Association of a genetic polymorphism of IL1RN with risk of acute pancreatitis in a Korean ethnic group

BACKGROUND/AIMS: Several epidemiological studies have validated the association of interleukin gene polymorphisms with acute pancreatitis (AP) in different populations. However, there have been few studies in Asian ethnic groups. We aimed to investigate the relationships between inflammatory cytokine polymorphisms and AP as pilot research in a Korean ethnic group. METHODS: Patients who had been diagnosed with AP were prospectively enrolled. DNA was extracted from whole blood, and DNA sequencing was subsequently performed. Single-nucleotide polymorphisms (SNPs) of the interleukin 1β (IL1B), interleukin 1 receptor antagonist (IL1RN), and tumor necrosis factor α (TNFA) genes of patients with AP were compared to those of normal controls. RESULTS: Between January 2011 and January 2013, a total of 65 subjects were enrolled (40 patients with AP vs. 25 healthy controls). One intronic SNP (IL1RN −1129T>C, rs4251961) was significantly associated with the risk of AP (odds ratio, 0.304; 95% confidence interval, 0.095 to 0.967; p = 0.043). However, in our study, AP was not found to be associated with polymorphisms in the promoter regions of inflammatory cytokine genes, including IL1B (−118C>T, c47+242C>T, +3954C/T, and −598T>C) and TNFA (−1211T>C, −1043C>A, −1037C>T, −488G>A, and −418G>A). CONCLUSIONS: IL1RN −1129T>C (rs4251961) genotypes might be associated with a significant increase of AP risk in a Korean ethnic group.

Role of MyD88-adaptor-like gene polymorphism rs8177374 in modulation of malaria severity in the Pakistani population

Abstract Introduction: The present study was designed to investigate the association between rs8177374 polymorphism and malaria symptoms due to exposure of Plasmodium vivax and Plasmodium falciparum. Materials and methods: A total of 454 samples were included in the study (228 malaria patients and 226 healthy individuals). Malaria patients, divided into P. vivax and P. falciparum groups on the basis of the causative species of Plasmodium, were categorized into mild and severe on the basis of clinical outcomes according to WHO criteria. Healthy individuals were used as controls. Allele specific PCR based strategy was used for the identification of rs8177374 SNP. Results: MyD88-adaptor-like gene polymorphism was associated with susceptibility to malaria (p < 0.001). C allele frequency (0.74) was higher in the population compared to T allele frequency (0.26). CT genotype increased the susceptibility of malaria (OR: 2.661; 95% CI: 1.722-4.113) and was positively associated with mild malaria (OR: 5.609; 95% CI: 3.479-9.044, p = 0.00). On the other hand, CC genotype was associated with severe malaria (OR: 3.116; 95% CI: 1.560-6.224, p = 0.00). P. vivax infection rate was higher in CT genotype carriers compared to other genotypes (OR: 3.616; 95% CI: 2.219-5.894, p < 0.001). Conclusion: MyD88-adaptor-like/TIR domain containing adaptor protein polymorphism for single nucleotide polymorphism rs8177374 is related with the susceptibility of malaria.

Progress on mechanisms for pathogensto evade NOD-like receptor and Toll-like receptor signaling pathways / 浙江大学学报·医学版

The innate immune system provides a first line of defense against invading pathogens, in which the pattern recognition receptors (PRR) recognize pathogen-associated molecular patterns (PAMP) and initiate the downstream signaling pathways to eliminate the encountered pathogens. There are two main classes of such signaling pathways: NOD-like receptor (NLR) signaling pathway and Toll-like receptor (TLR) signaling pathway. The microbial pathogens under selective pressure have evolved numerous mechanisms to avoid and/or manipulate the NLR and TLR signal transduction for survival and replication. To evade the NLR signaling pathway, pathogens interfere and/or inhibit inflammasome activation in innate immune cells by producing virulence factors or reducing PAMPs expression. The mechanisms for pathogens to evade TLR signaling pathway include: inhibition of mitogen activated protein kinases (MAPKs) cascade reaction, inhibition of NF-КB activation, and interference of down-stream signal transduction by producing Toll/interleukin-1 receptor (TIR)-containing proteins which bind directly with TLRs or adaptor proteins in the signaling pathway.

Significance of ST2 in the Early Diagnosis and Treatment of Graft-Versus-Host Disease--Review / 中国实验血液学杂志

Graft-versus-host disease (GVHD) is a major complication of allo-hematopoietic stem cell transplantation. It is reported that IL-2R, TNFR1, elafin (for skin GVHD) and REG-3α (for gastrointestinal GVHD) can be used in the early diagnosis of acute GVHD, but they cannot predict the response to therapy independently. Therefore, it is urgent to find a biomarker to predict GVHD and glucocorticoid resistance. ST2 is a member of IL-1 receptor family and specially binds to IL-33. Researchers have found that higher ST2 level is associated with increased GVHD risk, glucocorticoid resistance and transplantation-related mortality. This review focuses on the structure, function, signal transduction pathway of ST2/IL-33, and its roles in diagnosis and treatment of autoimmune diseases and GVHD.

Minimally traumatic alveolar ridge augmentation with a tunnel injectable thermo-sensitive alginate scaffold

Injectable bone substitutes and techniques have been developed for use in minimally invasive procedures for bone augmentation. Objective : To develop a novel injectable thermo-sensitive alginate hydrogel (TSAH) as a scaffold to induce bone regeneration, using a minimally invasive tunnelling technique. Material and Methods : An injectable TSAH was prepared from a copolymer solution of 8.0 wt% Poly(N-isopropylacrylamide) (PNIPAAm) and 8.0 wt% AAlg-g-PNIPAAm. In vitro properties of the material, such as its microstructure and the sustained release of recombinant human bone morphogenetic protein-2 (rhBMP-2), were investigated. Then, with the subperiosteal tunnelling technique, this material, carrying rhBMP-2, was injected under the labial periosteum of the maxillary anterior alveolar ridge in a rabbit model. New bone formation was evaluated by means of X-ray, micro-computed tomography (micro-CT), fluorescence labelling, histological study, and immunohistochemistry study. Results : The material exhibited good injectability and thermo-irreversible properties. SEM showed an interconnected porous microstructure of the TSAH. The result of ALP activity indicated sustained delivery of BMP-2 from the TSAH from days 3 to 15. In a rabbit model, both TSAH and TSAH/rhBMP-2 induced alveolar ridge augmentation. The percentage of mineralised tissue in the TSAH/rhBMP-2 group (41.6±3.79%) was significantly higher than in the TSAH group (31.3±7.21%; p<0.05). The density of the regenerating tissue was higher in the TSAH/rhBMP-2 group than in the other groups (TSAH group, positive control, blank control; p<0.05). Conclusions : The TSAH provided convenient handling properties for clinical application. To some extent, TSAH could induce ridge augmentation and mineral deposition, which can be enhanced when combined with rhBMP-2 for a minimally invasive tunnelling injection. .

TIRAP rs8177374 gene polymorphism increased the risk of pulmonary tuberculosis in Zahedan, southeast Iran

OBJECTIVE@#To evaluate the possible association between Toll-interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP; also known as MAL) rs1893352 and rs8177374 (S180L) gene polymorphisms and pulmonary tuberculosis (PTB) in a sample of Iranian population.@*METHODS@#This case-control study was performed on 174 PTB and 177 healthy subjects. Tetra amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) was used to detect the polymorphisms.@*RESULTS@#Our finding showed that neither the overall Chi-square comparison of PTB and control subjects nor the logistic regression analysis indicated any association between rs1893352 polymorphism and PTB. Regarding rs8177374 polymorphism, the CT genotype as well as CT+TT increased the risk of PTB in comparison with CC genotype (OR=4.73, 95% CI=2.65-8.45, P<0.0001 and OR=6.47, 95% CI=3.68-11.38, P<0.0001, respectively). The rs8177374 T allele increased the risk of PTB in comparison with C allele (OR=4.21, 95% CI=2.43-7.26, P<0.0001).@*CONCLUSIONS@#Our finding indicates that TIRAP rs8177374 polymorphism is associated with PTB in a sample of Iranian population.

Heparin inhibits burn-induced spleen cell apoptosis by suppressing interleukin-1 expression / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Epidermal burn injury may trigger significant apoptosis of the spleen cells, which might be caused by a burn-induced systemic inflammatory reaction. Heparin has been shown to possess anti-inflammatory properties. Interleukin 1 (IL-1) is centrally important among pro-inflammatory cytokines. We hypothesized that heparin might inhibit burn-induced apoptosis in the spleen via suppression of the IL-1 pathway.</p><p><b>METHODS</b>Burn injury was performed on IL-1 R+/+ ( IL-1 receptor wild-type mouse) and IL-1 R-/- (IL-1 receptor knock-out mouse) mice, and they were then treated with heparin, saline or IL-1 receptor antagonist IL-Ra. Apoptosis, IL-1α and IL-1β expression were assessed in the spleens and serum. Survival curve analysis was further applied to elucidate the mechanism of heparin's protective properties.</p><p><b>RESULTS</b>Burn induced significant apoptosis (sham: 3.6%± 2.1% vs. burn: 28.8%± 5.9%; P < 0.001) and remarkable expression o IL-1α and IL-1β in the mouse spleens and serum. Heparin reduced the burn-induced apoptosis in the spleens (heparin treated: 8.6%± 3.4%, P < 0.005), which could be blocked by IL-1Ra. Heparin markedly decreased both IL-1α and IL-1β expression in the spleens and serum of burned mice. IL-1 R-/- mice demonstrated considerably less apoptosis in the spleens and had a higher survival rate after burns. Heparin did not significantly decrease apoptosis in the spleen and the mortality rate in IL-1 R-/- mice after burns.</p><p><b>CONCLUSION</b>Heparin inhibits burn-induced apoptosis of the spleen cells by suppressing IL-1 expression in mice.</p>

Potential biomarkers for the clinical prognosis of severe dengue

Currently, several assays can confirm acute dengue infection at the point-of-care. However, none of these assays can predict the severity of the disease symptoms. A prognosis test that predicts the likelihood of a dengue patient to develop a severe form of the disease could permit more efficient patient triage and treatment. We hypothesise that mRNA expression of apoptosis and innate immune response-related genes will be differentially regulated during the early stages of dengue and might predict the clinical outcome. Aiming to identify biomarkers for dengue prognosis, we extracted mRNA from the peripheral blood mononuclear cells of mild and severe dengue patients during the febrile stage of the disease to measure the expression levels of selected genes by quantitative polymerase chain reaction. The selected candidate biomarkers were previously identified by our group as differentially expressed in microarray studies. We verified that the mRNA coding for CFD, MAGED1, PSMB9, PRDX4 and FCGR3B were differentially expressed between patients who developed clinical symptoms associated with the mild type of dengue and patients who showed clinical symptoms associated with severe dengue. We suggest that this gene expression panel could putatively serve as biomarkers for the clinical prognosis of dengue haemorrhagic fever.

Research on the changes of IL-1 receptor and TNF-alpha receptor in rats with cerebral ischemia reperfusion and the chronergy of acupuncture intervention / 中国针灸

<p><b>OBJECTIVE</b>To explore the intervention timing of acupuncture in treatment of cerebral infarction and the relationship of cerebral ischemia reperfusion injury with inflammatory cytokine receptor.</p><p><b>METHODS</b>One hundred and ten male healthy Wistar rats were randomly divided into a normal group (n=10), a sham operation group (n=10), a model group (n=10), an acupuncture at non-acupoint group (non-acupoint group, n=40), an acupuncture with regaining consciousness method group (regaining consciousness group, n=40). Four subgroups were set up 1 h ischemia reperfusion in 1 h group, 3 h group, 6 h group, 12 h group in the two acupuncture groups, 10 rats in each subgroup. Two acupuncture groups were treated with acupuncture at four time points (1 h, 3 h, 6 h and 12 h after ischemia reperfusion), and "Shuigou" (GV 26) and "Neiguan" (PC 6) were selected in regaining consciousness group, and the non-acupoints below the bilateral costal region were selected in non-acupoint group. At the corresponding time point, the tissues of the brain were removed and interleukin1 receptor (IL-1RI) and tumor necrosis factor receptor (TNFR-I) mRNA and protein changes were detected by using real-time quantitative polymerase chain reaction and immunoblot assay.</p><p><b>RESULTS</b>The expression of IL-1RI and TNFR-I mRNA and protein in the model group were significantly higher than that in normal group, sham operation group, regaining consciousness group and non-acupoint group (P<0.01, P<0.05). The expression of IL-1RI and TNFR-I mRNA and protein in regaining consciousness group was weakest at 3 h after reperfusion followed successively by 6 h, 1 h, 12 h, and there was no significantly change of IL-1RI and TNFR-I mRNA and protein expression in non-acupoint group among different timing points, but which was decreased as compared with those in the model group at the same time point (all P<0.05).</p><p><b>CONCLUSION</b>Acupuncture can reduce the expression of IL-1RI and TNFR-I mRNA and protein in rats with cerebral ischemia reperfusion, inhibit the excessive expression of proinflammatory cytokine receptor, block apoptosis signal transduction and extend time window for treatment of cerebral ischemia, so as to play the protective effect for brain. Within 3 h of ischemia is the best time for intervention of acupuncture treatment.</p>

Interleukin-1 receptor antagonist gene polymorphism in patients with multidrug-resistant Acinetobacter baumannii-associated pneumonia

Multidrug-resistant Acinetobacter baumannii [MDRAB]-associated pneumonia has been a common disease and a therapeutic problem in hospitals. Interleukin-1 receptor antagonist [IL-1ra] has been considered a required role for host immune defense in pneumonia disease. The aim of this study was to investigate whether the variable nucleotide tandem repeat polymorphism of the IL-1ra gene was associated with MDRAB-related pneumonia. Sixty-six pneumonia patients were enrolled in the study: 36 subjects had MDRAB-related pneumonia and 30 controls had non-MDRAB pneumonia. Polymerase chain reaction, restriction fragment length polymorphism, and agarose gel electrophoresis techniques were used to determine the IL-1ra genotype. The frequencies of the IL-1ra genotype in the MDRAB-related pneumonia cases were A1/A1, 0.889 and A1/A2, 0.111; the frequencies of the IL-1ra genotype in the controls were A1/A1, 0.333 and A1/A2, 0.667. A statistically significant difference was determined [P < 0.05]. We also observed an increase in the frequency of IL-1ra A1 allele in the MDRAB-related pneumonia group. A statistically significant difference was determined [P<0.05]. We suggested that IL-1ra polymorphism was associated with the risk of MDRAB-related pneumonia

Synergy between adiponectin and interleukin-1beta on the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in fibroblast-like synoviocytes

To determine whether adiponectin may have synergistic effects in combination with the proinflammatory cytokine interleukin (IL)-1beta regarding the production of proinflammatory mediators during arthritic joint inflammation, synovial cells from rheumatoid arthritis (RA) patients were treated with adiponectin, IL-1beta, and their combination for 24 h. Culture supernatant was collected and analyzed by enzyme-linked immunosorbent assay for levels of IL-6, IL-8, prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs). Adiponectin-mediated intracellular signaling pathways were investigated to elucidate the molecular mechanisms underlying their synergy. The association of proinflammatory mediators with adiponectin was investigated in the synovial fluid of arthritis patients. Adiponectin functioned synergistically with IL-1beta to activate IL-6, IL-8, and PGE2 expression in RA fibroblast-like synoviocytes; Levels of VEGF, MMP-1, and MMP-13 were not synergistically stimulated. Adiponectin and IL-1beta each increased the expression of both adiponectin receptor 1 and IL-1 receptor 1. However, adiponectin and IL-1beta did not synergistically support the degradation of IkappaB-alpha or the nuclear translocation of NF-kappaB. Synergistically increased gene expression was significantly inhibited by MG132, an NF-kappaB inhibitor. Supporting the in vitro results, IL-6 and IL-8 levels were positively associated with adiponectin in synovial joint fluid from patients with RA, but not osteoarthritis (OA). In conclusion, adiponectin and IL-1beta may synergistically stimulate the production of proinflammatory mediators through unknown signaling pathways during arthritic joint inflammation. Adiponectin may be more important to the pathogenesis of RA than previously thought.

O polimorfismo do antagonista do receptor da interleucina-1 (IL1RN) como fator contribuinte para gravidade da cardite reumática em brasileiros / Interleukin-1 receptor antagonist gene (IL1RN) polymorphism as a contributing factor for the severity of rheumatic carditis in a brazilian cohort

A febre reumática (FR) é uma doença imuno-mediada, na qual citoquinas pró-inflamatórias têm um importante papel. Uma produção exacerbada de interleucina-1 (IL-1) parece ser um evento precoce entre as anormalidades imunológicas observadas na FR. O antagonista do receptor de IL-1 (IL1-RA) é um inibidor competitivo endógeno do receptor da IL-1. A razão IL-1RA/IL-1 é importante na determinação da intensidade e duração da resposta inflamatória. O alelo 2 (A2) do gene codificador do IL1-RA (IL1RN) tem sido relacionado a um número de doenças inflamatórias e autoimunes, bem como a uma maior resistência a infecções. Considerando que a FR é uma doença inflamatória autoimune desencadeada por uma infecção bacteriana, nós avaliamos o polimorfismo do IL1RN com o intuito de determinar possível relevância na susceptibilidade à FR e suas manifestações clínicas. O genótipo de 84 pacientes com FR e 84 controles pareados por raça foram determinados através da análise do número de repetições em tandem de 86pb no segundo íntron do IL1RN. O DNA foi extraído de leucócitos de sangue periférico e amplificado com sondas específicas. Dados sobre as manifestações clínicas da FR foram obtidos através de questionários padronizados e extensa revisão de prontuários. Cardite foi definida como sopro cardíaco novo auscultado por médico treinado com a correspondente regurgitação ou estenose valvar ao ecocardiograma. Cardite foi definida como grave na presença de insuficiência cardíaca congestiva ou da indicação de cirurgia cardíaca. A associação estatística entre genótipos, FR e suas variações clínicas foram determinadas. A presença do alelo 1 (A1) e do genótipo A1/A1 foram menos freqüentemente encontradas entre pacientes com cardite severa quando comparado a pacientes sem esta manifestação (OR= 0.11, p=0.031; OR= 0.092, p=0.017)...

Rheumatic fever (RF) is an immune-mediated disease in which proinflammatory cytokines play an important role. Exacerbated Interleukin-1 (IL- 1) production seems to be an early event in the immunological abnormalities that are observed in RF. The Interleukin-1 receptor antagonist (IL-1ra) is an endogenous competitive inhibitor of IL-1. The IL-1ra/IL-1 ratio is important in evaluating the intensity and duration of the inflammatory response. The second allele (A2) for the IL-1ra gene (IL1RN) has been related to a number of inflammatory and autoimmune diseases as well as to a greater resistance to infections. Considering that RF is an inflammatory autoimmune disease that is triggered by a bacterial infection, we have evaluated the IL1RN polymorphism and its possible relevance to the susceptibility to RF and its clinical manifestations. The genotypes of 84 RF patients (Jones criteria) and 84 normal race-matched controls were determined through the analysis of the number of 86-bp tandem repeats in the second intron of IL1RN. The DNA was extracted from peripheral-blood leukocytes and amplified with specific primers. Clinical manifestations of RF were obtained through a standardized questionnaire and an extensive chart review. Carditis was defined as new onset cardiac murmur that was perceived by a trained physician with corresponding valvae regurgitation or stenosis on echocardiogram. Carditis was classified as severe in the presence of congestive heart failure or upon the indication for cardiac surgery. The statistical association among the genotypes, RF and its clinical variations was determined. The presence of allele 1 and the genotype A1/A1 were found less frequently among patients with severe carditis when compared to patients without this manifestation (OR= 0.11, p=0.031; OR= 0.092, p=0.017). Neither allele 1 nor allele 2 were associated with the presence of RF (p=0.188; p=0.106), overall carditis (p=0.578 and p=0.767), polyarthritis (p=0.343 and p=0.313) and chorea (p=0.654 and p=0.633). In conclusion, for this Brazilian cohort, the polymorphism of the IL-1ra gene is a relevant factor for rheumatic heart disease severity.

IL-1, IL-1R and TNFalpha gene polymorphisms in Iranian patients with multiple sclerosis

Different research groups have extensively studied the associations of cytokine gene polymorphisms in different diseases. The role of cytokines gene polymorphisms in multiple sclerosis [MS], as a chronic Immune-mediated neurodegenerative disease, has been previously reported in the various populations. For determining pro-inflammatory cytokine gene polymorphisms, 100 relapsing remitting multiple sclerosis [RRMS] Iranian patients and 140 normal individuals as control enrolled in this study. DNA of each sample was extracted by a modified salting out method. Cytokine single gene nucleotide polymorphisms including IL-1alpha -889, IL-1beta [-511 and +3962], IL-1R pst1 1970, IL-1RA mspal 11100, and TNF-alpha [-308 and -238] were determined by using the PCR-SSP method. The results of our data indicate the decrease in frequency of IL-1alpha TC-889 genotype [p=0.002], IL-1beta TC +3962 genotype [p=0.004], IL-1R T pst1 1970 allele [p= 0.0001], IL-1 RA TC Mspa1 11100 genotype [p=0.009], TNF-alpha A-308 allele [p=0.0002] and AG genotype [p=0.00001] in the patients group versus normal subjects. On the other hand the frequency of IL-1alpha TT -889 genotype [p=0.028], IL-1R C pst1 1970 allele [p=0.0001] and CC genotype [p=0.00006], TNFalpha G -308 allele [p=0.0002] and GG genotype [p=0.000001] decreased significantly in the patients versus normal subjects. These results suggest that polymorphic variations of these pro-inflammatory cytokines may play an important role in susceptibility of Iranian multiple sclerosis patients

lnterleukin-1 beta, lnterleukin-1 receptor antagonist and tumor necrosis factor-alpha, in children with simple febrile convulsions

Pro- and anti inflammatory cytokines regulate the febrile response during infection. Febrile convulsions [FCs] conversely are associated with rapid onset of high fever. Activation of the cytokine network has been shown in previous studies of FCs and cytokines. In this study, the association between cytokines and FCs was further investigated. lnterleukin-1 beta [IL-1 beta], interleukin-1 receptor antagonist [IL-1RA], and tumor necrosis factor-a [TNF-a] plasma levels were measured with enzyme-linked immunosorbent assay in 40 children with FCs and in 20 age-matched febrile controls immediately on arrival at the emergency room or pediatric clinic. Cerebrospinal fluid [C.S.F.] level of these cytokines also, was measured in 7 FC children. The plasma IL-1 beta level was lower in FC children when compared with controls [mean +/- SD, 19.5 +/- 7.72 pg/ml vs. 57.2 +/- 10.43 pg/ml; p = 0.1], but the difference was not statistically significant. FC patients had significantly higher plasma IL-1RA levels [mean +/- SD, 15357 +/- 4870 pg/ml vs. 3963 +/- 2950 pg/ml; p = 0.0005]. The plasma IL-1RA/IL-1p ratio was significantly higher in FC patients compared with controls [mean, 7875 vs. 69.283; p < 0.0001]. There was no significant difference in plasma TNF-alpha level between FC patients and controls [mean +/- SD, 7.42 +/- 3.12 pg/ml vs. 6.71 +/- 4.8; p = 0.63]. In C.S.F, IL-1RA was detectable in 5, IL-1beta in one and TNF-alpha was undetectable in the 7 studied FC patients. Logistic regression analysis was used to find the most significant predisposing factors for FCs. In this analysis, the high plasma IL-1RA/IL-1beta ratio was the most significant factor connected to FCs [OR, 41.5; 95% CI, 4.9-352.8]. Present results support the hypothesis that the cytokine network is activated and could have a role in the pathogenesis of FCs

Effect of interleukin-1 beta on growth hormone gene expression and its possible molecular mechanism in rat MtT/S somatotroph cells / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To elucidate the effect of interleukin-1 beta (IL-1 beta) on human growth hormone (hGH) gene expression in a rat somatotropic pituitary cell line MtT/S.</p><p><b>METHODS</b>Stably transfected MtT/S cells were firstly established by transfecting 484-Luc1 plasmid which contained hGH gene promoter -484 to +30 bp and luciferase reporter gene. The effect of IL-1 beta on hGH gene expression was determined by assaying the luciferase activities. RT-PCR method was also used to determine whether IL-1 recepor mRNA was expressed in MtT/S cells.</p><p><b>RESULTS</b>The 10(3) U/mL IL-1 beta stimulated secretion and synthesis of GH, and promoted the 5'-promoter activity of GH gene in stably transfected MtT/SGL cells with the action of 1.38 times above the control. Among inhibitors of signaling transduction pathways, mitogen-activated protein kinase kinase (MAPKK/MEK) inhibitor PD98059 (40 micromol/L) and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 (5 micromol/L) completely blocked the stimulatory effect of IL-1 beta, and phosphatidylinositol-3-kinase (PI3-K) inhibitor LY294002 partly abolished the effect of IL-1 beta. Western blot analysis further confirmed the activation of phosphorylated MEK and p38 MAPK in MtT/SGL cells. Neither over-expression of Pit-1 nor inhibition of Pit-1 expression affected induction of hGH promoter activity by IL-1 beta. A series of deletion constructs of hGH promoter were created to identify the DNA sequence that mediated the effect of IL-1 beta, and results showed that the stimulatory effect of IL-1 beta was abolished following deletion of the -196 to -132 bp fragment.</p><p><b>CONCLUSIONS</b>IL-1 beta promotes GH secretion and synthesis in rat MtT/S somatotroph cells. The stimulatory effect of IL-1 beta on hGH gene promoter appears to require the activation of MEK, p38 MAPK, PI3-K, and a fragment of promoter sequence that spans the -196 to -132 bp of the gene, but it may be unlinked with Pit-1 protein.</p>

Differential T-helper 2 cell function predominance in pregnant rheumatoid arthritis females: a possible concept for pregnancy-induced amelioration

Despite being a physiological process, pregnancy has been noted by clinicians to have various impacts on different diseases in general and on immune-modulated diseases in particular. Concerning rheumatoid arthritis [RA], several studies reported a favorable outcome of the disease during pregnancy. Several researches looked at this pregnancy-induced improvement as a result of a change in the T helper 1/T helper 2 [Th1/Th2] function with predominance of Th2 function. To assess the status of serum levels of soluble tumor necrosis factor receptor [sTNF-R], interleukin-1 receptor antagonist [IL-1Ra] and soluble CD30 [sCD30] -during the three trimesters of pregnancy- in pregnant ladies and evaluate their relations to disease activity in RA patients. The study was performed on 21 pregnant RA patients, of whom only 17 completed the study. They were subjected to clinical assessment of their disease activity and had their sera tested for the level of the three aforementioned indirect Th2 cell function markers. This clinical examination and serum tests were performed once in each pregnancy trimester. These results were compared to those of thirty other controls: ten non-pregnant RA patients, ten pregnant healthy subjects and ten non-pregnant healthy subjects. The study showed definite and significant higher levels of sTNF-R and IL-1Ra in pregnant RA patients and pregnant healthy subjects when compared with non-pregnant controls. These rises of markers levels were negatively correlated with the disease activity. There were no corresponding differences in levels of sCD30 in the two groups. We conclude that during pregnancy there is a differential predominance of Th2 cell function involving an increase in some anti-inflammatory cytokines that could explain the clinical improvement of RA during pregnancy

Toll-like receptor signal transduction

Toll-like receptors (TLRs) are the archetypal pattern recognition receptors in sensing exogenous pathogens. Activation of TLRs is a first line of defense of the immune system, leading to the activation and recruitment of neutrophils and macrophages to sites of infection and enhances antimicrobial activity. The TLR signaling through different intracellular molecules, such as MAP kinases and IkappaB kinases which are conserved signaling elements for many receptors, leads to a distinct set of proinflammatory gene expressions. However, how these pathways differentially and precisely control the transcription of identical genes remains largely unknown. Our review focuses on the details of up-to- date signaling molecules including negative regulators and their role in controlling innate immune response. We also stress the importance of developing systemic approaches for the global understanding of TLR signaling so that appropriate drug therapeutic targets can be identified for regulating inflammatory diseases.

Association of interleukin-1 gene cluster polymorphisms with ischemic stroke in a Chinese population.

BACKGROUND AND AIMS: Chronic inflammatory process plays an important role in atherothrombosis. Interleukin-1 (IL-1) is one of the key modulators of the inflammatory response and its activity is critically regulated by its receptor antagonist (IL-1Ra). A variable number tandem repeat polymorphism in intron 2 of IL-1Ra gene and a C to T single base polymorphism in the promoter of IL-1beta gene (C(-511)-->T) have been reported to affect the levels of IL-1 as well as its antagonist, IL-1Ra. It is also reported in several studies that these polymorphisms are associated with the susceptibility to cardio-cerebral vascular disease. However, data are limited in China. In this article, we studied the relationships between these polymorphisms and the risk of ischemic stroke in China. MATERIALS AND METHODS: One hundred and twelve patients committed ischemic stroke were compared with 95 demographically matched healthy volunteers. RESULTS: The frequencies of the IL-1Ra 1/1 genotype and IL-1Ra allele 1 (Ra*1 allele) in stroke patients were significantly higher than those in healthy volunteers [93.7% vs. 82.1%, P =0.014; 0.964 vs. 0.905, P =0.007]. No significant differences were found in the IL-1beta -511 genotype and the allele distribution between the two groups. CONCLUSIONS: Our results implicated that IL-1 gene polymorphism might be associated with the susceptibility to ischemic stroke.

Expression of human interleukin-1 receptor antagonist in the transfected chondrocytes of temporomandibular joint / 华西口腔医学杂志

<p><b>OBJECTIVE</b>To investigate the expression of the human interleukin-1 receptor antagonist (hIL-1ra) in the transfected chondrocytes of temporomandibular joint (TMJ).</p><p><b>METHODS</b>Chondrocytes of TMJ in vitro were transfected by hIL-1ra gene via cationic liposome as a medium. The stable transfected cells were selected by G418. The proliferations of the transduced cell were examined with the growth curve, cell population doubling time. The protein expressing in different periods was detected by immunocytochemistry and enzyme-linked immunosorbent assay (ELISA).</p><p><b>RESULTS</b>The proliferation suppression of gene transfected cells fell significantly with compared to normal cells. The expression of hIL-1ra was detected in the cell plasma and the cell culture supernatant. The highest expression of IL-1ra protein was at the time of 48 hours after gene transfection. The transiently transfected cells were secreted IL-1ra protein continuously 28 days and the stably transduced cells were secreted IL-1ra protein till 72 days.</p><p><b>CONCLUSION</b>This study showed that hIL-1ra protein expressed positively in the cell plasma and the culture supernatant after gene transfection within a certain periods.</p>

Interleukin-1 receptor antagonist among chronic renal failure pediatric patients with and without hemodialysis

During hemodialysis [HD], human blood leucocytes in circulation are exposed to several extraneous challenges, thus stimulated to secrete many inflammatory cytokines and its inhibitors as inter-leukin-1 and interieukin-1 receptor antagonist [IL-Ira]. The aim of this study was to investigate difference in the level of IL-IRa synthesis by peripheral blood mononuclear cells [PBMC] between CRF patients under conservative treatment and CRF patients under hemodialysis, and if this cytokine-specific inhibitory protein of PBMC can be used as a marker of dialysis related morbidity. The study included 44 subjects divided into 3 groups: [A] control group, [B] Chronic renal failure[CRF] under conservative treatment, [C] CRF under HD. Peripheral blood mononuclear cells [PBMC] were separated by ficoll-Hypaque. Spontaneous and Phytohemagglutinin [PHA] stimulated total IL-1Ra synthesis [cell-associated and secreted] by cultured PBMC was measured using EL-ISA method. The results of the study revealed that there were significant spontaneous total IL-IRa synthesis by PBMC in dialysis patients [group C] 2812 +/- 836 and in patients with conservative treatment [group B] 1791.2 +/- 252 compared to control group [group A] 940 +/- 227.8 [P value <0.001]. There were significant spontaneous total IL-IRa synthesis by PBMC in dialysis patients [group C] 2812 +/- 836 compared to patients with conservative treatment [group B] 1791.2 +/- 252 [P value <0.001]. There were significant PHA stimulated total IL-IRa synthesis by PBMC in dialysis patients [group C] 34041 +/- 8906 and in patients with conservative treatment [group B] 8565 +/- 1244 compared to control group [group A] 2980 +/- 608 [P value <0.001]. There were significant PHA stimulated total IL-IRa synthesis by PBMC in dialysis patients [group C] 34041 +/- 8906 compared to patients with conservative treatment [group B] 8565 +/- 1244 [P value <0.001]. There was positive correlation between PHA stimulated total synthesis of ILIRa and spontaneous total synthesis of ILIRa by PBMC in the 3 groups [P value <0.001]. There was significant correlation between IL-IRa [spontaneous and stimulated] with blood pressure, urea and creatinine level [P value <0.001]. This study concluded that PBMC of CRF patients synthesize significant level of IL-IRa compared to PBMC of healthy subjects. Also, PBMC of CRF patients on HD synthesize significant level of IL-IRa compared to PBMC of CRF under conservative treatment. Lastly, IL-IRa synthesis by PBMC of CRF patients was correlated with blood urea, serum creatinine and blood pressure level