Polimorfismos genéticos da interleucina-1 e o risco de periodontite periapical crônica numa população de Antioquia, Colômbia / Il-1 gene polymorphisms and the risk of chronic periapical periodontitis in a population from Antioquia, Colombia

Objetivo: Determinar a frequência de polimorfismos bialélicos em IL-1A (rs1800587, posição − 889) e IL-1B(rs1143634, posição + 3954) numa amostra de indivíduos da região de Antioquia, Colômbia, com diagnóstico de periodontite periapical crônica ou periápice saudável; avaliando sua possível associação, junto com o hábito de fumar, no desenvolvimento de periodontite perirradicular. Materiais e métodos: A amostra incluída neste estudo consistiu em 54 indivíduos da região de Antioquia, Colômbia com diagnóstico clínico e imaginológico de periodontite periapical crônica (n = 27) ou com periápice saudável (n = 27). O genótipo dos indivíduos foi determinado utilizando-se análises dos polimorfismos do comprimento de fragmentos de restrição (RFLPs), após realizada a extração do DNA da mucosa oral. Resultados: Foi encontrada umaassociação, embora não estatisticamente significativa, entre o efeito combinado de fumar e apresentar pelo menos um alelo mutante em IL-1B (rs1143634, posição + 3954, C/T), com o desenvolvimento de periodontite periapical (OR = 4,8; 0,2 – 99,1). Isto mesmo ocorreu com as variáveis de fumar (OR = 3,7; 0,5 – 29,2), ou apresentar pelo menos um alelo mutante em IL-1A (rs1800587, posição − 889, C/T) (OR = 3,2; 0,5 – 19,0). Conclusão: A presença de polimorfismos genéticos bialélicos em IL-1 parece constituir, junto com o hábito de fumar, fatores de risco para o desenvolvimento de periodontite apical crônica após o desenvolvimento de necrose pulpar.

Objective: The aim of this study was to determine the frequency of biallelic polymorphisms in IL-1A (rs1800587,position − 889) and IL-1B (rs1143634, position + 3954) in a sample of individuals from Antioquia department, diagnosed with chronic periapical periodontitis or healthy periapex, evaluating their possible association, together with tobacco habits, in the development of perirradicular periodontitis. Material and methods: The sample consisted of 54 individuals with a clinical and imagenologic diagnosis of chronic periapical periodontitis (n = 27) or healthy periapex (n = 27). The genotype of individuals was determined by using restriction fragment length polymorphism (RFLPs), after the DNA extraction from buccal mucosa. Results: Association was found, although not statistically significant, between the combined effect of smoking and having at least one mutated allele in IL-1B (+ 3954 position, C/T), with the development of periapical periodontitis (OR = 4.8, 0.2 – 99.1). Also, smoking (OR = 3.7, 0.5 – 29.2), or having at least one mutated allele in IL-1A (rs1800587, position − 889, C / T) (OR = 3.2, 0.5 – 19.0), were associated with periapical periodontitis development, even though with p values greater than 0.05. Conclusion: The presence of biallelic genetic polymorphisms in IL-1 appears to be, along with smoking, risk factors for chronic apical periodontitis after the development of dental pulp necrosis.

Effects of adenovirus-mediated bFGF, IL-1Ra and IGF-1 gene transfer on human osteoarthritic chondrocytes and osteoarthritis in rabbits

The study investigated the effects of adenovirus-mediated gene transfection of basic fibroblast growth factor (bFGF), bFGF combined with interleukin-1 receptor antagonist protein (IL-Ra) and/or insulin-like growth factor-1 (IGF-1) both in human osteoarthritis (OA) chondrocytes and rabbits OA model. Human OA chondrocytes were delivered by adenovirus-mediated bFGF, IL-Ra and IGF-1 vectors, respectively. Chondrocyte proliferation, glycosaminoglycan (GAG) content, expression of type II collagen, ADAMTS-5, MMP-13, MMP-3 and TIMP-1 were determined. Rabbit OA model was induced by anterior cruciate ligament transaction (ACLT) in knees. Adenoviral vectors encoding human bFGF, IL-Ra and IGF-1 were injected intraarticularly into the knee joints after ACLT. The effects of adenovirus- mediated gene transfection on rabbit OA were evaluated. In vitro, the transfected genes were expressed in cell supernatant of human OA chondrocytes. AdbFGF group significantly promoted chondrocyte proliferation, and increased GAG and type II collagen synthesis than in the OA group. As two or three genes were transfected in different combinations, there was significant enhancement on the GAG content, type II collagen synthesis, and TIMP-1 levels, while ADAMTS-5, MMP-13, and MMP-3 levels were reduced. In vivo, the transfected genes were expressed in synovial fluid of rabbits. Intraarticular delivery of bFGF enhanced the expression of type II collagen in cartilage and decreased cartilage Mankin score compared with the OA control group (P = 0.047; P < 0.01, respectively). Multiple-gene transfection in different combinations showed better results than bFGF transfection alone. This study suggests that bFGF gene transfection is effective in treating experimental OA. Multiple gene transfection has better biologic effects on OA.

Influence of IL-1 gene polymorphism on the periodontal microbiota of HIV-infected Brazilian individuals

This study investigated the association of IL-1A (+4845) and IL-1B (+3954) gene polymorphism with the subgingival microbiota and periodontal status of HIV-infected Brazilian individuals on highly active antiretroviral therapy (HAART). One hundred and five subjects were included in the study, distributed into 2 HIV groups [29 chronic periodontitis (CP+) and 30 periodontally healthy (H+)]; and 2 non-HIV groups (29 CP- and 17 H- patients). IL-1A and B were genotyped by PCR and restriction enzyme digestion. Thirty-three bacterial species were detected by checkerboard. Overall, we observed a prevalence of the allele 2 in the IL1-A and IL-1B polymorphism at 30.5 percent and 25.7 percent, respectively. Only 11.4 percent of all patients were composite genotype-positive, and 75 percent of those were HIV-infected. No significant associations between polymorphism of the IL-1 gene and periodontitis or HIV infection were observed. Likewise, no significant differences in the frequency and counts of any bacterial species were found between individuals with and without allele 2 (IL-1A or IL-1B). The data indicated that the IL-1 gene polymorphism is neither associated with periodontal destruction nor with high levels of subgingival species, including putative periodontal pathogens in HIV Brazilian individuals on HAART.

Polimorfismo genético de interleuquina-1: Asociación con cáncer gástrico en la población de alto riesgo del Centroccidente de Venezuela / lnterleukin-1 genetic polymorphism: Association with gastric cancer in the high-risk Central-Western population of Venezuela

Background: Genetic predisposition may play a role in the prevalence of gastric cancer (GC). Aim: To investigate the relationship between selected interleukin-1 (IL-1) loci polymorphisms and gastric cancer risk in the Central-Western region of Venezuela, where gastric cancer represents the first cause of cancer-related deaths. Material and methods: In a case-control study, we compared the frequencies of IL-1B-511 and IL-1B+3954 biallelic polymorphism, and the pentallelic VNTR of IL-IRN in 84 gastric adenocarcinoma paraffin-embedded biopsies and 84 endoscopic biopsies from cancer-free controls. Results: No significant increase in genotypic frequencies in gastric cancer was observed for any of the IL-1B-511 allelic combinations. However, in alogistic regression analysis, a significant association emerged for the IL- 1B+3954C carrier genotype (odds ratio (OR): 6.2; 95% confidence intervals (CI) 1.3-28.8). On the other hand, a significantly higher risk was evidenced for the IL-IRN*2/*2 genotype (OR: 7.0; 95% CI 2.3-21.5). Only patients with awell/moderately-differentiated adenocarcinoma that were homozygotes for the IL-IRN*2/*2 genotype, had a higher risk than the complete gastric cancer group (OR: 8.1, 95% CI 2.5-26.8). Some genotype combinations among IL-1B-511, IL-1B+3954 and IL-IRN showed an increased risk for developing gastric cancer and well/moderate differentiated adenocarcinoma, that was dependent of the presence of IL-IRN*2/*2 genotype. Conclusions: IL-IRN*2/*2 genotype is associated with increased risk of gastriccancer in the Venezuelan population.

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.

Upregulation of Proinflammatory Cytokines in the Fetal Brain of the Gaucher Mouse

Gaucher disease is caused by a deficiency of glucocerebrosidase. Patients with Gaucher disease are divided into three major phenotypes: chronic nonneuronopathic, acute neuronopathic, and chronic neuronopathic, based on symptoms of the nervous system, the severity of symptoms, and the age of disease onset. The characteristics of patients with acute neuronopathic- and chronic neuronopathic-type Gaucher disease include oculomotor abnormalities, bulbar signs, limb rigidity, seizures and occasional choreoathetoid movements, and neuronal loss. However, the mechanisms leading to the neurodegeneration of this disorder remain unknown. To investigate brain dysfunction in Gaucher disease, we studied the possible role of inflammation in neurodegeneration during development of Gaucher disease in a mouse model. Elevated levels of the proinflammatory cytokines, IL-1alpha, IL-1beta, IL-6, and TNF-alpha, were detected in the fetal brains of Gaucher mice. Moreover, the levels of secreted nitric oxide and reactive oxygen species in the brains of Gaucher mice were higher than in wild-type mice. Thus, accumulated glucocerebroside or glucosylsphingosine, caused by glucocerebrosidase deficiency, may mediate brain inflammation in the Gaucher mouse via the elevation of proinflammatory cytokines, nitric oxide, and reactive oxygen species.

Ethnicity greatly influences the interleukin-1 gene cluster(IL-1b promoter, exon-5 and IL-1Ra) polymorphisms: a pilot study of a north Indian population.

There is considerable evidence that polymorphisms in the regulatory regions of cytokine genes are highly influenced by ethnicity. Polymorphisms in interleukin 1-beta (IL-1beta) and IL-1 receptor antagonist (IL-1Ra) genes, respectively encoding a potent inflammatory agent and an antagonist, which combines with IL-1 receptors competitively, have been associated with a number of diseases like systemic lupus erythematosus, rheumatoid arthritis, sepsis, kidney diseases, and cancer. In this study, we therefore evaluated the distribution of interleukin-1 gene cluster (IL-1beta promoter region, exon-5 and IL-1Ra) gene polymorphisms in 206 healthy north Indian subjects, using PCR-based restriction analysis. We also constructed various haplotypes and estimated the linkage disequilibrium (LD). We found that genotype and allelic frequencies for these cytokines were conspicuously different when compared among different ethnic populations. The haplotype 'T-E1-1' predominated (41.7%) while the least common was 'C-E2-2' (2%) in our population. Genetic linkage between three loci of IL-1 gene showed strong association among the variants in controls (D'=0.42, p<0.001). Our results suggest that the frequency and distribution of the polymorphisms in India are substantially different from other populations and ethnic groups. Thus they signify an impact of ethnicity and provide a basis for future epidemiological and clinical studies.

Niveles plasmáticos de citoquinas IL-1ß, IL2 e IL-4 en niños diabéticos tipo 1 de diagnóstico reciente y su asociación con anticuerpos ß pancreáticos / Plasma levels of interleukin-1, interleukin-2 and interleukin-4 in recently diagnosed type 1 diabetic children and their association with ß-pancreatic autoantibodies

Background: Type 1 diabetes is an organ specifc autoimmune disease whose incidence is increasing worldwide. A functional imbalance in cytokine production resulting in dominance of T helper (Th1) over Th2-type response has been suggested to play a critical role in the pathogenesis of type 1 diabetes. Aim: To measure serum concentrations of interleukin (IL)-1ß, IL-2 and IL-4 in children with recently diagnosed type 1 diabetes and to evaluate the autoimmune response measuring glutamic acid decarboxylase (GAD65) and tyrosine phosphatase like (IA-2) autoantibodies. Patients and Methods: 120 diabetic children and 118 age and gender matched control children, were recruited for this study. Circulating levels of IL-1ß, IL-2 and IL-4 were measured by ELISA. GAD65 and IA-2 were measured by RIA. Results: Circulating levels of IL-1ß were elevated in type 1 diabetic children as compared to the control group (9.3±7.3 and 4.9±3.8 pg/ml respectively, p=0,01). Serum concentration of IL-2 was also higher in diabetic patients (19.8±13.1 and 11.3±9.1 pg/ml respectively, p=0,01). No differences in serum IL-4 were observed between diabetics and control. Diabetic children with one or two positive autoantibodies (IA-2 and/or GAD65) had significantly higher levels of IL-1ß and IL-2 and lower levels of IL-4 than diabetic children without positive autoantibodies. High concentrations of IL-1ß were associated with an early onset of the disease. Conclusions: High levels of IL-1ß and IL-2 were found in diabetic children with recent diagnosis of the disease. Diabetics with positive antibodies against GAD65 and IA-2 had higher levels of IL-1ß and IL-2 and lower levels of IL-4 than their counterparts without positive antibodies.

Protein kinase A mediates microglial activation induced by plasminogen and gangliosides

In the injured brain, microglia is known to be activated and produce proinflammatory mediators such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS). We investigated the role of protein kinase A (PKA) in microglial activation by both plasminogen and gangliosides in rat primary microglia and in the BV2 immortalized murine microglial cell line. Both plasminogen and gangliosides induced IL-1beta, TNF-alpha and iNOS mRNA expression, and that this expression was inhibited by the addition of the PKA inhibitors, KT5720 and H89. Both plasminogen and gangliosides activated PKA and increased the DNA binding activity of the cAMP response element- binding protein (CREB). Furthermore, KT5720 and H89 reduced the DNA binding activities of CREB and NF-kappaB in plasminogen-treated cells. These results suggest that PKA plays an important role in plasminogen and gangliosides- induced microglial activation.

The Role of Interleukin-1beta Gene Polymorphism in the Gastric Carcinogenesis / 대한소화기학회지

BACKGROUND/AIMS: This study was aimed to investigate the polymorphism of interleukin-1beta(IL-1B) and IL-1 receptor antagonist (IL-1RN) gene and the relationship between genotypes and development of gastric adenocarcinoma in Korean, and to investigate the role of Helicobactor pylori (H. pylori) infection. METHODS: The study population comprised of 258 patients with gastric adenocarcinoma. They were classified according to Lauren's classification and the status of H. pylori infection. Genomic DNA was extracted from the gastric tissue. As a control, genomic DNA from peripheral lymphocyte of 100 healthy individuals was used. The amplified products of -511 bp and -31 bp fragments in the IL-1B by PCR were digested by restriction enzyme and separated for RFLP. Variable number tandem repeats were amplified and subjected to RFLP of IL-1RN. RESULTS: There was no significant difference in the genotype of IL-1B-511T and IL-1B-31C between the adenocarcinoma group and the control group. IL-1RN allele 1 homozygote in the intestinal type showed high frequency of 91.7% (p=0.007). In the H. pylori-positive group of the adenocarcinoma, the frequency of IL-1B-31C was significantly higher than that of H. pylori-negative group (p=0.045). CONCLUSIONS: The single nucleotide polymorphism of IL-1B-31C may contribute to the development of the gastric adenocarcinoma in the H. pylori-positive population.

The role of macrophages in wound age estimation during the wound healing process / 法医学杂志

The article reviewed the advance and the forensic meaning of macrophage on the wound age estimation during the wound healing process in resent years. It has also been summarized the relationship between macrophages and wound age estimation on the expression of cytokines derived from macrophages, the changes of macrophage phenotypes and the development process of phagosomes in macrophages after wounding. It is suggested that some regular and characteristic changes of macrophage should be a useful mark to wound age estimation and reminds therefore further study in this field.

Age-related regional difference of interleukin-1 expression in rat brain after lipopolysaccharide treatment

Aging is associated with altered immune responses including dysregulation of cytokine production. Of cytokines, interleukin-1 (IL-1) family has been primarily involved with central nervous system. To evaluate the age-related different response of IL-1 family following peripheral administration of lipopolysaccharide (LPS), immunohistochemical study of IL-1beta and IL-1 receptor expression was performed on Sprague-Dawley rat brain. Experimental animals were divided into four groups; saline-treated young (3-5 months) and old (over 24 months), and LPS-treated young and old groups. After intraperitoneal (i.p.) injection of LPS, three to five rats within each group were killed at 1, 2, 4, 8 and 16 hr. After fixation in 4% neutral buffered formalin, the brain slices were paraffin-embedded. Immunohistochemical staining using labelled streptavidin biotin was performed. The results showed that IL-1beta immunoreactivity was seen in the endothelial cell of pons in both LPS-reated young and old rats, with slightly longer persistency in old group. IL-1RI immunoreactivity appeared initially in the neurons of cerebral cortex in LPS-treated old group, compared with predominantly the cerebellum in LPS-treated young group. In conclusion, our study shows that there is age-related, different neuronal localization of IL-1RI expression at different points of time after LPS treatment.