Mature tau pathology is not improved by interfering with interleukin-1 receptor signaling in two mouse models of tauopathy

Prior work suggests that the cytokine interleukin-1β (IL-1β) may be a key regulator of tau pathology in the presence of amyloidosis. Here, we tested the possible benefits of interleukin-1 receptor antagonist (IL-1RA) gene therapy in two mouse models of tauopathy. We performed intracranial injections in the rTg4510 model, achieving approximately 300-fold over-expression in the hippocampus, and systemic injections in the PS19 model, resulting in approximately 10-fold over-expression. In neither model did we find substantial treatment effects with IL-1RA over-expression. We found large increases in Il1b gene expression in these mouse models, but considerably smaller increases in IL-1β protein. These data suggest that interleukin-1 receptor antagonist may not be a viable therapeutic strategy for pure tauopathies but cannot rule out possible benefits in amyloid-enhanced tauopathy, which appear to have larger elevations of IL-1β.

The relationship between interleukin-1 and its receptor antagonist gene polymorphism and bone mineral density in postmenopausal Korean women

A recent study in German and Italian families associated variants in the interleukin-1 receptor antagonist (IL1RA) gene with asthma. The aim of the present study was to further investigate the role of single nucleotide polymorphisms (SNPs) in the IL1RA gene in the development of atopy and lifelong asthma in a population-based study. DNA samples from the German centres of the European Community Respiratory Health Survey were analysed for genetic variants in the IL1RA gene and the development of asthma, atopy and bronchial hyperreactivity. Carriers of the rare G allele of SNP rs447713 had a significantly increased risk of developing asthma (P = 0.0013) and allergic sensitization (P = 0.0119). Carriers of the rare C allele of SNP rs3087271 had an increased risk of asthma (P = 0.0227) and high immunoglobulin E (IgE) levels (P = 0.0232). A haplotype built from eight SNPs in the IL1RA gene (A-C-A-G-A-C-G-A) was associated with a higher prevalence of asthma (P = 0.007) and high total IgE (P = 0.02). Bronchial hyperreactivity was positively associated with the haplotype A-C-G-G-A-C-G-C (P = 0.02) and negatively with the A-C-G-G-A-C-T-C (P = 0.03). A previously described association between IL1RA and asthma in families could be reproduced in a population-based sample. The genetic variants of IL1RA gene do not to seem to affect asthma alone, but to act as modulators of asthma-related traits as well, where different haplotypes drive the development of different phenotypes.

IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort

We investigated the relation between polymorphisms in the interleukin-1(IL-1) and IL-1 receptor antagonist (IL-1ra) gene, and bone mineral density (BMD) in postmenopausal Korean women. The IL-1alpha C(-889)T polymorphism, and IL-1beta C(-511)T polymorphism were examined by restriction fragment length polymorphism, and 86-bp variable number tandem repeat polymorphism in the IL-1ra gene was analyzed by the polymerase chain reaction and electrophoresis in 202 postmenopausal Korean women. Serum osteocalcin, and C-telopeptide of type I collagen were measured using a radioimmunoassay and enzyme-linked immunosorbent assay, respectively. BMD at the lumbar spine and proximal femur was measured by dual-energy X-ray absorptiometer. No significant differences in BMD or in serum bone markers levels were noted across the IL-1alpha or IL-1beta genotype. There were no significant differences in the distribution of IL-1alpha or IL-1beta genotype according to the status of bone mass. BMD in women carrying the A2 allele of the IL-1ra gene was significantly lower than those without this allele, and the A2 allele was more frequent in osteoporotic women than in normal women. These data suggest that IL-1ra gene VNTR polymorphism is a genetic factor that may affect BMD in Korean women.

Multiplex Targeted Epigenome Editing Utilizing CRSPR/Cas9 for Potent Anti-Inflammatory Gene Therapy in Lung Transplant

Interleukin-1 (IL-1) receptor antagonist gene polymorphism in normal weight obese syndrome: Relationship to body composition and IL-1 α and β plasma levels

Immune functions seem to have connections to variations in body fat mass. Studies of knockout mice indicate that endogenous interleukin (IL)-1 can suppress mature-onset obesity. To systematically investigate our hypotheses that single-nucleotide polymorphisms (SNPs) and/or haplotypes variants in the IL-1 gene system are associated with fat mass. The Gothenburg osteoporosis and obesity determinants (GOOD) study is a population-based cross-sectional study of 18-20 year-old men (n=1068), from Gothenburg, Sweden. Major findings were confirmed in elderly men (n=3014) from the Swedish part of the osteoporotic fractures in men (MrOS) multicenter population-based study. The genotype distributions and their association with body fat mass in different compartments, measured with dual-energy X-ray absorptiometry (DXA). Out of 15 investigated SNPs in the IL-1 receptor antagonist (IL1RN) gene, a recently identified 3' untranslated region C>T (rs4252041, minor allele frequency=4%) SNP was associated with the primary outcome total fat mass (P=0.003) and regional fat masses, but not with lean body mass or serum IL-1 receptor 1 (IL1RN) levels. This SNP was also associated with body fat when correcting the earlier reported IL1RN+2018 T>C (rs419598) SNP (in linkage disequilibrium with a well-studied variable number tandem repeat of 86 bp). The association between rs4252041 SNP and body fat was confirmed in the older MrOS population (P=0.03). The rs4252041 SNP was part of three haplotypes consisting of five adjacent SNPs that were identified by a sliding window approach. These haplotypes had a highly significant global association with total body fat (P<0.001). None of the other investigated members of the IL-1 gene family displayed any SNPs that have not been described previously to be significantly associated with body fat. The IL1RN gene, shown to enhance obesity by suppressing IL-1 effects in experimental animals, have not [corrected] previously described gene polymorphisms and haplotypes that are associated with fat, but not lean mass in two populations of men.

We have previously found association between an allele of the interleukin-1 (IL-1) receptor antagonist gene (IL1RN) and several inflammatory diseases, where IL-1 has been implicated in the inflammatory mechanism. We have now, therefore, tested the association of this specific allele (IL1RN*2) with complications of diabetes which have an inflammatory tissue component. We have tested the allele frequency of IL1RN*2 in 128 patients with insulin-dependent and 125 with non-insulin-dependent diabetes mellitus (NIDDM). There was a significant association between carriage of IL1RN*2 and diabetic nephropathy (P<0.001, Pcorrected<0.0012). The association was significant in both types of diabetes, but the observed increase was highest in NIDDM, rising to double the control levels. It appears that IL1RN*2 is a novel genetic marker of severity of inflammatory complications of diseases rather than a marker of disease susceptibility. If the DNA polymorphism is associated with altered gene function, new therapeutic interventions may be possible.

To assess whether the A2-type IL-1RA polymorphism is associated with Graves' disease and Graves' ophthalmopathy. Several reports have described a genetic association between the A2 allele of the interleukin-1 receptor antagonist (IL-1RA) gene and certain inflammatory and autoimmune diseases, suggesting that certain loci within the IL-1-related genes may modulate the autoimmune inflammatory response. Recently, we demonstrated marked differences in the expression and regulation of IL-1RA gene and protein between orbital fibroblasts derived from patients with active Graves' ophthalmopathy and healthy individuals. A total of 144 white European patients with Graves' disease were genotyped to compare their IL-1RA A2 allele frequency with that of 174 healthy controls. The polymerase chain reaction was used to amplify the pentallelic variable-number tandem-repeat locus in intron 2 of the IL-1RA gene. We found no significant differences in IL-1RA A2 allele frequencies (0.20 and 0.26 respectively) and IL-1RA A2 carriage rates (31% and 40% respectively) between patients with Graves' disease and the control group. Moreover, presence or absence of Graves' ophthalmopathy in patients with Graves' disease was not related to significant differences in IL-1RA A2 allele frequencies and IL-1RA A2 carriage rates. Our data do not support an association between the IL-1RA A2 allele and Graves' disease or Graves' ophthalmopathy in our study population. Thus the A2-type IL-1RA gene polymorphism does not appear to indicate an increased susceptibility to develop Graves' disease and Graves' ophthalmopathy. Mechanisms unrelated to the IL-1RA A2 allele may be responsible for altered IL-1RA production within the orbital tissues in Graves' ophthalmopathy.

ObjectivesTo study the possible contribution of interleukin-1 receptor antagonist (IL-1Ra) gene polymorphisms to the susceptibility of febrile convulsions.BackgroundFebrile seizures (FSs) are considered the most common seizure disorder in childhood. They are considered a major cause of emergency department visits and a source of family anxiety. FSs of children involve an interaction between the immune-inflammatory process, cytokine activation, and genetic factors.Patients and methodsThis was a case–control study and included 55 children diagnosed to have febrile convulsions and 28 healthy children with no history of any type of convulsions or any neurological disorders. IL-1Ra gene polymorphisms were genotyped by PCR and compared in both groups.ResultsThe most common genotype for the IL-1Ra gene in both groups was I/I. The IL-1Ra I/I homozygote was significantly more frequent in patients with FSs than in healthy controls (76.4 vs. 46.3%, P = 0.01). In addition, IL-1Ra I/II genotype was significantly associated with resistance to FSs (P = 0.001). There were no significant differences between the studied groups regarding the distribution of other genotypes of IL-Ra gene. IL-1Ra allele I is associated with higher susceptibility to FSs among members of the case group (P = 0.03). However, IL-1Ra allele II is associated with resistance to FSs among the healthy control group (P = 0.01).ConclusionIL-1Ra I/I homozygous genotype is significantly associated with febrile convulsions.

712: Association Of Interleukin-1 and Interleukin-1 receptor antagonist (IL-1RN) gene expression with maternal and fetal IL-1RN genotype and chorioamnionitis in preterm birth

Recent reports have shown that allele 2 of the IL-1 receptor antagonist (IL-1Ra) gene is over-represented in ulcerative colitis (UC). Healthy individuals carrying allele 2 of this gene have increased production of IL-1Ra protein. Since the final outcome of the biological effects of IL-1 beta may depend on the relative proportion of these two cytokines, we have studied if a TaqI polymorphism in the IL-1 beta gene, which is relevant to IL-1 beta protein production, may be involved in the genetic susceptibility to UC and Crohn's disease (CD), in association with the established IL-1Ra gene polymorphism. Polymorphisms in the closely linked genes for IL-1 beta and IL-1Ra were typed in 100 unrelated Dutch patients with UC, 79 with CD, and 71 healthy controls. The polymorphic regions in exon 5 of the IL-1 beta gene and in intron 2 of the IL-1Ra gene, were studied by polymerase chain reaction (PCR)-based methods. The IL-1 beta allele frequencies in UC and CD patients did not differ from those in healthy controls. In order to study if the IL-1 beta gene polymorphism might participate synergistically with the IL-1Ra gene polymorphism in susceptibility to UC and CD, individuals were distributed into carriers and non-carriers of allele 2 of the genes encoding IL-1 beta and IL-1Ra, in each of the patient groups and controls. Results indicated a significant association of this pair of genes, estimated by the odds ratio (OR) after performing Fisher's exact test, in the UC group (P = 0.023, OR = 2.81), as well as in the CD group (P = 0.01, OR = 3.79). Thus, non-carriers of IL-1 beta allele 2 were more often present in the subgroup of patients carrying the IL-1Ra allele 2. By contrast, no association of these alleles was detected in the group of healthy controls (P = 1.00, OR = 0.92). These results suggest that the IL-1 beta/IL-1Ra allelic cluster may participate in defining the biological basis of predisposition to chronic inflammatory bowel diseases.

The pathophysiology and susceptibility of children to primary immune thrombocytopenia (ITP) are linked to polymorphisms of the interleukin (IL)-1B and IL-1 receptor (IL-1R) antagonist genes. To investigate the association between the susceptibility and severity of primary ITP in children and the IL-1B and IL-1R antagonist gene polymorphisms. This comparative case-control study was conducted at the Menoufia University Hospital Hematology and Oncology Unit, Pediatric Department, between August 2022 and September 2023. The children were divided into patients (28 boys, 22 girls) who received hospital and outpatient clinic care and controls (50 healthy age- and sex-matched children). The mutant homozygous GG genotype and mutant G allele of rs16944 of the IL1B gene were considerably greater in patients than in controls (P<0.001). Furthermore, the mutant homozygous II/II genotype and heterozygous I/II genotype of the IL-1R antagonist gene were considerably greater in the case versus control group. The mutant II allele was significantly more prevalent in patients versus controls (P<0.001). IL-1B and IL-1R antagonists may have a major impact on the development of immune thrombocytopenia. Furthermore, we found a relationship between IL-1B and IL-1R antagonist gene polymorphisms and the etiology of and children's susceptibility to primary immune thrombocytopenia.

Rheumatoid arthritis (RA) is a systemic autoimmune disease, which is manifested as an inflammatory polyarthritis. Authors aimed to analyze the relationship between serum hepcidin, 25 amino acid protein, concentration and the anemia profiles of RA and to estimate whether it could reflect the disease activity of RA. Also, this study was conducted to explore the linkage between interleukin-1 (IL-1) receptor antagonist gene (IL-1RN) polymorphism, proinflammatory cytokine, and RA. One hundred and eighty five RA patients were enrolled in the study. For all, the following criteria were measured: RA disease activities, anemia profiles, serum concentration of hepcidin using enzyme-linked immunosorbent assay, and DNA samples were used to study genotypes of IL-1RN gene by polymerase chain reaction. Mean concentration of serum pro-hepcidin was (93.6 ± 31.5 ng/mL) in 185 RA patients. An increased frequency of the IL-1RN*1 and IL-1RN*2 alleles was relative to active RA (DAS28 > 5.1) than those with inactive to moderate RA (DAS28 ≤ 5.1). Both hepcidin and IL-1RN gene showed significant correlation with each other as well with RA disease activity parameters and anemia profile. IL-1RN gene was significantly correlated with laboratory anemia profile apart from transferritin. There was a significant difference among pro-hepcidin concentration and IL-1RN frequency regarding patients with anemia of chronic disease and those without. In conclusion, both serum concentration of pro-hepcidin and IL-1RN genotypes frequency reflect the disease activity, regardless of the anemia states in RA patients, thus they may be another potential markers for disease activity of RA.