SURFACTANT PROTEIN A: AN INNATE IMMUNE MODULATOR AND THERAPEUTIC IN ASTHMA.

Surfactant Protein A (SP-A) is an innate immune modulator produced by the lung with known protective effects against bacteria and viruses. Its role in asthma, an inflammatory lung disease that affects 10% of the world's population, is not entirely known. In this review, we demonstrate that SP-A confers protection against exposure to interleukin-13, a type 2 cytokine integral to eosinophilic asthma, in a mouse model of SP-A deficiency, a house dust mite model of asthma, and in human bronchial epithelial cells from participants with asthma. We also show that small peptides derived from SP-A, such as the major allele of single nucleotide polymorphism (SNP) rs1965708, which includes the carbohydrate recognition domain of SP-A2 at position 223, reduce airway hyperresponsiveness, airway eosinophils, and mucus in a mouse model of asthma. These data suggest that SP-A has beneficial effects relevant to asthma and that an SP-A peptide may have a new therapeutic use in asthma.

Interleukin Profiling in Atopic Dermatitis and Chronic Nodular Prurigo.

The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.

Association of IL13 polymorphisms with susceptibility to myocardial infarction: A case-control study in Chinese population.

BACKGROUND: Inflammatory cytokines play a major role in the pathogenesis of myocardial infarction (MI). Although information on the importance of interleukin 13 (IL13) in human MI is limited, it has been well documented in the mouse model. Genetic variation in the IL13 gene has been associated with the structure and expression of the IL13. In the present study, we hypothesized that IL13 common genetic variants would be associated with a predisposition to the development of MI. MATERIALS AND METHODS: The present study enrolled 305 MI patients and 310 matched healthy controls. Common genetic polymorphisms in the IL13 gene (rs20541, rs1881457, and rs1800925) were genotyped using the TaqMan SNP genotyping method. Plasma levels of IL13 were measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: In MI patients, minor alleles of the IL13 rs1881457 and rs1800925 polymorphisms were less common than in healthy controls [rs1881457: AC (P = 0.004, OR = 0.61), C (P = 0.001, OR = 0.66); rs1800925: CT (P = 0.006, OR = 0.59)]. Further haplotype analysis of three studied SNPs revealed a significant association with predisposition to MI. Interestingly, IL13 rs1881457 and rs1800925 were linked to plasma levels of IL13: the reference genotype had higher levels, heterozygotes were intermediate, and the alternate genotype had the lowest levels. CONCLUSIONS: In the Chinese population, IL13 (rs1881457 and rs180092) variants are associated with different plasma IL13 levels and offer protection against MI development. However, additional research is required to validate our findings in different populations, including descent samples.

Single-cell transcriptomics analysis of bullous pemphigoid unveils immune-stromal crosstalk in type 2 inflammatory disease.

Bullous pemphigoid (BP) is a type 2 inflammation- and immunity-driven skin disease, yet a comprehensive understanding of the immune landscape, particularly immune-stromal crosstalk in BP, remains elusive. Herein, using single-cell RNA sequencing (scRNA-seq) and in vitro functional analyzes, we pinpoint Th2 cells, dendritic cells (DCs), and fibroblasts as crucial cell populations. The IL13-IL13RA1 ligand-receptor pair is identified as the most significant mediator of immune-stromal crosstalk in BP. Notably, fibroblasts and DCs expressing IL13RA1 respond to IL13-secreting Th2 cells, thereby amplifying Th2 cell-mediated cascade responses, which occurs through the specific upregulation of PLA2G2A in fibroblasts and CCL17 in myeloid cells, creating a positive feedback loop integral to immune-stromal crosstalk. Furthermore, PLA2G2A and CCL17 contribute to an increased titer of pathogenic anti-BP180-NC16A autoantibodies in BP patients. Our work provides a comprehensive insight into BP pathogenesis and shows a mechanism governing immune-stromal interactions, providing potential avenues for future therapeutic research.

Association of IL-13 rs20541, FOXP3 rs3761548 genes polymorphisms and serum level of IL-13 with allergic asthma in Egyptian patients.

The interleukin 13 (IL-13) gene single nucleotide polymorphisms (SNPs) are frequently linked to increased vulnerability to allergic asthma. Forkhead box protein P3 (FOXP3) is an important molecule in the formation of regulatory T cells (Treg). The genetic variants that alter FOXP3 function may have a role in the development of asthma and other allergic disorders. We aimed to determine the association of IL-13 rs20541, FOXP3 rs3761548 genes SNPs and serum levels of IL-13 with allergic asthma patients. In this case-control study, 41 Egyptian patients with allergic asthma were included. Age and gender matched. 41 normal volunteers were considered the controls. All subjects were examined for IL-13 rs20541 and FOXP3 rs3761548 SNPs by the polymerase chain reaction /restriction fragment length polymorphism technique. The serum level of IL-13 was assessed by the enzyme linked immunosorbent assay (ELISA). AA genotype at IL-13 rs20541 SNP was statistically significantly different between the studied groups (p= 0.042). Also, a statistically significant difference was detected when compared AA genotype to GG genotype as AA genotype was three times at risk for asthma (p1=0.031) (OR=3.95) and A allele increased the risk of asthma by about 3 times (OR=3.2). AA genotype at FOXP3 rs3761548 SNP was statistically significantly different between the studied groups (p=0.013). Also, a statistically significant difference was detected when compared AA genotype to CC genotype as AA genotype was 7 times at risk for asthma (p1=0.003) (OR=7.04) and A allele increased the risk of asthma by about 3 times (p<0.001) (OR=3.07). The serum level of IL-13 was statistically significant different between both groups (p<0.001). We can conclude that IL-13 could be a useful tool for predicting allergic asthma. Patients with AA genotype of IL-13 rs20541 and AA genotype of FOXP3 rs3761548 have a higher risk for developing allergic asthma.

Transcriptomic Expression of T2-Inflammation Genes in Peripheral Blood Mononuclear Cells and Longitudinal Clinical Outcomes in Asthma: Insights from the COREA Study.

BACKGROUND: Gene expression can provide distinct information compared to clinical biomarkers in the context of longitudinal clinical outcomes in asthma patients. OBJECTIVE: This study examined the association between the gene expression levels of upstream (IL-25, IL-33, and TSLP) and downstream cytokines (IL-5, IL-4, and IL-13) in the T2 inflammatory pathway with a 12-month follow-up of exacerbation, lung function, and steroid use. METHODS: Transcriptomic sequencing analysis was performed on peripheral blood mononuclear cells from 279 adult asthmatics. Survival analysis and linear mixed-effect models were used to investigate potential differences between the high-level and low-level gene expression groups and the clinical outcomes. Analysis was performed separately for the upstream, downstream, and all 6 cytokines. RESULTS: In general, T2 inflammatory cytokine gene expression showed a weak correlation with blood eosinophil counts (all r < 0.1) and clinical outcomes. Among moderate-to-severe eosinophilic asthma (MSEA) patients, individuals with elevated levels of downstream cytokines were at increased risk of time-to-first exacerbation (p = 0.044) and a greater increase of inhaled corticosteroid use over time (p = 0.002) compared to those with lower gene expression. There was no association between baseline T2 inflammatory cytokine gene expression and the longitudinal changes in lung function over time among MSEA patients. CONCLUSION: These findings suggest that, among MSEA patients, the gene expression levels of downstream cytokines in the T2 inflammatory pathway may serve as indicators for endotyping asthma.

Association of CTACK, IL-2, and IL-13 with increased risk of lung cancer: A Mendelian randomization study.

BACKGROUND: In recent years, relevant studies have reported that inflammatory cytokines are related to the occurrence of cancer. However, the correlation with lung cancer is not clear. This study used the Mendelian random grouping method to investigate the correlation between inflammatory factors and lung cancer in different populations. METHODS: We obtained the single nucleotide polymorphisms (SNPs) of inflammatory cytokines through the open database and the SNPs of lung cancer (European and East Asian) through the IEU OpenGWAS project. Inverse variance-weighted (IVW) MR analyses were used to determine the causalities of exposures and outcomes. Supplementary analyses were also performed using weighted median and MR-Egger regressions. Afterward, sensitivity analyses were performed to test the robustness. Search the ChEMBL database for target drugs and indications for CTACK, IL-2, and IL-13. RESULTS: By IVW method, we found that CTACK, IL-2, and IL-13 were associated with an increased risk of lung cancer in the European population (CTACK, OR = 1.098, 95 % CI 1.001-1.204, P = 0.047; IL-2, OR = 1.112, 95 % CI 1.009-1.225, P = 0.032; IL-13, OR = 1.068, 95 % CI 1.007-1.132, P = 0.029), while only IL-13 was associated with an increased risk of lung cancer in the East Asian population (IL-13, OR = 1.110, 95 % CI 1.010-1.220, P = 0.030). The weighted median and MR-Egger regression methods were in the same direction as the IVW effect sizes. Furthermore, no evidence of multidirectionality was detected using the MR-Egger intercept as a sensitivity analysis. Currently, there are no approved or phase III studied indications for CTACK, IL-2, and IL-13 targets in lung cancer. CONCLUSION: The study outcomes supported that the inflammatory cytokines CTACK, IL-2, and IL-13 increase the risk of lung cancer. There is a lack of indications for drugs in these three targets. We explored the causal relationship between inflammatory cytokines and lung cancer, providing a basis for future cancer prediction models and targets for anti-tumor therapy.

[H3K27 acetylation promotes lncRNA OIP5-AS1 transcription and induces apoptosis of nasal epithelial cells in allergic rhinitis through up-regulation of TLR4].

Objective To investigate the effect of lysine 27 residue of histone H3 (H3K27) acetylation modification on the transcriptional promotion of long noncoding RNA OPA interacting protein 5-antisense RNA 1 (lncRNA OIP5-AS1) and apoptosis of nasal epithelial cells (NECs) in allergic rhinitis (AR) via regulating Toll-like receptor 4 (TLR4). Methods Interleukin-13 (IL-13) was used to treat NECs to establish an AR cell model. Real-time quantitative PCR was utilized to detect the expressions of OIP5-AS1 and TLR4 in nasal mucosal tissues of AR patients and in the in vitro cell model. The concentrations of macrophage colony-stimulating factor (GM-CSF), eotaxin-1, and mucin 5AC (MUC5AC) were detected by ELISA. The apoptosis of NECs was determined by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL). A dual-luciferase report experiment was carried out to verify the relationship between OIP5-AS1 and TLR4. Chromatin immunoprecipitation (ChIP) assay was performed to verify H3K27 acetylation of histones in the OIP5-AS1 promoter region. Results Compared with healthy controls and untreated NECs, OIP5-AS1 and TLR4 were both up-regulated in nasal mucosal tissues from AR patients and IL-13-stimulated NECs. Knockdown of OIP5-AS1 decreased the level of TLR4 in IL-13-treated NECs, while overexpression of OIP5-AS1 increased the level of TLR4. Inhibition of OIP5-AS1 reduced the apoptosis rate, and inhibited the secretion of GM-CSF, eotaxin-1, and MUC5AC from IL-13-treated NECs, while overexpression of TLR4 partially reversed the effects of OIP5-AS1 knockdown on NEC apoptosis and the secretion of GM-CSF, eotaxin-1, and MUC5AC. In addition, H3K27 acetylation was markedly enriched in the promoter region of OIP5-AS1, and H3K27 acetylation promoted the expression of OIP5-AS1 in IL-13-treated NECs. Conclusion H3K27 acetylation promotes OIP5-AS1 transcription and induces NEC apoptosis in AR via upregulation of TLR4.

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

MEF2D facilitates liver metastasis of gastric cancer cells through directly inducing H1X under IL-13 stimulation.

Liver metastasis is the most common metastatic occurrence in gastric cancer patients, although the precise mechanism behind it remains unclear. Through a combination of proteomics and quantitative RT-PCR, our study has revealed a significant correlation between the upregulation of myocyte enhancer factor-2D (MEF2D) and both distant metastasis and poor prognosis in gastric cancer patients. In mouse models, we observed that overexpressing or knocking down MEF2D in gastric cancer cells respectively promoted or inhibited liver metastasis. Furthermore, our research has demonstrated that MEF2D regulates the transcriptional activation of H1X by binding to the H1X promoter. This regulation leads to the upregulation of H1X, which, in turn, promotes the in vivo metastasis of gastric cancer cells along with the upregulation of the downstream gene ß-CATENIN. Additionally, we found that the expression of MEF2D and H1X at both mRNA and protein levels can be induced by the inflammatory factor IL-13, and this induction exhibits a time gradient dependence. In human gastric cancer tissues, the expression of IL13RA1, the receptor for IL-13, positively correlates with the expression of MEF2D and H1X. IL13RA1 has been identified as an intermediate receptor through which IL-13 regulates MEF2D. In conclusion, our findings suggest that MEF2D plays a crucial role in promoting liver metastasis of gastric cancer by upregulating H1X and downstream target ß-CATENIN in response to IL-13 stimulation. Targeting MEF2D could therefore be a promising therapeutic strategy for the clinical management of gastric cancer. STATEMENT OF SIGNIFICANCE: MEF2D promotes its transcriptional activation in gastric cancer cells by binding to the H1X promoter and is upregulated by IL-13-IL13RA1, thereby promoting distant metastasis of gastric cancer.

Inflammatory cytokines mediating the effect of oral lichen planus on oral cavity cancer risk: a univariable and multivariable mendelian randomization study.

BACKGROUND: While observational studies and experimental data suggest a link between oral lichen planus (OLP) and oral cavity cancer (OCC), the causal relationship and the role of inflammatory cytokines remain unclear. METHODS: This study employed a univariable and multivariable Mendelian Randomization (MR) analysis to investigate the causal relationship between OLP and the risk of OCC. Additionally, the potential role of inflammatory cytokines in modulating this association was explored. Instrumental variables were derived from genetic variants associated with OLP (n = 377,277) identified in Finngen R9 datasets, with 41 inflammatory cytokines as potential mediators, and OCC (n = 4,151) as the outcome variable. Analytical methods including Inverse Variance Weighted (IVW), Weighted Median, MR-Egger, and MR-PRESSO were utilized to assess the causal links among OLP, inflammatory cytokines, and OCC risk. Multivariable MR (MVMR) was then applied to quantify the mediating effects of these cytokines in the relationship between OLP and increased OCC risk. RESULTS: MR analysis provided strong evidence of a causal relationship between OLP (OR = 1.417, 95% CI = 1.167-1.721, p < 0.001) and the risk of OCC. Furthermore, two inflammatory cytokines significantly influenced by OLP, IL-13 (OR = 1.088, 95% CI: 1.007-1.175, P = 0.032) and IL-9 (OR = 1.085, 95% CI: 1.005-1.171, P = 0.037), were identified. Subsequent analysis revealed a significant causal association only between IL-13 (OR = 1.408, 95% CI: 1.147-1.727, P = 0.001) and higher OCC risk, establishing it as a potential mediator. Further, MVMR analysis indicated that IL-13 (OR = 1.437, 95% CI = 1.139-1.815, P = 0.002) mediated the relationship between OLP and OCC, accounting for 8.13% of the mediation. CONCLUSION: This study not only elucidates the potential causal relationship between OLP and the risk of OCC but also highlights the pivotal mediating role of IL-13 in this association.

Highly pathogenic PRRSV upregulates IL-13 production through nonstructural protein 9-mediated inhibition of N6-methyladenosine demethylase FTO.

Porcine reproductive and respiratory syndrome virus (PRRSV), a highly infectious virus, causes severe losses in the swine industry by regulating the inflammatory response, inducing tissue damage, suppressing the innate immune response, and promoting persistent infection in hosts. Interleukin-13 (IL-13) is a cytokine that plays a critical role in regulating immune responses and inflammation, particularly in immune-related disorders, certain types of cancer, and numerous bacterial and viral infections; however, the underlying mechanisms of IL-13 regulation during PRRSV infection are not well understood. In this study, we demonstrated that PRRSV infection elevates IL-13 levels in porcine alveolar macrophages. PRRSV enhances m6A-methylated RNA levels while reducing the expression of fat mass and obesity associated protein (FTO, an m6A demethylase), thereby augmenting IL-13 production. PRRSV nonstructural protein 9 (nsp9) was a key factor for this modulation. Furthermore, we found that the residues Asp567, Tyr586, Leu593, and Asp595 were essential for nsp9 to induce IL-13 production via attenuation of FTO expression. These insights delineate PRRSV nsp9's role in FTO-mediated IL-13 release, advancing our understanding of PRRSV's impact on host immune and inflammatory responses.

[Zhuyu Pills promote polarization of macrophages toward M2 phenotype to prevent atherosclerosis via PPARγ/NF-κB signaling pathway].

This article aims to investigate the effect of Zhuyu Pills on atherosclerosis and decipher the underlying mechanism. The mouse model of atherosclerosis was induced by a high-fat diet, and the total modeling period was 12 weeks. A total of 47 ApoE~(-/-) mice successfully modeled were randomized into 5 groups, including 10 in the model group, 9 in each of low-, medium-, and high-dose(130.54, 261.08 and 522.16 mg·kg~(-1)·d~(-1), respectively) Zhuyu Pills groups, and 10 in the atorvastatin calcium(10.40 mg·kg~(-1)·d~(-1)) group. In addition, 10 C57BL/6J mice were included as the normal group. The mice in the normal group and model group were administrated with an equal volume of sterile distilled water, and those in other groups with corresponding agents by gavage once a day for 12 weeks. At the end of drug intervention, the levels of total cholesterol(TC), triglyceride(TG), high-density lipoprotein cholesterol(HDL-C), and low-density lipoprotein cholesterol(LDL-C) were measured by the biochemical method. Hematoxylin-eosin(HE) staining was employed to observe the plaque distribution in the aortic region. The serum levels of pro-inflammatory cytokines tumor necrosis factor-α(TNF-α) and interleukin(IL)-6 in M1 macrophages and anti-inflammatory cytokines IL-13 and IL-4 in M2 macrophages were determined by enzyme-linked immunosorbent assay(ELISA). The expression levels of inducible nitric oxide synthase(iNOS) and arginase-1(Arg-1) were examined by immunofluorescence. Real-time fluorescence quantitative polymerase chain reaction(real-time PCR) was employed to measure the mRNA levels of peroxisome proliferator-activated receptor γ(PPARγ), nuclear factor-κB(NF-κB), Arg-1, and iNOS in the aorta. Western blot was employed to determine the protein levels of PPARγ and NF-κB in the aorta. The results showed that compared with the normal group, the modeling elevated the TC, TG, and LDL-C levels, lowered the HDL-C level, caused large area thickening of the aortic intima, elevated the TNF-α and IL-6 levels, lowered the IL-4 and IL-13 levels, down-regulated the mRNA and protein levels of PPARγ and Arg-1, and up-regulated the mRNA and protein levels of iNOS and NF-κB in the aorta(P<0.01). Compared with the model group, low-, medium-, and high-dose Zhuyu Pills and atorvastatin calcium lowered the TC, TG, and LDL-C levels, elevated the HDL-C level, reduced the plaque area in a concentration-dependent manner, lowered the TNF-α and IL-6 levels, elevated the IL-4 and IL-13 levels, up-regulated the mRNA and protein levels of PPARγ and Arg-1, and down-regulated the mRNA and protein levels of NF-κB and iNOS in the aorta(P<0.05 or P<0.01). In conclusion, Zhuyu Pills may play an anti-atherosclerosis role by regulating PPARγ/NF-κB signaling pathway, inhibiting the polarization of macrophages toward the M1 phenotype, promoting the polarization of macrophages toward the M2 phenotype, and improving the inflammatory microenvironment of macrophages.

Down-Regulation of INSR Restores Th17/Treg Immune Balance and Alleviates Airway Hyperviscosity in Asthmatic Mice via Inactivation of STAT3 Pathway.

BACKGROUND: Allergic asthma (AA) is a prevalent chronic airway inflammation disease. In this study, this study aims to investigate the biological functions and potential regulatory mechanisms of the insulin receptor (INSR) in the progression of AA. METHODS: BALB/c mice (n = 48) were randomly divided into the following groups: control group, AA group, AA+Lentivirus (Lv)-vector short hairpin RNA (shRNA) group, AA+Lv-vector group, AA+Lv-INSR shRNA group, and AA+Lv-INSR group. The pulmonary index was calculated. mRNA and protein expression levels of INSR, signal transducer and activator of transcription 3 (STAT3), Janus kinase 2 (JAK2), phosphorylated-STAT3 (p-STAT3), phosphorylated-JAK2 (p-JAK2), alpha-smooth muscle actin (α-SMA), febrile neutropenia (FN), mucin 5AC (MUC5AC), and mucin 5B (MUC5B) were examined using reverse-transcription quantitative PCR (RT-qPCR) and western blot assays. Positive expressions of INSR, retinoic acid-related orphan receptor gamma-t (RORγt), and forkhead box protein P3 (Foxp3) were quantified by immunohistochemistry. Fluorescence intensities of α-SMA and FN were detected by immunofluorescence. Pathological morphology was observed through hematoxylin-eosin (H&E) staining, Masson staining, and Periodic Acid-Schiff (PAS) staining. Contents of immunoglobulin E (IgE), interleukin-6 (IL-6), eotaxin, interleukin-4 (IL-4), interleukin-13 (IL-13), interferon-γ (IFN-γ), interleukin-17 (IL-17), and interleukin-10 (IL-10) were quantified using enzyme-linked immunosorbent assay (ELISA). The percentage of T helper 17 (Th17) and regulatory T (Treg) cells was determined through flow cytometry. RESULTS: Compared to the control group, expression levels of INSR, p-STAT3, p-JAK2, α-SMA, FN, MUC5AC, MUC5B, RORγt, and Foxp3, as well as IgE, IL-6, eotaxin, IL-4, IL-13, and IL-17 contents, pulmonary index, glycogen-positive area (%), and Th17 cell percentage significantly increased (p < 0.05). Additionally, pulmonary histopathological deterioration and collagen deposition were aggravated, while Treg cell percentage and IFN-γ and IL-10 contents remarkably decreased (p < 0.05). The overexpression of INSR further exacerbated the progression of allergic asthma, but the down-regulation of INSR reversed the trends of the above indicators. CONCLUSIONS: The down-regulation of INSR alleviates airway hyperviscosity, inflammatory infiltration, and airway remodeling, restoring Th17/Treg immune balance in AA mice by inactivating the STAT3 pathway.

Epithelial overexpression of IL-33 induces eosinophilic esophagitis dependent on IL-13.

BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium-derived cytokine IL-33 is associated with type 2 immune responses and elevated in esophageal biopsy specimens from patients with EoE. OBJECTIVE: We hypothesized that overexpression of IL-33 by the esophageal epithelium would promote the immunopathology of EoE. METHODS: We evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL-33 in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2-/-, eosinophil-deficient, and IL-13-/- mice. Finally, EoE33 mice were treated with dexamethasone. RESULTS: EoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and TH2 cells. Marked increases in levels of type 2 cytokines, including IL-13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL-13 in EoE33 mice abrogated pathologic changes in vivo. EoE33 mice were responsive to steroids. CONCLUSIONS: IL-33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL-33 may play a pivotal role in the etiology of EoE by activating the IL-13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery.

Evaluation of antibody and T Cell immunity response in different immunization groups of inactive and mRNA COVID-19 vaccines.

This study aimed to evaluate the antibody and T cell responses of homologous and heterologous booster doses for SARS-CoV-2 vaccines. Our study was performed on those with two doses of mRNA vaccine BNT162b2 (2B, n:44), those with heterologous booster dose BNT162b2 vaccine after two doses of inactivated vaccine CoronaVac (2S+1B, n:44), those with homologous booster dose vaccine CoronaVac after two doses of vaccine CoronaVac (3S, n:44) SARS-CoV-2 IgG antibody levels were significantly higher in individuals who received heterologous boosters(p<0.001). IFN-Ɣ, IL-2 and IL-13 median values were detected higher in 2S+1B group than in 3S group, respectively (p=0.112, p=0.057, p=0.341). Although the antibody levels in 2S+1B group were similar (p=0.153) to the 2B group; IFN-Ɣ, IL-2 and IL-13 levels were higher (p<0.001). In conclusion, supplementing an improved strategy based on inactivated vaccines with an mRNA vaccine as a heterologous booster is likely to be more beneficial in the course of the pandemic.

Role and Molecular Mechanisms of Alternative Splicing of Th2-Cytokines IL-4 and IL-5 in Atopic Bronchial Asthma.

Bronchial asthma (BA) is a heterogeneous chronic inflammatory disease of the respiratory tract. Allergic (atopic) asthma is the most common (up to 80% of cases) phenotype developing through the Th2-dependent mechanisms involving cytokines: IL-4, IL-5, IL-9, and IL-13. The genes encoding Th2-cytokines have a mosaic structure (encode exons and introns). Therefore, several mature mRNA transcripts and protein isoforms can be derived from a single mRNA precursor through alternative splicing, and they may contribute to BA pathogenesis. Analysis of the published studies and databases revealed existence of the alternative mRNA transcripts for IL-4, IL-5, and IL-13. The alternative transcripts of IL-4 and IL-5 carry open reading frames and therefore can encode functional proteins. It was shown that not only alternative mRNA transcripts exist for IL-4, but alternative protein isoforms, as well. Natural protein isoform (IL-4δ2) lacking the part encoded by exon-2 was identified. Similarly, alternative mRNA transcript with deleted exon-2 (IL-5δ2) was also identified for IL-5. In this review, we summarize current knowledge about the identified alternative mRNA transcripts and protein isoforms of Th2-cytokinins, first of all IL-4 and IL-5. We have analyzed biological properties of the alternative variants of these cytokines, their possible role in the allergic asthma pathogenesis, and considered their diagnostic and therapeutic potential.

Associations of inflammatory cytokines with inflammatory bowel disease: a Mendelian randomization study.

Objectives: Previous studies have confirmed a link between specific inflammatory cytokines and inflammatory bowel disease (IBD), but the causal relationship between them is not completely clear. This Mendelian Randomization (MR) study aims to evaluate the causal relationship between 18 inflammatory cytokines and inflammatory bowel disease. Method: Two-sample Mendelian randomization utilized genetic variances associated with IBD from two extensive publicly available genome-wide association studies (GWAS) (Crohn's Disease (CD): 12,194 cases and 28,072 controls; Ulcerative Colitis (UC): 12,336 cases and 33,609 controls). The data of inflammatory cytokines was acquired from a GWAS including 8,293 healthy participants. We used inverse variance weighted method, MR-Egger, weighted median, simple model and weighted model to evaluate the causal relationship between inflammatory cytokines and IBD. Sensitivity analysis includes heterogeneity and pleiotropy analysis to evaluate the robustness of the results. Results: The findings indicated suggestive positive associations between Interleukin-13 (IL-13) and macrophage migration inhibitory factor (MIF) with CD (odds ratio, OR: 1.101, 95%CI: 1.021-1.188, p = 0.013; OR: 1.134, 95%CI: 1.024-1.255, p = 0.015). IL-13 also displayed a significant positive correlation with UC (OR: 1.099, 95%CI: 1.018-1.186, p = 0.016). Stem cell factor (SCF) was suggested to be associated with the development of both CD and UC (OR: 1.032, 95%CI: 0.973-1.058, p = 0.012; OR: 1.038, 95%CI: 1.005-1.072, p = 0.024). Conclusion: This study proposes that IL-13 may be a factor correlated with the etiology of IBD (CD and UC), while MIF just be specifically associated with CD. Additionally, SCF appears more likely to be involved in the downstream development of IBD (CD and UC).

Genetic polymorphisms and asthma: findings from a case - control study in the Madeira island population

BACKGROUND: Asthma is a complex disease influenced by multiple genetic and environmental factors. While Madeira has the highest prevalence of asthma in Portugal (14.6%), the effect of both genetic and environmental factors in this population has never been assessed. We categorized 98 asthma patients according to the Global Initiative for Asthma (GINA) guidelines, established their sensitization profile, and measured their forced expiratory volume in 1second (FEV1) and forced vital capacity (FVC) indexes. Selected single nucleotide polymorphisms (SNPs) were analysed as potential markers for asthma susceptibility and severity in the interleukin 4 (IL4), interleukin 13 (IL13), beta-2-adrenergic receptor (ADRB2), a disintegrin and metalloprotease 33 (ADAM33), gasdermin-like (GSDML) and the signal transducer and activator of transcription 6 (STAT6) genes comparatively to a population reference set. RESULTS: Although mites are the major source of allergic sensitization, no significant difference was found amongst asthma severity categories. IL4-590*CT/TT and IL4-RP2*253183/183183 were found to predict the risk (2-fold) and severity (3 to 4-fold) of asthma and were associated with a lower FEV1 index. ADRB2-c.16*AG is a risk factor (3.5-fold), while genotype GSDML-236*TT was protective (4-fold) for moderate-severe asthma. ADAM33-V4*C was associated to asthma and mild asthma by the transmission disequilibrium test (TDT). Finally, ADAM33-V4*CC and STAT6-21*TT were associated with higher sensitization (mean wheal size ≥10mm) to house dust (1.4-fold) and storage mite (7.8-fold). CONCLUSION: In Madeira, IL4-590C/T, IL4-RP2 253/183, GSDML-236C/T and ADAM33-V4C/G SNPs are important risk factors for asthma susceptibility and severity, with implications for asthma healthcare management.