] i induced by Glu in a dose dependent pattern. MK 801 inhibited the effect of Glu on [Ca 2+ ] i, and also inhibited the effect of IL 1β on [Ca 2+ ] i induced by Glu, while verapamil did not influence the effect of Glu or IL 1β. It is concluded that IL 1β, as a neuromodulator, can facilitate the activation of NMDA receptor by Glu, induce the increase of intracellular calcium, which enhances the excitement of neuron.展开更多
Protective effect of interleukin 1β (IL 1β) on motor neurons was studied after peripheral nerve injury. Twenty Wistar rats were divided into 2 groups randomly. The right sciatic nerve of each rat was resected. Aft...Protective effect of interleukin 1β (IL 1β) on motor neurons was studied after peripheral nerve injury. Twenty Wistar rats were divided into 2 groups randomly. The right sciatic nerve of each rat was resected. After silicon tubulization of sciatic nerve in rat, 15 μl 1 ng/ml IL 1β and PBS solution were injected into the silicon capsule respectively. Enzyme histochemistry was performed to show acetyle cholesterase (AchE) and nitric oxide staining (NOS) activity of spinal α motor neurons in spinal segments 2 weeks later. Neurons were counted and the diameter and cross sectional (c/s) area of neurons were analyzed by using computer image analysis system. The results showed that as compared with the normal side, both enzyme activities significantly changed in motor neurons in PBS group. The diameter and c/s area of both neurons changed significantly too ( P< 0 01). These results suggest that exogenous IL 1β protects α motor neurons from degeneration and necrosis after peripheral nerve injury.展开更多
The in vivo effects of Phytolacca acinosa poly-saccharides I (PEP-I) on immunologic cytotoxicity of mouse peritoneal macrophages and its production of tumor necrosis factor (TNF) and interleukin 1 (IL-1) were studied....The in vivo effects of Phytolacca acinosa poly-saccharides I (PEP-I) on immunologic cytotoxicity of mouse peritoneal macrophages and its production of tumor necrosis factor (TNF) and interleukin 1 (IL-1) were studied. PEP-I 80 or 160 mg kg was given ip twice every 4 day. Both doses were found to have significant enhancing activity on macrophages cytotoxicity against S180 sarcoma cells and malignant transformed fibroblast L929 cells. Peritoneal activated macrophages were incubated with LPS for 2 and 24 hrs to induce TNF and IL-1, respectively. The TNF and IL-1 activities were tested from cytotoxicity against L929 cells in an absorbence assay of enzymatic reaction and proliferation of thymocytes co-stimulated assay separately. The optimal time for TNF production was found on day 8. Significant increases in TNF and IL-1 were observed. In comparison of the effect of PEP-I on TNF with that of known priming agent BCG, there was no difference between them, but PEP-I had a high effect on IL-1. These results suggest that cytotoxicity of macrophages primed by PEP-I is closely related to its TNF and IL-1 production.展开更多
A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury(TBI). Depression is one of these long-term complications that influences many aspects of life. Depression can limit...A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury(TBI). Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.展开更多
Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis.Obesity is an independent disease state that has been reported as a common risk ...Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis.Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease(NAFLD),retinopathy,critical limb ischemia,and impaired angiogenesis.Sterile inflammation driven by high-fat diet,increased formation of reactive oxygen species,alteration of intracellular calcium level and associated release of inflammatory mediators,are the main common underlying forces in the pathophysiology of NAFLD,ischemic retinopathy,stroke,and aging brain.This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein(TXNIP)to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states.Finally,the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.展开更多
Regulation of the adhesion molecules expression by cytokine in vascular endothelial cells was investigated. Human umbilical vein endothelial cells (HUVEC) were stimulated with cytokines, TNF α (1-250 U/ml) or IL 1...Regulation of the adhesion molecules expression by cytokine in vascular endothelial cells was investigated. Human umbilical vein endothelial cells (HUVEC) were stimulated with cytokines, TNF α (1-250 U/ml) or IL 1β (0.1-50 U/ml) for 24 h. HUVEC were also cultured with cytokines, TNF α (100 U/ml) or IL 1β (10 U/ml), for 4-72 h, cell surface expression of adhesion molecules (ICAM 1 and VCAM 1) were detected and quantitated by immunocytochemical methods and computerized imaging analysis technique. Adhesion molecules expression were up regulated by TNF α, IL 1β in a concentration and time dependent manner. Some significant differences were observed between the effects of cytokines on the ICAM 1 and on VCAM 1 expression. Cytokines might directly induce the expression of ICAM 1 and VCAM 1 in vascular endothelial cells. Our observations indicate differential functions of the two adhesion molecules during the evolution of inflammatory responses in stroke.展开更多
Patients with obstructive jaundice have a high susceptibility to infection in the process of treatment and the reason for this is not fully understood. It was postulated that it may bear some relations to abnormalitie...Patients with obstructive jaundice have a high susceptibility to infection in the process of treatment and the reason for this is not fully understood. It was postulated that it may bear some relations to abnormalities of immune function. In this article. 28 cases of obstructive jaundice were selected to investigate alternation of monocyte immune function with the purpose of exploring mechanism of high susceptibility to infection from the perspective of immunology. The results showed that interleukin 1 production by monocytes significantly decreased and prostaglandin E2 increased, HLA-DR expression of monocytes was markably depressed. HLA-DR expression of monocytes was further decreased with recovery slower than non-jaundiced patients after operation. All this may be responsible for high susceptibility to infection in the process of treatment of obstructive jaundice .展开更多
Interleukin(IL)1 superfamily members are a cornerstone of a variety of inflammatory processes occurring in various organs including the liver.Progression of acute and chronic liver diseases regardless of etiology depe...Interleukin(IL)1 superfamily members are a cornerstone of a variety of inflammatory processes occurring in various organs including the liver.Progression of acute and chronic liver diseases regardless of etiology depends on the stage of hepatocyte damage,the release of inflammatory cytokines and disturbances in gut microbiota.IL1 cytokines and re-ceptors can have pro-or anti-inflammatory roles,even dual functionalities conditioned by the microenvironment.Devel-oping novel therapeutic strategies to block the IL1/IL1R sign-aling pathways seems like a reasonable option.This mode of action is now exploited by anakinra and canakinumab,which are used to treat different inflammatory illnesses,and studies in liver diseases are on the way.In this mini review,we have focused on the IL1 superfamily members,given their cru-cial role in liver inflammation diseases,specifically discussing their potential role in developing new treatment strategies.展开更多
Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in y-secretase component genes.We and other researchers showed that nicastrin (NCSTN) ...Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in y-secretase component genes.We and other researchers showed that nicastrin (NCSTN) is the most frequently mutated gene in familial AI.In this study,we generated a keratin 5-Cre-driven epidermis-specific Ncstn conditional knockout mutant in mice.We determined that this mutant recapitulated the major phenotypes of AI,including hyperkeratosis of hair follicles and inflammation.In Ncstnflox/flox;K5-Cre mice,the IL-36a expression level markedly increased starting from postnatal day 0 (P0),and this increase occurred much earlier than those of TNF-α,IL-23A,IL-1 3,and TLR4.RNA-Seq analysis indicated that Sprr2d,a member of the small proline-rich protein 2 family,in the skin tissues of the Ncstnflox/flox,;K5-Cre mice was also upregulated on P0.Quantitative reverse-transcription polymerase chain reaction showed that other Sprr2 genes had a similar expression pattern.Our findings suggested that IL-36a might be a key inflammatory cytokine in the pathophysiology of AI and implicate malfunction of the skin barrier in the pathogenesis of AI.展开更多
To investigate the effect of lipopoly^saccharide(LPS) and dialyzer membrane on cytokine gene expression and protein production in uremic patients on continuous ambulatory peritoneal dialysis(CAPD) and regular hemodial...To investigate the effect of lipopoly^saccharide(LPS) and dialyzer membrane on cytokine gene expression and protein production in uremic patients on continuous ambulatory peritoneal dialysis(CAPD) and regular hemodialysis(HD) Methods Interleukin 1β(IL 1β) and interleukin 1 receptor antagonist(IL 1Ra) produced by cultured peripheral blood mononuclear cells(PBMC) after exposure to cuprammonium(Cup) membrane, polysulfone(PS) membranes or endotoxin were detected using enzyme linked immunoabsorbent assay mRNA expression was determined simultaneously by in situ hybridiztion Results In the absence of endotoxin, a small amount of IL 1β and IL 1Ra was produced by PBMC harvested from HD and CAPD patients after incubation with Cup or PS during subsequent 24 hour culture For healthy controls, IL 1β was barely detectable just above the detection limit Although no differences could be found in protein synthesis between Cup and PS, in situ hybridization showed that Cup induced markedly higher level mRNA coding for IL 1β and IL 1Ra In contrast, when subsequently stimulated with endotoxin, PBMC incubated with Cup could produce significantly larger amount of IL 1β and IL 1Ra compared with either unstimulated cells or post incubation PBMC with PS LPS stimulated PBMC in healthy subjects produced similar amount of IL 1β and markedly lower IL 1Ra as compared with uremic patients on HD and CAPD Conclusions Two steps are required in healthy control for IL 1β and IL 1Ra production: induction of mRNA transcription by membrane contact, followed by LPS induced translation, while in uremic patients on HD or CAPD bioincompatibility membrane and LPS have a synergetic effect on IL 1β and IL 1Ra production There exists an unbalance between IL 1β and its specific inhibitor in maintenance dialysis patients展开更多
基金supported by UniversitàCattolica(D1 intramural funds to RP)Italian Ministry of University and Research(PRIN 2022ZYLB7B,P2022YW7BP funds to CG).
文摘Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.
文摘BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.
基金National Natural Science Foundation of China(grant numbers:82172502 and 81974127).
文摘Background:Amyotrophic lateral sclerosis(ALS)is irreversible and fatal within 3-5 years,with limited options for treatment.It is imperative to develop a symptom-based treatment that may increase the survival of ALS patients and improve their quality of life.Inflammation status,especially elevated interleukin 1β(IL1β),has been reported to play a critical role in ALS progression.Our study determined that neutralizing circulating IL1βslows down the progression of ALS in an ALS mouse model.Methods:The ALS mouse model was developed by microinjection of lentivirus-carrying OPTN^(E478G)(optineurin,a mutation from ALS patients)into the intra-motor cortex of mice.Peripheral circulating IL1βwas neutralized by injecting anti-IL1βan-tibody into the tail vein.Enzyme-linked immunosorbent assay(ELISA)and real-time polymerase chain reaction(RT-PCR)were carried out to determine the protein and gene expression levels of IL1β.TUNEL assay was used to assess the neural cell death.Immunofluorescent staining of MAP2 and CASP3 was accomplished to evaluate neuronal cell apoptosis.Glial fibrillary acidic protein staining was performed to ana-lyze the number of astrocytes.Rotarod test,grip strength test,balance beam test,and footprint test were conducted to assess the locomotive function after anti-IL1βtreatment.Results:The model revealed that neuroinflammation contributes to ALS progression.ALS mice exhibited elevated neuroinflammation and IL1βsecretion.After anti-IL1βtreatment,ALS mice revealed decreased neural cell death and astrogliosis and gained improved muscle strength and motor ability.Conclusions:Blocking IL1βis a promising strategy to slow down the progression of ALS.
基金Supported by The Chinese Human Liver Proteome Project, No. 2004BA711A19-08National 863 Project, No.2007AA02Z100
文摘AIM: To evaluate the effects of positive regulation of recombinant human interleukin 1 receptor antagonist (rhIL-1Ra) on hepatic tissue recovery in acute liver injury in mice induced by carbon tetrachloride (CCl 4 ). METHODS: Acute liver damage was induced by injecting 8-wk-old mice with CCl 4 1 mL/kg (1:3 dilution in corn oil) intraperitoneally (ip). Survival after liver failure was assessed by injecting 8-wk-old mice with a lethal dose of CCl 4 2.6 mL/kg (1:1 dilution in corn oil) ip. Mice were subcutaneously injected with 1 mg/kg recombinant human IL-1Ra twice a day after CCl 4 treatment for 5 d. Serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels were determined with a commercial assay kit. Serum IL-1β, IL-1Ra levels were measured by enzyme-linked immunosorbent assay kit. Quantitative real-time polymerase chain reaction was used to determine liver IL-1β, IL-1Ra and IL-6 expression during CCl 4-induced acute liver injury. Liver sections were stained with hematoxylin-eosin. A histology-injury grading system was used to evaluate the degree of necrosis after acute liver injury. Proliferating cell nuclear antigen (PCNA) staining was used to evaluate the role of rhIL-1Ra in promoting hepatocyte proliferation. RESULTS: Quantitative analysis showed a higher level of IL-6 mRNA expression and reduced serum AST and ALT levels in the livers of the rhIL-1Ra-treated group at the early phase of CCl 4-induced acute liver injury. Histological examination indicated a decrease in centrilobular necrotic areas in mice treated with rhIL-1Ra, and a novel role of rhIL-1Ra in promoting hepatocyte proliferation was also supported by an increase of PCNA staining. All these results, accompanied by a strong survival benefit in rhIL-1Ra-treated vs PBS-treated groups, demonstrated that rhIL-1Ra administration ameliorated the histological damage and accelerated the regeneration and recovery process of the liver. CONCLUSION: rhIL-1Ra could be further developed as a novel therapeutic agent for the treatment of acute liver injury because of its ability to reduce hepatocellular damage and facilitate liver regeneration.
基金supported by the National 863 Project(2012AA10A403)the Natural Science Foundation of Ningbo City of China(2014A610187)the Scientific Research Foundation of Graduate School of Ningbo University(G14041)
文摘Interleukin 1β(IL-1β), the first interleukin to be characterized, plays a key role in regulating the immune response. In this study, we determined the c DNA and genomic DNA sequences of the IL-1β gene from the large yellow croaker, Larimichthys crocea. Phylogenetic analysis indicated that the IL-1β(Lc IL-1β) gene was most closely related to that of European seabass(Dicentrarchus labrax), sharing 67.8% amino acid identity. In healthy large yellow croaker, Lc IL-1β transcription was detected in all tested tissues, with the highest level found in the head kidney. Upon Vibrio alginolyticus infection, Lc IL-1β transcription in all tested tissues was significantly upregulated. Intraperitoneal injection of recombinant Lc IL-1β(r Lc IL-1β) improved the survival rate and reduced the tissue bacterial load after V. alginolyticus infection. In addition, r Lc IL-1β induced monocytes/macrophages(MO/MΦ) chemotaxis and increased phagocytosis and bactericidal activity in vitro. These results suggest that Lc IL-1β plays an important role in the large yellow croaker immune response against V. alginolyticus.
文摘To investigate the effect of calcitonin gene related peptide (CGRP) on bone resorption mediated by interleukin 1β(IL 1β) in vitro , the osteoclasts isolated from the long bones of newborn SD rats were co cultured with osteoblasts on ivory slices placed in 24 well plates . 24 h later, conditioned media containing CGRP and/or IL 1β were added to the wells respectively, and continued culturing for 48 h. After the cells were stripped off by ultrasonication, the ivory slices were stained in toludine blue. The number and the total area of resorption lacunae on each slice were measured by computer imaging analysis system. Our results showed that IL 1β significantly stimulated bone resorption, but CGRP inhibited the effect mediated by IL 1β in a dose dependent manner. It is suggested that CGRP may inhibit osteoclastic bone resorption through two ways: One is that CGRP functions directly on osteoclasts to block their activation; the other is that CGRP regulates the release of cytokines by osteoblasts and indirectly affects the function of osteoclasts.
文摘BACKGROUND: Interleukin 1β-converting enzyme (ICE) gene expression can induce neuronal apoptosis. However, the dynamic changes in ICE gene expression and its effects on neuronal apoptosis under cerebral ischemia/reperfusion conditions remain unclear. OBJECTIVE: To observe neuronal apoptosis and changes in ICE gene expression in the frontal cortex and hippocampus following ischemia/reperfusion injury. DESIGN, TIME AND SETTING: A randomized, controlled animal study was conducted at the Laboratory of Experimental Animal Center, the Second Hospital of Jilin University and Central Laboratory, the Second Hospital of Jilin University, China, from November 2008 to September 2009. MATERIALS: The ICE gene primer sequence (TaKaPa Co., Dalian, China), FACScan Flow cytometer (Becton Dickinson, Franklin Lakes, N J, USA), and Perkin Elmer GeneAmp PCR system 2400 (Perkin Elmer, Waltham, MA, USA) were used in this study. METHODS: A total of 45 healthy, adult, male, Kunming mice were randomly assigned to normal control (n = 5), sham surgery (n = 5), and model (n = 35) groups. The mice in the model group were equally and randomly subdivided into seven subgroups according to various reperfusion time points (1 hour, 1,3, 7, 14, 28, and 42 days). Animal models of ischemia/reperfusion injury were established by bilateral carotid artery ligation in the model group. The mice in the sham surgery group only received saline perfusion and surgery for carotid artery exposure. MAIN OUTCOME MEASURES: Neuronal apoptosis in the frontal cortex and hippocampus of mice was measured using flow cytometry. The time course of ICE mRNA levels in the frontal cortex and hippocampus were quantified using reverse transcription-polymerase chain reaction. RESULTS: Neuronal apoptosis in the frontal cortex and hippocampus peaked at 3 days following ischemia/reperfusion injury (P 〈 0.05). ICE mRNA expression increased in the frontal cortex at 1 day following ischemia/reperfusion injury (P 〈 0.05), decreased at 3 days, and then peaked at 14 days (P 〈 0.05). ICE mRNA expression increased in the hippocampus at 3 days following ischemia/reperfusion injury (P 〈 0.05), peaked at 7 days (P 〈 0.05), and then decreased gradually to normal levels at 28 days. CONCLUSION: Neuronal apoptosis peaked at 3 days following ischemia/reperfusion injury, and both apoptosis and ICE mRNA levels remained high for 2 weeks after injury. Early apoptosis may result from increased ICE mRNA expression.
文摘Summary: To explore the mechanism of interleukin-1beta ( IL-1β) in the onset of seizure and the effect of IL-1β on the expression of adenylyl cyclase (AC) in rats with seizure induced by L-glutamate. Experimental rats were first injected with IL-1β and then L-glutamate (a dose under the threshold) was injected into the right lateral ventricle. The rats were sacrificed 4 h after the onset of epileptic activity and examined for changes in behavior, immunohistochemistry and compared with those with seizure induced by L-glutamate alone. It was found that the expression of AC in hippocampal and neocortex of rats with seizure induced by IL-1β and L-glutamate were stronger than that of control group (P<0.05), without significant difference found between the L-glutamate group and IL-1β plus L-glutamate group in the expression of AC, the latent period and the severity of seizure. When IL-ra were given (i.c.v.) first, there was no epileptic activity and the expression of AC did not increase. There were no differences in the expression of AC of rats with IL-1ra and that of control rats. But when 2-methyl-2-(carboxycyclopropyl)glycine (MCCG) was given (i.c.v.) first, the strongest expression of AC, the shortest latent period and the the most serious seizure activities were observed. The results indicated that IL-1β could facilitate the onset of epilepsy induced by L-glutamate through IL-1R, metabotropic glutamate receptors might work with IL-1R and the increased expression of AC might be involved in the process.
文摘To investigate the intracellular mechanism that interleukin 1β (IL 1β) facilitates epileptic seizure and neuronal damage, the effect of IL 1β alone or IL 1β plus glutamate (Glu) on the intracellular free calcium ([Ca 2+ ] i) of single cultured hippocampal neuron was examined by using EPC 9 light electricity measurement system. The results showed that IL 1β of different concentrations (5×10 3 U/L, 10×10 3 U/L, 20×10 3 U/L, 30×10 3 U/L, 50×10 3 U/L, 100×10 3 U/L) failed to affect the neuronal [Ca 2+ ] i, but IL 1β could facilitate the augmentation of neuronal [Ca 2+ ] i induced by Glu in a dose dependent pattern. MK 801 inhibited the effect of Glu on [Ca 2+ ] i, and also inhibited the effect of IL 1β on [Ca 2+ ] i induced by Glu, while verapamil did not influence the effect of Glu or IL 1β. It is concluded that IL 1β, as a neuromodulator, can facilitate the activation of NMDA receptor by Glu, induce the increase of intracellular calcium, which enhances the excitement of neuron.
文摘Protective effect of interleukin 1β (IL 1β) on motor neurons was studied after peripheral nerve injury. Twenty Wistar rats were divided into 2 groups randomly. The right sciatic nerve of each rat was resected. After silicon tubulization of sciatic nerve in rat, 15 μl 1 ng/ml IL 1β and PBS solution were injected into the silicon capsule respectively. Enzyme histochemistry was performed to show acetyle cholesterase (AchE) and nitric oxide staining (NOS) activity of spinal α motor neurons in spinal segments 2 weeks later. Neurons were counted and the diameter and cross sectional (c/s) area of neurons were analyzed by using computer image analysis system. The results showed that as compared with the normal side, both enzyme activities significantly changed in motor neurons in PBS group. The diameter and c/s area of both neurons changed significantly too ( P< 0 01). These results suggest that exogenous IL 1β protects α motor neurons from degeneration and necrosis after peripheral nerve injury.
文摘The in vivo effects of Phytolacca acinosa poly-saccharides I (PEP-I) on immunologic cytotoxicity of mouse peritoneal macrophages and its production of tumor necrosis factor (TNF) and interleukin 1 (IL-1) were studied. PEP-I 80 or 160 mg kg was given ip twice every 4 day. Both doses were found to have significant enhancing activity on macrophages cytotoxicity against S180 sarcoma cells and malignant transformed fibroblast L929 cells. Peritoneal activated macrophages were incubated with LPS for 2 and 24 hrs to induce TNF and IL-1, respectively. The TNF and IL-1 activities were tested from cytotoxicity against L929 cells in an absorbence assay of enzymatic reaction and proliferation of thymocytes co-stimulated assay separately. The optimal time for TNF production was found on day 8. Significant increases in TNF and IL-1 were observed. In comparison of the effect of PEP-I on TNF with that of known priming agent BCG, there was no difference between them, but PEP-I had a high effect on IL-1. These results suggest that cytotoxicity of macrophages primed by PEP-I is closely related to its TNF and IL-1 production.
基金supported in part by a Kentucky Spinal and Head Injury Trust trainee fellowshipsupported by National Institutes of Health under award numbers R00 AG044445(to ADB)P30 GM110787(to ADB)
文摘A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury(TBI). Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.
文摘Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis.Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease(NAFLD),retinopathy,critical limb ischemia,and impaired angiogenesis.Sterile inflammation driven by high-fat diet,increased formation of reactive oxygen species,alteration of intracellular calcium level and associated release of inflammatory mediators,are the main common underlying forces in the pathophysiology of NAFLD,ischemic retinopathy,stroke,and aging brain.This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein(TXNIP)to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states.Finally,the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.
文摘Regulation of the adhesion molecules expression by cytokine in vascular endothelial cells was investigated. Human umbilical vein endothelial cells (HUVEC) were stimulated with cytokines, TNF α (1-250 U/ml) or IL 1β (0.1-50 U/ml) for 24 h. HUVEC were also cultured with cytokines, TNF α (100 U/ml) or IL 1β (10 U/ml), for 4-72 h, cell surface expression of adhesion molecules (ICAM 1 and VCAM 1) were detected and quantitated by immunocytochemical methods and computerized imaging analysis technique. Adhesion molecules expression were up regulated by TNF α, IL 1β in a concentration and time dependent manner. Some significant differences were observed between the effects of cytokines on the ICAM 1 and on VCAM 1 expression. Cytokines might directly induce the expression of ICAM 1 and VCAM 1 in vascular endothelial cells. Our observations indicate differential functions of the two adhesion molecules during the evolution of inflammatory responses in stroke.
文摘Patients with obstructive jaundice have a high susceptibility to infection in the process of treatment and the reason for this is not fully understood. It was postulated that it may bear some relations to abnormalities of immune function. In this article. 28 cases of obstructive jaundice were selected to investigate alternation of monocyte immune function with the purpose of exploring mechanism of high susceptibility to infection from the perspective of immunology. The results showed that interleukin 1 production by monocytes significantly decreased and prostaglandin E2 increased, HLA-DR expression of monocytes was markably depressed. HLA-DR expression of monocytes was further decreased with recovery slower than non-jaundiced patients after operation. All this may be responsible for high susceptibility to infection in the process of treatment of obstructive jaundice .
基金Croatian Ministry of Science and Education dedicated to multi-institutional fund-ing of scientific activity at the J.J.Strossmayer University of Osijek,Osijek,Croatia,grant number ZUP2018-90(to Ines Bilić Ćurčić).
文摘Interleukin(IL)1 superfamily members are a cornerstone of a variety of inflammatory processes occurring in various organs including the liver.Progression of acute and chronic liver diseases regardless of etiology depends on the stage of hepatocyte damage,the release of inflammatory cytokines and disturbances in gut microbiota.IL1 cytokines and re-ceptors can have pro-or anti-inflammatory roles,even dual functionalities conditioned by the microenvironment.Devel-oping novel therapeutic strategies to block the IL1/IL1R sign-aling pathways seems like a reasonable option.This mode of action is now exploited by anakinra and canakinumab,which are used to treat different inflammatory illnesses,and studies in liver diseases are on the way.In this mini review,we have focused on the IL1 superfamily members,given their cru-cial role in liver inflammation diseases,specifically discussing their potential role in developing new treatment strategies.
基金This work was financially supported by the National Key Research and Development Program of China(No.2016Y FC0905100)the CAMS Innovation Fund for Medical Sciences(No.2016-I2M-1-002)+3 种基金the National Natural Science Foundation of China(NSFCNos.81788101 and 81230015)the Beijing Municipal Science and Technology Commission(No.Z151100003915078)for Xue Zhangby the National NSFC(No.31271345)for Yaping Liu.
文摘Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in y-secretase component genes.We and other researchers showed that nicastrin (NCSTN) is the most frequently mutated gene in familial AI.In this study,we generated a keratin 5-Cre-driven epidermis-specific Ncstn conditional knockout mutant in mice.We determined that this mutant recapitulated the major phenotypes of AI,including hyperkeratosis of hair follicles and inflammation.In Ncstnflox/flox;K5-Cre mice,the IL-36a expression level markedly increased starting from postnatal day 0 (P0),and this increase occurred much earlier than those of TNF-α,IL-23A,IL-1 3,and TLR4.RNA-Seq analysis indicated that Sprr2d,a member of the small proline-rich protein 2 family,in the skin tissues of the Ncstnflox/flox,;K5-Cre mice was also upregulated on P0.Quantitative reverse-transcription polymerase chain reaction showed that other Sprr2 genes had a similar expression pattern.Our findings suggested that IL-36a might be a key inflammatory cytokine in the pathophysiology of AI and implicate malfunction of the skin barrier in the pathogenesis of AI.
文摘To investigate the effect of lipopoly^saccharide(LPS) and dialyzer membrane on cytokine gene expression and protein production in uremic patients on continuous ambulatory peritoneal dialysis(CAPD) and regular hemodialysis(HD) Methods Interleukin 1β(IL 1β) and interleukin 1 receptor antagonist(IL 1Ra) produced by cultured peripheral blood mononuclear cells(PBMC) after exposure to cuprammonium(Cup) membrane, polysulfone(PS) membranes or endotoxin were detected using enzyme linked immunoabsorbent assay mRNA expression was determined simultaneously by in situ hybridiztion Results In the absence of endotoxin, a small amount of IL 1β and IL 1Ra was produced by PBMC harvested from HD and CAPD patients after incubation with Cup or PS during subsequent 24 hour culture For healthy controls, IL 1β was barely detectable just above the detection limit Although no differences could be found in protein synthesis between Cup and PS, in situ hybridization showed that Cup induced markedly higher level mRNA coding for IL 1β and IL 1Ra In contrast, when subsequently stimulated with endotoxin, PBMC incubated with Cup could produce significantly larger amount of IL 1β and IL 1Ra compared with either unstimulated cells or post incubation PBMC with PS LPS stimulated PBMC in healthy subjects produced similar amount of IL 1β and markedly lower IL 1Ra as compared with uremic patients on HD and CAPD Conclusions Two steps are required in healthy control for IL 1β and IL 1Ra production: induction of mRNA transcription by membrane contact, followed by LPS induced translation, while in uremic patients on HD or CAPD bioincompatibility membrane and LPS have a synergetic effect on IL 1β and IL 1Ra production There exists an unbalance between IL 1β and its specific inhibitor in maintenance dialysis patients