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1.
Nat Commun ; 15(1): 3795, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38714679

ABSTRACT

The incidence of Lyme borreliosis has risen, accompanied by persistent symptoms. The innate immune system and related cytokines are crucial in the host response and symptom development. We characterized cytokine production capacity before and after antibiotic treatment in 1,060 Lyme borreliosis patients. We observed a negative correlation between antibody production and IL-10 responses, as well as increased IL-1Ra responses in patients with disseminated disease. Genome-wide mapping the cytokine production allowed us to identify 34 cytokine quantitative trait loci (cQTLs), with 31 novel ones. We pinpointed the causal variant at the TLR1-6-10 locus and validated the regulation of IL-1Ra responses at transcritpome level using an independent cohort. We found that cQTLs contribute to Lyme borreliosis susceptibility and are relevant to other immune-mediated diseases. Our findings improve the understanding of cytokine responses in Lyme borreliosis and provide a genetic map of immune function as an expanded resource.


Subject(s)
Cytokines , Lyme Disease , Quantitative Trait Loci , Lyme Disease/immunology , Lyme Disease/genetics , Lyme Disease/microbiology , Humans , Cytokines/genetics , Cytokines/metabolism , Male , Female , Interleukin-10/genetics , Adult , Genome-Wide Association Study , Middle Aged , Interleukin 1 Receptor Antagonist Protein/genetics , Borrelia burgdorferi/immunology , Borrelia burgdorferi/genetics , Anti-Bacterial Agents , Polymorphism, Single Nucleotide , Genetic Predisposition to Disease , Aged
2.
Front Immunol ; 15: 1381447, 2024.
Article in English | MEDLINE | ID: mdl-38646532

ABSTRACT

Undiagnosed monogenic diseases represent a challenging group of human conditions highly suspicious to have a genetic origin, but without conclusive evidences about it. We identified two brothers born prematurely from a non-consanguineous healthy couple, with a neonatal-onset, chronic disease characterized by severe skin and bone inflammatory manifestations and a fatal outcome in infancy. We conducted DNA and mRNA analyses in the patients' healthy relatives to identify the genetic cause of the patients' disease. DNA analyses were performed by both Sanger and next-generation sequencing, which identified two novel heterozygous IL1RN variants: the intronic c.318 + 2T>G variant in the father and a ≈2,600-bp intragenic deletion in the mother. IL1RN mRNA production was markedly decreased in both progenitors when compared with healthy subjects. The mRNA sequencing performed in each parent identified two novel, truncated IL1RN transcripts. Additional experiments revealed a perfect intrafamilial phenotype-genotype segregation following an autosomal recessive inheritance pattern. The evidences shown here supported for the presence of two novel loss-of-function (LoF) IL1RN pathogenic variants in the analyzed family. Biallelic LoF variants at the IL1RN gene cause the deficiency of interleukin-1 receptor antagonist (DIRA), a monogenic autoinflammatory disease with marked similarities with the patients described here. Despite the non-availability of the patients' samples representing the main limitation of this study, the collected evidences strongly suggest that the patients described here suffered from a lethal form of DIRA likely due to a compound heterozygous genotype at IL1RN, thus providing a reliable genetic diagnosis based on the integration of old medical information with currently obtained genetic data.


Subject(s)
Heterozygote , Interleukin 1 Receptor Antagonist Protein , Mutation , Pedigree , Female , Humans , Infant, Newborn , Male , Fatal Outcome , Hereditary Autoinflammatory Diseases/genetics , Hereditary Autoinflammatory Diseases/diagnosis , Interleukin 1 Receptor Antagonist Protein/genetics , Phenotype
3.
Cytokine ; 179: 156595, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38581865

ABSTRACT

BACKGROUND: Biomarkers are biochemical indicators that can identify changes in the structure or function of systems, organs, or cells and can be used to monitor a wide range of biological processes, including cancer. Interleukin-1 receptor antagonist (IL1RA) is an important inflammatory suppressor gene and tumor biomarker. The goal of this study was to investigate the expression of IL1RA, its probable carcinogenic activity, and its diagnostic targets in oral squamous cell carcinoma (OSCC). RESULTS: We discovered that IL1RA was expressed at a low level in OSCC tumor tissues compared to normal epithelial tissues and that the expression declined gradually from epithelial hyperplasia through dysplasia to carcinoma in situ and invasive OSCC. Low IL1RA expression was associated not only with poor survival but also with various clinicopathological markers such as increased infiltration, recurrence, and fatalities. Following cellular phenotyping investigations in OSCC cells overexpressing IL1RA, we discovered that recovering IL1RA expression decreased OSCC cell proliferation, migration, and increased apoptosis. CONCLUSIONS: In summary, our investigation highlighted the possible involvement of low-expression IL1RA in OSCC cells in promoting invasive as well as metastatic and inhibiting apoptosis, as well as the efficacy of IL1RA-focused monitoring in the early detection and treatment of OSCC.


Subject(s)
Apoptosis , Carcinoma, Squamous Cell , Cell Movement , Cell Proliferation , Interleukin 1 Receptor Antagonist Protein , Mouth Neoplasms , Humans , Mouth Neoplasms/pathology , Mouth Neoplasms/metabolism , Mouth Neoplasms/genetics , Interleukin 1 Receptor Antagonist Protein/metabolism , Interleukin 1 Receptor Antagonist Protein/genetics , Cell Movement/genetics , Prognosis , Male , Female , Middle Aged , Cell Line, Tumor , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/genetics , Gene Expression Regulation, Neoplastic , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Aged , Adult
4.
J Am Vet Med Assoc ; 262(S1): S109-S120, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38631386

ABSTRACT

OBJECTIVE: To evaluate the effects of a gene transfer approach to IL-1ß inhibition in an equine osteochondral chip fragment model of joint injury using a self-complementary adeno-associated virus with interleukin receptor antagonist transgene cassette (scAAVIL-1ra), as posttraumatic osteoarthritis in horses, similar to people, is a significant clinical problem. ANIMALS: 16 horses were utilized for the study. METHODS: All horses had an osteochondral chip fragment induced arthroscopically in one middle carpal joint while the contralateral joint was sham operated. Eight horses received either scAAVIL-1ra or saline in the osteoarthritis joint. Horses were evaluated over 70 days clinically (lameness, imaging, and biomarker analysis) and euthanized at 70 days and evaluated grossly, with imaging and histopathology. RESULTS: The following findings were statistically significant. Injection of scAAVIL-1ra resulted in high synovial fluid levels of IL-1ra (0.5 to 9 µg/mL) throughout the duration of the experiment (70 days). Over the duration, we observed scAAVIL-1ra to improve lameness (lameness score relative improvement of 1.2 on a scale of 0 to 5), cause suppression of prostaglandin E2 (a relative decline of 30 pg/mL), and result in histological improvement in articular cartilage (decreased chondrocyte loss and chondrone formation) and subchondral bone (less osteochondral splitting and osteochondral lesions). Within the synovial membrane of scAAVIL-1ra-treated joints, we also observed perivascular infiltration with CD3-positive WBCs, suggesting lymphocytic T-cell perivascular infiltration commonly observed with viral transduction. CLINICAL RELEVANCE: These data provide support for further evaluation and optimization of scAAVIL-1ra gene therapy to treat equine osteoarthritis.


Subject(s)
Genetic Therapy , Horse Diseases , Interleukin 1 Receptor Antagonist Protein , Osteoarthritis , Animals , Horses , Osteoarthritis/veterinary , Osteoarthritis/therapy , Osteoarthritis/pathology , Interleukin 1 Receptor Antagonist Protein/genetics , Horse Diseases/therapy , Genetic Therapy/veterinary , Female , Male
5.
Haemophilia ; 30(3): 752-764, 2024 May.
Article in English | MEDLINE | ID: mdl-38439143

ABSTRACT

INTRODUCTION: Poor response to platelet and recombinant factor VII administration is a major problem in patients with Glanzmann Thrombasthenia (GT). The risk factors associated with poor response to treatment in these patients are unknown. Some genetic variations of cytokines may contribute to therapy resistance. AIMS: We evaluated, for the first time, whether genetic polymorphisms on cytokine genes are related to poor treatment response in GT patients. METHODS: We enrolled 30 patients with GT (15 resistant and 15 non-resistant) and 100 healthy controls. Gene polymorphisms of IL-10 and TNF-α were analysed using TaqMan Realtime PCR, and IL-1, IL-1R1 and IL-1RN were investigated with the RFLP method. In-silico analyses were performed to predict the potential impact of these polymorphisms. RESULTS: In the resistant group, all patients had a variant of the IL-10 gene at the -1082 position (rs1800896), with a GG genotype that was significantly more frequent than the non-resistant group. Analysis between healthy controls and GT patients revealed a probable correlation between rs3783550, rs3783553, rs3917356 and rs2234463 and GT. The In-silico study indicated that TNF-α rs1800629 and IL-10 rs1800896 polymorphisms result in different allelic expressions which may contribute to poor response to therapy. CONCLUSIONS: These findings suggest that polymorphisms in the IL-10 and IL-1 receptor antagonist genes may play a role in poor therapy response in GT patients. In addition, some polymorphisms in IL-1α, IL1-ß, IL-1R1 and IL-R antagonists might be involved in the GT progression.


Subject(s)
Interleukin 1 Receptor Antagonist Protein , Thrombasthenia , Humans , Male , Female , Thrombasthenia/genetics , Thrombasthenia/drug therapy , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-10/genetics , Child , Polymorphism, Single Nucleotide , Recombinant Proteins/therapeutic use , Adolescent , Genotype , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Child, Preschool , Receptors, Interleukin-1 Type I/genetics , Adult , Case-Control Studies , Polymorphism, Genetic
6.
Int Immunopharmacol ; 128: 111528, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38241845

ABSTRACT

With the improvement of global dietary conditions, non-alcoholic fatty liver disease (NAFLD) has gradually become prevalent. As the number of NAFLD patients increases, the coexistence of diseases associated with it has come into focus. In this study, based on immune phenotypes, intercellular communication activities, and clinical manifestations of NAFLD patients, IL1RN was identified as a central pro-inflammatory factor. Subsequently, potential downstream biological pathways of IL1RN in liver tissues and various cell types were enriched to describe its functions. Transcription factors Nfkb1, Jun, and Sp1, significantly associated with these functions, were also enriched. Functional studies of IL1RN suggest its potential to trigger autoimmune diseases. Given this, Mendelian randomization analysis was used to explore the causal relationship between NAFLD and various autoimmune diseases, with IL1RN considered as an intermediary introduced into Mendelian randomization studies. The results indicate that IL1RN and its partially related proteins play a certain mediating role in the process of NAFLD inducing rheumatoid arthritis (RA). Finally, additional research results suggest that intrahepatic ALT levels may influence IL1RN levels, possibly through amino acid metabolism.


Subject(s)
Arthritis, Rheumatoid , Autoimmune Diseases , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/metabolism , Arthritis, Rheumatoid/genetics , Phenotype , Genome-Wide Association Study , Interleukin 1 Receptor Antagonist Protein/genetics
7.
Int J Mol Sci ; 25(1)2024 Jan 04.
Article in English | MEDLINE | ID: mdl-38203822

ABSTRACT

The aim of this study was to evaluate the possible relationships between polymorphisms in the interleukin-1 (IL-1) A, IL-1B, and IL-1RN genes and concentrations of the inflammatory mediators IL-1ß, tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2) in peri-implant crevicular fluid (PICF). A cross-sectional analytical study was conducted on 51 patients with dental implants. Samples from the buccal mucosa were obtained, and genetic analysis was performed using the real-time polymerase chain reaction (PCR) technique for IL-1A and IL-1B and PCR and restriction fragment length polymorphism analysis for IL-1RN. For the biochemical analysis, the concentrations of IL-1ß and TNF-α were analyzed using multiplexed fluorescent sphere immunoassays, and PGE2 by enzyme-linked immunosorbent assay. In patients with detected IL-1RN polymorphism, there was an increase in the concentration of the three mediators with statistically significant differences in the mean values of TNF-α and PGE2, regardless of peri-implant health status (p = 0.002 and p = 0.049, respectively). The concentrations of all three mediators were positively and significantly correlated (IL-1ß vs. TNF-α Rho = 0.480, p < 0.001; IL-1ß vs. PGE2 Rho = 0.382, p = 0.006; and TNF-α vs. PGE2 Rho = 0.528, p < 0.001). We can conclude that the IL-1RN polymorphism exerts an influence on the PICF immune response, which may explain the influence of this genetic polymorphism on the occurrence of peri-implantitis.


Subject(s)
Dental Implants , Dinoprostone , Gingival Crevicular Fluid , Interleukin 1 Receptor Antagonist Protein , Interleukin-1beta , Tumor Necrosis Factor-alpha , Humans , Cross-Sectional Studies , Dinoprostone/metabolism , Interleukin-1beta/metabolism , Polymorphism, Genetic , Tumor Necrosis Factor-alpha/metabolism , Interleukin 1 Receptor Antagonist Protein/genetics
8.
Arthritis Rheumatol ; 76(1): 119-129, 2024 01.
Article in English | MEDLINE | ID: mdl-37471469

ABSTRACT

OBJECTIVE: Human leukocyte antigen (HLA)-DRB1*15:01 has been recently associated with interstitial lung disease (LD), eosinophilia, and drug reactions in systemic juvenile idiopathic arthritis (sJIA). Additionally, genetic variants in IL1RN have been linked to poor response to anakinra. We sought to reproduce these findings in a prospective cohort study of patients with new-onset sJIA treated with anakinra as first-line therapy. METHODS: HLA and IL1RN risk alleles were identified via whole-genome sequencing. Treatment responses and complications were compared between carriers versus noncarriers. RESULTS: Seventeen of 65 patients (26%) carried HLA-DRB1*15:01, comparable with the general population, and there was enrichment for HLA-DRB1*11:01, a known risk locus for sJIA. The rates of clinical inactive disease (CID) at 6 months, 1 year, and 2 years were generally high, irrespective of HLA-DRB1 or IL1RN variants, but significantly lower in carriers of an HLA-DRB1*11:01 allele. One patient, an HLA-DRB1*15:01 carrier, developed sJIA-LD. Of the three patients with severe drug reactions to biologics, one carried HLA-DRB1*15:01. The prevalence of eosinophilia did not significantly differ between HLA-DRB1*15:01 carriers and noncarriers at disease onset (6.2% vs 14.9%, P = 0.67) nor after the start of anakinra (35.3% vs 37.5% in the first 2 years of disease). CONCLUSION: We observed high rates of CID using anakinra as first-line treatment irrespective of HLA-DRB1 or IL1RN variants. Only one of the 17 HLA-DRB1*15:01 carriers developed sJIA-LD, and of the three patients with drug reactions to biologics, only one carried HLA-DRB1*15:01. Although thorough monitoring for the development of drug hypersensitivity and refractory disease courses in sJIA, including sJIA-LD, remains important, our data support the early start of biologic therapy in patients with new-onset sJIA irrespective of HLA-DRB1 background or IL1RN variants.


Subject(s)
Arthritis, Juvenile , Biological Products , Eosinophilia , Humans , Arthritis, Juvenile/drug therapy , Arthritis, Juvenile/genetics , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/therapeutic use , HLA-DRB1 Chains/genetics , Prospective Studies , Biological Products/therapeutic use , Eosinophilia/drug therapy , Receptors, Interleukin-1/therapeutic use
9.
J Investig Med ; 72(1): 17-25, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37803493

ABSTRACT

The most important complication of familial Mediterranean fever (FMF) is secondary amyloidosis. The aim of this study is to investigate the risk of developing FMF-related amyloidosis with macrophage migration inhibitory factor (MIF), interleukin 4 (IL-4), and IL-1 receptor antagonist (IL-1RA) variants. This study included 62 FMF patients with amyloidosis, 110 FMF patients without amyloidosis, and 120 controls. The clinical information of the patient groups was compared. MIF-173G/C, IL-4 variant number tandem repeat (VNTR), and IL-1RA VNTR variants were analyzed for all participants. The use of colchicine, pleurisy, and appendectomy was more common in FMF patients with amyloidosis than in FMF patients without amyloidosis. MIF-173G/C C/C genotype and C allele were higher in both patient groups compared to controls. IL-1RA VNTR A1/A2 and A1/A4 genotypes and A1-A4 alleles were more common in both patient groups than controls. The IL-4 VNTR P1 allele was more common in FMF patients with amyloidosis compared to controls. The MIF-173G/C allele and the IL-1RA VNTR A1-A4 allele are associated with FMF in the Turkish population but not with amyloidosis risk in FMF patients. The IL-4 VNTR P1 allele is more common in FMF patients with amyloidosis than in healthy individuals.


Subject(s)
Amyloidosis , Familial Mediterranean Fever , Macrophage Migration-Inhibitory Factors , Humans , Amyloidosis/genetics , Familial Mediterranean Fever/complications , Familial Mediterranean Fever/genetics , Genetic Predisposition to Disease , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin-4/genetics , Intramolecular Oxidoreductases/genetics , Macrophage Migration-Inhibitory Factors/genetics , Polymorphism, Single Nucleotide , Tandem Repeat Sequences
10.
Genome Med ; 15(1): 108, 2023 Dec 04.
Article in English | MEDLINE | ID: mdl-38049854

ABSTRACT

BACKGROUND: In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses. METHODS: We used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and ß-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones). RESULTS: Circulating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S ß = - 0.67, P-value = 1.88 × 10-6 and HOMA-B ß = 0.59, P-value = 1.88 × 10-5; IL-1RA ~ HOMA-S ß = - 0.51, P-value = 8.49 × 10-5 and HOMA-B ß = 0.48, P-value = 5.71 × 10-4). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P-value = 9.79 × 10-6), though these associations were not consistent in all sensitivity analyses. CONCLUSIONS: The findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased ß-cell function. GIP's effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.


Subject(s)
Diabetes Mellitus, Type 2 , Gastric Inhibitory Polypeptide , Insulin Resistance , Interleukin 1 Receptor Antagonist Protein , Humans , African People , Blood Glucose , Complement Factor D/genetics , Diabetes Mellitus, Type 2/complications , Genome-Wide Association Study , Ghana , Glucagon-Like Peptide 1 , Insulin/genetics , Insulin Resistance/genetics , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin-6/genetics , Kenya , Mendelian Randomization Analysis , Risk Factors , Nigeria , Gastric Inhibitory Polypeptide/genetics
11.
Front Endocrinol (Lausanne) ; 14: 1278273, 2023.
Article in English | MEDLINE | ID: mdl-37941911

ABSTRACT

Aims: Epidemiological evidence for the link of interleukin 1 (IL-1) and its inhibition with cardiovascular diseases (CVDs) remains controversial. We aim to investigate the cardiovascular effects of IL-1 receptor antagonist (IL-1Ra) and underlying mechanisms. Methods: Genetic variants identified from a genome-wide association study involving 30,931 individuals were used as instrumental variables for the serum IL-1Ra concentrations. Genetic associations with CVDs and cardiometabolic risk factors were obtained from international genetic consortia. Inverse-variance weighted method was utilized to derive effect estimates, while supplementary analyses employing various statistical approaches. Results: Genetically determined IL-1Ra level was associated with increased risk of coronary heart disease (CHD; OR, 1.07; 95% CI: 1.03-1.17) and myocardial infarction (OR, 1.13; 95% CI: 1.04-1.21). The main results remained consistent in supplementary analyses. Besides, IL-1Ra was associated with circulating levels of various lipoprotein lipids, apolipoproteins and fasting glucose. Interestingly, observed association pattern with CHD was reversed when adjusting for apolipoprotein B (OR, 0.84; 95%CI: 0.71-0.99) and slightly attenuated on accounting for other cardiometabolic risk factors. Appropriate lifestyle intervention was found to lower IL-1Ra concentration and mitigate the heightened CHD risk it posed. Conclusion: Apolipoprotein B represents the key driver, and a potential target for reversal of the causal link between serum IL-1Ra and increased risk of CHD/MI. The combined therapy involving IL-1 inhibition and lipid-modifying treatment aimed at apolipoprotein B merit further exploration.


Subject(s)
Coronary Disease , Myocardial Infarction , Humans , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Genome-Wide Association Study , Coronary Disease/etiology , Coronary Disease/genetics , Apolipoproteins B , Apolipoproteins , Interleukin-1/genetics , Receptors, Interleukin-1/genetics
12.
Front Immunol ; 14: 1240754, 2023.
Article in English | MEDLINE | ID: mdl-37781392

ABSTRACT

Background: The interleukin-1 pathway has been linked to pancreatic diseases. We applied the Mendelian randomization approach to explore whether higher interleukin-1 receptor antagonist (IL-1RA) levels reduce the risk of acute and chronic pancreatitis and pancreatic cancer. Methods: Genetic variants associated with blood IL-1RA levels at the genome-wide significance level and located 5MB downstream or upstream of the IL1RN gene were extracted from a genome-wide meta-analysis of 21,758 participants. After pruning, genetic variants without linkage disequilibrium were used as genetic instrument for IL-1RA. Summary-level data on acute and chronic pancreatitis and pancreatic cancer were obtained from the UK Biobank and FinnGen studies. The associations were meta-analyzed for one outcome from two sources. Results: Genetically predicted higher levels of IL-1RA were associated with a lower risk of acute and chronic pancreatitis and pancreatic cancer. In the meta-analysis of UK Biobank and FinnGen, the combined odds ratio was 0.87 (95% confidence interval [CI] 0.77-0.97, P=0.003) for acute pancreatitis, 0.73 (95% CI 0.65-0.82, P=2.93×10-8) for chronic pancreatitis, and 0.86 (95% CI 0.77-0.96, P=0.009) for pancreatic cancer per one standard deviation increment in genetically predicted levels of IL-1RA. Conclusion: This study suggests a protective role of IL-1RA in three major pancreatic diseases, which hints the therapeutic potentials of IL-1RA in pancreatic diseases.


Subject(s)
Pancreatic Neoplasms , Pancreatitis, Chronic , Humans , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Acute Disease , Mendelian Randomization Analysis , Receptors, Interleukin-1 , Pancreatitis, Chronic/drug therapy , Pancreatitis, Chronic/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics
13.
ACS Biomater Sci Eng ; 9(11): 6282-6292, 2023 11 13.
Article in English | MEDLINE | ID: mdl-37906515

ABSTRACT

In order to scale up culture therapeutic cells, such as mesenchymal stromal cells (MSCs), culture in suspension bioreactors using microcarriers (µCs) is preferred. However, the impact of microcarrier type on the resulting MSC secretory activity has not been investigated. In this study, two poly(ethylene glycol) hydrogel formulations with different swelling ratios (named "stiffer" and "softer") were fabricated as µC substrates to culture MSCs and MSCs genetically modified to express the interleukin-1 receptor antagonist (IL-1Ra-MSCs). Changes in cell number, secretory and angiogenic activity, and changes in MAPK signaling were evaluated when cultured on hydrogel µCs, as well as on tissue culture plastic-based Synthemax µCs. We demonstrated that culture on stiffer µCs increased secretion of IL-1Ra compared to culture on Synthemax µCs by IL-1Ra-MSCs by 1.2- to 1.6-fold, as well as their in vitro angiogenic activity, compared to culture on Synthemax µCs, while culture on both stiffer and softer µCs altered the secretion of several other factors compared to culture on Synthemax µCs. Changes in angiogenic activity corresponded with increased gene expression and secretion of hepatocyte growth factor by MSCs cultured on softer µCs by 2.5- to 6-fold compared to MSCs cultured on Synthemax µCs. Quantification of phosphoprotein signaling with the MAPK pathway revealed broad reduction of pathway activation by IL-1Ra-MSCs cultured on both stiffer and softer µCs compared to Synthemax, where phosphorylated c-Jun, ATF2, and MEK1 were reduced specifically on softer µCs. Overall, this study showed that µC surfaces can influence the secretory activity of genetically modified MSCs and identified associated changes in MAPK pathway signaling, which is a known central regulator of cytokine secretion.


Subject(s)
Interleukin 1 Receptor Antagonist Protein , Mesenchymal Stem Cells , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin 1 Receptor Antagonist Protein/metabolism , Mesenchymal Stem Cells/metabolism , Cell Culture Techniques/methods , Biocompatible Materials , Hydrogels/pharmacology , Hydrogels/metabolism , Polyethylene Glycols/pharmacology , Polyethylene Glycols/metabolism
14.
Gene Ther ; 30(12): 792-800, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37696981

ABSTRACT

Gene therapy approaches using adeno-associated viral vectors have been successfully tested in the equine post-traumatic osteoarthritis (PTOA) model. Owing to differences in the levels of transgene expression and adverse tissue reactions observed in published studies, we sought to identify a safe therapeutic dose of scAAVIL-1ra in an inflamed and injured joint that would result in improved functional outcomes without any adverse events. scAAVIL-1ra was delivered intra-articularly over a 100-fold range, and horses were evaluated throughout and at the end of the 10-week study. A dose-related increase in IL-1ra levels with a decrease in PGE2 levels was observed, with the peak IL-1ra concentration being observed 7 days post-treatment in all groups. Perivascular infiltration with mononuclear cells was observed within the synovial membrane of the joint treated with the highest viral dose of 5 × 1012 vg, but this was absent in the lower-dosed joints. The second-highest dose of scAAVeqIL-1ra 5 × 1011 vg demonstrated elevated IL-1ra levels without any cellular response in the synovium. Taken together, the data suggest that the 10-fold lower dose of 5 × 1011vg scAAVIL-1ra would be a safe therapeutic dose in an equine model of PTOA.


Subject(s)
Interleukin 1 Receptor Antagonist Protein , Osteoarthritis , Animals , Horses/genetics , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/metabolism , Pilot Projects , Genetic Vectors , Osteoarthritis/therapy , Osteoarthritis/metabolism , Models, Animal
15.
Mol Biol Rep ; 50(10): 8575-8587, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37644369

ABSTRACT

OBJECTIVE: This study aimed to examine the association between the interleukin-1 receptor antagonist gene (IL-1RN) and coronary in-stent restenosis (ISR) through the analysis of the VNTR variant based on the previously reported results. MATERIALS AND METHODS: The samples were classified into two clearly defined groups: the case group, which comprised 45 patients diagnosed with in-stent restenosis (ISR+), and the control group, which included 60 patients without ISR (ISR-). Polymerase chain reaction (PCR) was performed to examine the 86-bp VNTR variant of the IL-1RN gene. RESULTS: In the analysis of six identified groups consisting of variant alleles of 86 base pairs of VNTR of the IL-1RN gene statistically significant difference was observed for the presence of IL1RN*2 allele between cases and controls (p = 0.04, OR; 0.045). CONCLUSION: Individuals with allele 2 of the IL-1Ra gene may be more predisposed to ISR. This could be due to an imbalance between IL-1Ra and IL-1ß which is crucial in preventing the initiation or advancement of inflammatory diseases in specific organs. The observed phenomenon can be characterized by increased production of IL-1ß and potential reduction of IL-1Ra as a result of functional VNTR variation in IL-RN gene.


Subject(s)
Coronary Restenosis , Interleukin 1 Receptor Antagonist Protein , Humans , Interleukin 1 Receptor Antagonist Protein/genetics , Alleles , Stents , Constriction, Pathologic , Receptors, Interleukin-1
16.
Cancer Discov ; 13(10): 2248-2269, 2023 10 05.
Article in English | MEDLINE | ID: mdl-37486241

ABSTRACT

KRAS mutations are causally linked to protumor inflammation and are identified as driving factors in tumorigenesis. Here, using multiomics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splicing confers vital anti-inflammatory effects in KRAS-mutant iCCA. In KRAS-mutant iCCA mice, both IL1RN-201/203 upregulation and anakinra treatment ignited a significant antitumor immune response by altering neutrophil recruitment and phenotypes. Furthermore, anakinra treatment synergistically enhanced anti-PD-1 therapy to activate intratumoral GZMB+ CD8+ T cells in KRAS-mutant iCCA mice. Clinically, we found that high IL1RN-201/203 levels in patients with KRAS-mutant iCCA were significantly associated with superior response to anti-PD-1 immunotherapy. SIGNIFICANCE: This work describes a novel inflammatory checkpoint mediated by IL1RN alternative splicing variants that may serve as a promising basis to develop therapeutic options for KRAS-mutant iCCA and other cancers. This article is featured in Selected Articles from This Issue, p. 2109.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Humans , Animals , Mice , Proto-Oncogene Proteins p21(ras)/genetics , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/pathology , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/pathology , Inflammation/drug therapy , Inflammation/genetics
17.
Twin Res Hum Genet ; 26(3): 231-235, 2023 06.
Article in English | MEDLINE | ID: mdl-37458219

ABSTRACT

Preeclampsia (PE) is a hypertensive disorder of pregnancy. PE patients were reported to have higher serum levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) than those in healthy controls. However, whether the expressions of these inflammation biomarkers have a causal relationship with PE is unspecified. We applied the Mendelian randomization method to infer the causal relationship between inflammation biomarkers (e.g., CRP, IL-6, interleukin 1 receptor antagonist [IL-1ra] and TNF-α) and PE. Single nucleotide polymorphisms (SNPs) strongly related to inflammation biomarkers were used as instrumental variables. CRP, IL-1ra and IL-6 levels showed no significant effect on PE progression, while the genetic predicted higher level of TNF-α significantly increased the risk of PE (OR per 1-SD increase in TNF-α: 4.33; 95% CI [1.99, 9.39]; p = .00021). The findings suggest that pro-inflammatory activity of TNF-α could be a determinant for PE progression. More antenatal care should be given to those pregnant women with higher level of inflammation biomarkers, especially TNF-α.


Subject(s)
Interleukin-6 , Pre-Eclampsia , Female , Humans , Pregnancy , Interleukin-6/genetics , Tumor Necrosis Factor-alpha/genetics , Interleukin 1 Receptor Antagonist Protein/genetics , Pre-Eclampsia/genetics , Pre-Eclampsia/metabolism , Mendelian Randomization Analysis , Inflammation/genetics , C-Reactive Protein/genetics , Biomarkers
18.
Immunity ; 56(7): 1485-1501.e7, 2023 07 11.
Article in English | MEDLINE | ID: mdl-37315560

ABSTRACT

The interleukin 1 (IL-1) pathway signals through IL-1 receptor type 1 (IL-1R1) and emerges as a central mediator for systemic inflammation. Aberrant IL-1 signaling leads to a range of autoinflammatory diseases. Here, we identified a de novo missense variant in IL-1R1 (p.Lys131Glu) in a patient with chronic recurrent multifocal osteomyelitis (CRMO). Patient PBMCs showed strong inflammatory signatures, particularly in monocytes and neutrophils. The p.Lys131Glu substitution affected a critical positively charged amino acid, which disrupted the binding of the antagonist ligand, IL-1Ra, but not IL-1α or IL-1ß. This resulted in unopposed IL-1 signaling. Mice with a homologous mutation exhibited similar hyperinflammation and greater susceptibility to collagen antibody-induced arthritis, accompanied with pathological osteoclastogenesis. Leveraging the biology of the mutation, we designed an IL-1 therapeutic, which traps IL-1ß and IL-1α, but not IL-1Ra. Collectively, this work provides molecular insights and a potential drug for improved potency and specificity in treating IL-1-driven diseases.


Subject(s)
Osteomyelitis , Receptors, Interleukin-1 , Mice , Animals , Receptors, Interleukin-1/genetics , Osteomyelitis/drug therapy , Osteomyelitis/genetics , Osteomyelitis/pathology , Inflammation/genetics , Inflammation/pathology , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/pharmacology , Signal Transduction , Mutation
19.
BMC Biotechnol ; 23(1): 15, 2023 06 20.
Article in English | MEDLINE | ID: mdl-37340430

ABSTRACT

BACKGROUND: The interleukin-1 receptor antagonist (IL-1Ra) is a crucial molecule that counteracts the effects of interleukin-1 (IL-1) by binding to its receptor. A high concentration of IL-1Ra is required for complete inhibition of IL-1 activity. However, the currently available Escherichia coli-expressed IL-1Ra (E. coli IL-1Ra, Anakinra) has a limited half-life. This study aims to produce a cost-effective, functional IL-1Ra on an industrial scale by expressing it in the pyrG auxotroph Aspergillus oryzae. RESULTS: We purified A. oryzae-expressed IL-1Ra (Asp. IL-1Ra) using ion exchange and size exclusion chromatography (53 mg/L). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed that Asp. IL-1Ra is N-glycosylated and approximately 17 kDa in size. We conducted a comparative study of the bioactivity, binding kinetics, and half-life between Asp. IL-1Ra and E. coli IL-1Ra. Asp. IL-1Ra showed good bioactivity even at a low concentration of 0.5 nM. The in vitro half-life of Asp. IL-1Ra was determined for different time points (0, 24, 48, 72, and 96 h) and showed higher stability than E. coli IL-1Ra, despite exhibiting a 100-fold lower binding affinity (2 nM). CONCLUSION: This study reports the production of a functional Asp. IL-1Ra with advantageous stability, without extensive downstream processing. To our knowledge, this is the first report of a recombinant functional and stable IL-1Ra expressed in A. oryzae. Our results suggest that Asp. IL-1Ra has potential for industrial-scale production as a cost-effective alternative to E. coli IL-1Ra.


Subject(s)
Aspergillus oryzae , Interleukin 1 Receptor Antagonist Protein , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/chemistry , Aspergillus oryzae/genetics , Aspergillus oryzae/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Recombinant Proteins/metabolism , Interleukin-1/metabolism , Receptors, Interleukin-1/metabolism
20.
Funct Integr Genomics ; 23(2): 164, 2023 May 18.
Article in English | MEDLINE | ID: mdl-37198330

ABSTRACT

Interleukin-1 receptor antagonist (IL-1RA) has been shown to play an important role in cancer progression. However, its pathogenic effects and molecular mechanism in the malignant progression of esophageal squamous cell carcinoma (ESCC) remain largely unknown. This study was designed to explore the function of IL-1RA in ESCC and determine the relationship between IL-1RA and lymph node metastasis in ESCC patients. The clinical relevance of IL-1RA in relation to the clinicopathological features and prognosis of 100 ESCC patients was analyzed. The function and underlying mechanisms of IL-1RA in the growth, invasion, and lymphatic metastasis in ESCC were explored both in vitro and in vivo. The therapeutic effect of anakinra, an IL-1 receptor antagonist, on ESCC was also evaluated in animal experiments. Downregulation of IL-1RA was observed in ESCC tissues and cells and was found to be strongly correlated with pathological stage (P = 0.034) and lymphatic metastasis (P = 0.038). Functional assays demonstrated that upregulation of IL-1RA reduced cell proliferation, migration, and lymphangiogenesis both in vitro and in vivo. Mechanistic studies revealed that overexpression of IL-1RA activated the epithelial-to-mesenchymal transition (EMT) in the ESCC cells through activation of MMP9 and regulation of the expression and secretion of VEGF-C through the PI3K/NF-κB pathway. Anakinra treatment resulted in significant inhibition of tumor growth, lymphangiogenesis, and metastasis. IL-1RA inhibits lymph node metastasis of ESCC by regulating the EMT through activation of matrix metalloproteinase 9(MMP9) and lymphangiogenesis, driven by VEGF-C and the NF-κB signaling pathway. Anakinra may be an effective drug for the inhibition of ESCC tumor formation and lymph node metastasis.


Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Carcinogenesis/genetics , Cell Line, Tumor , Cell Proliferation , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/genetics , Esophageal Neoplasms/metabolism , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/genetics , Esophageal Squamous Cell Carcinoma/metabolism , Gene Expression Regulation, Neoplastic , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin 1 Receptor Antagonist Protein/metabolism , Lymphangiogenesis/genetics , Lymphatic Metastasis , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , NF-kappa B/genetics , Vascular Endothelial Growth Factor C/genetics , Vascular Endothelial Growth Factor C/metabolism
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