IL23R Gene Research Articles

Targeted plasma proteomics identifies MICA and IL1R1 proteins associated with HIV-1 reservoir size

HIV-1 reservoir shows high variability in size and activity among virally suppressed individuals. Differences in the size of the viral reservoir may relate to differences in plasma protein concentrations. We tested whether plasma protein expression levels are associated with levels of cell-associated (CA) HIV-1 DNA and RNA in 211 virally suppressed people living with HIV (PLHIV). Plasma concentrations of FOLR1, IL1R1, MICA, and FETUB showed a positive association with CA HIV-1 RNA and DNA. Moreover, SNPs in close proximity to IL1R1 and MICA genes were found to influence the levels of CA HIV-1 RNA and DNA. We found a difference in mRNA expression of the MICA gene in homozygotes carrying the rs9348866-A allele compared to the ones carrying the G allele (p<0.005). Overall, our findings pinpoint plasma proteins that could serve as potential targets for therapeutic interventions to lower or even eradicate cells containing CA HIV-1 RNA and DNA in PLHIV.

Suggestive evidence of genetic association of IL23R polymorphisms with chronic obstructive pulmonary disease risk in the Chinese population.

Chronic obstructive pulmonary disease (COPD) is a worldwide public health problem. Previous genetic association studies have identified several susceptibility loci in the interleukin genes that may participate in the nosogenesis of COPD. This study aimed to evaluate the relationship between IL23R loci and COPD susceptibility in the Chinese population. Agena MassARRAY technology was applied to genotype five single nucleotide polymorphisms (SNPs) in the IL23R gene in 498 COPD patients and 498 healthy people. The association between IL23R SNPs and COPD risk was calculated by logistic regression analysis, with odds ratios and 95% confidence intervals. The false-positive report probability analysis was noteworthy for evaluating the significant results. Also, haplotype analysis was performed among IL23R variants, and multifactor dimensionality reduction analysis was performed to assess the SNP-SNP interactions to predict the risk of COPD. Overall analysis showed that rs7517847 had a significant association with an increased risk of COPD. Age-stratified analysis revealed that rs7517847 was significantly related to an increased risk of COPD in people aged over 68 years old. Sex-stratified analysis illustrated a significant association between rs2295359 and rs7517847 and COPD risk in the female population. The significant association of COPD risk with IL23R SNPs was assessed by false-positive report probability values. Additionally, we observed that the haplotypes AAC and GGA formed by rs2201841, rs12743974 and rs10889677 were associated with a reduced risk of COPD (p = 0.009, p = 0.026). Also, the five-loci interaction model formed by rs2295359, rs7517847, rs2201841, rs12743974 and rs10889677 became the best predictor of COPD, with 10/10 cross-validation consistency and 52.4% testing balance accuracy. The research indicated a remarkable association between IL23R variants and COPD susceptibility in the Chinese population. Larger samples and functional research are required to ascertain the relationship between IL23R variants and COPD susceptibility.

The effect of microRNA-663b in the inhibition of interleukin-1-induced nucleus pulposus cell apoptosis and inflammatory response.

The aim of this study was to explore the role and pathological mechanism of microRNA-663b in interleukin-1beta (IL-1β)-induced inflammation and apoptosis of nucleus pulposus cells. First, the best concentration and time to construct the nucleus pulposus cell inflammation model was screen out. Overexpression or inhibition of miR-663b expression was performed by adding microRNA-663b mimic or microRNA-663b inhibitor. 293T cells were transfected according to experimental requirements. The luciferase activity of each group was detected to analyze the targeted regulation of microRNA-663b on interleukin-1 receptor (IL1R1). Compared with the mimic negative control (NC) group, the expression of inflammatory factors in the microRNA-663b overexpression group was inhibited (P<0.05), and the expression of type 2 collagen and polysaccharide protein increased (P<0.05), and the apoptosis of nucleus pulposus cells was inhibited (P<0.01), and the number of TUNEL-positive cells decreased significantly (P<0.01), and the microRNA and protein expression of IL1R1, the ratio of P-P65/P65 and phospho-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (P-IκBα)/nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) protein expression were significantly decreased (P<0.05). The expression of inflammatory factors in the miR-663b inhibitor group was significantly higher than that in the inhibitor NC group (P<0.01), and the expression of type 2 collagen and polysaccharide protein was significantly decreased (P<0.01), and the number of apoptosis cells and TUNEL staining positive cells increased (p<0.01). The expression of IL1R1 gene and protein was significantly increased (P<0.01). The ratio of P-P65/P65 and P-IκBα/IκBα protein expression increased (P<0.05). IL1R1 is a downstream target gene of microRNA-663b. MicroRNA-663b may down-regulate the expression of IL1R1 at the transcriptional level by targeting IL1R1, inhibit the inflammatory response of nucleus pulposus cells, and slow down the degeneration of nucleus pulposus cells.

The effect of microRNA-663b in the inhibition of interleukin-1-induced nucleus pulposus cell apoptosis and inflammatory response.

The aim of this study was to explore the role and pathological mechanism of microRNA-663b in interleukin-1beta (IL-1β)-induced inflammation and apoptosis of nucleus pulposus cells. First, the best concentration and time to construct the nucleus pulposus cell inflammation model was screen out. Overexpression or inhibition of miR-663b expression was performed by adding microRNA-663b mimic or microRNA-663b inhibitor. 293T cells were transfected according to experimental requirements. The luciferase activity of each group was detected to analyze the targeted regulation of microRNA-663b on interleukin-1 receptor (IL1R1). Compared with the mimic negative control (NC) group, the expression of inflammatory factors in the microRNA-663b overexpression group was inhibited (P<0.05), and the expression of type 2 collagen and polysaccharide protein increased (P<0.05), and the apoptosis of nucleus pulposus cells was inhibited (P<0.01), and the number of TUNEL-positive cells decreased significantly (P<0.01), and the microRNA and protein expression of IL1R1, the ratio of P-P65/P65 and phospho-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (P-IκBα)/nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) protein expression were significantly decreased (P<0.05). The expression of inflammatory factors in the miR-663b inhibitor group was significantly higher than that in the inhibitor NC group (P<0.01), and the expression of type 2 collagen and polysaccharide protein was significantly decreased (P<0.01), and the number of apoptosis cells and TUNEL staining positive cells increased (p<0.01). The expression of IL1R1 gene and protein was significantly increased (P<0.01). The ratio of P-P65/P65 and P-IκBα/IκBα protein expression increased (P<0.05). IL1R1 is a downstream target gene of microRNA-663b. MicroRNA-663b may down-regulate the expression of IL1R1 at the transcriptional level by targeting IL1R1, inhibit the inflammatory response of nucleus pulposus cells, and slow down the degeneration of nucleus pulposus cells.

Single nucleotide polymorphisms in ADAM17, IL23R and SLCO1C1 genes protect against infliximab failure in adults with Crohn’s disease

BackgroundTo predict primary failure of infliximab (IFX) therapy in Crohn’s disease (CD) and to identify patients who maintain long-term effectiveness to IFX is currently not feasible. Some genetic variations are proposed as potential biomarkers. AimWe assessed a set of single nucleotide polymorphisms (SNPs) in genes related to the IFX mechanism of action and the presence of HLA-DQA1 * 05 allele on the primary response and long-term durability in CD patients. MethodsA multi-centre cross-sectional study of IFX-exposed adult patients with CD was undertaken. Treatment persistence and time to failure were co-primary endpoints. DNA from the 131 patients was genotyped. Association between SNPs and clinical variables with IFX persistence was assessed. ResultsFailure to IFX was documented in 65 (49.6%) out of 131 patients. IFX persistence was associated either with carrying the TT genotype in ADAM17 rs10929587 (ORa=0.2; 95%CI=0.1–0.8; p = 0.021), or the CC genotype in SLCO1C1 rs3794271 (ORa=0.2; 95%CI=0.1–0.7; p = 0.008), according to multivariate logistic regression. In contrast, previous bowel resection increased the risk of IFX failure (ORa=2.8; 95%CI=1.1–7.3; p = 0.025). Cox regression analysis confirmed these findings and also identified IL23R rs10489629-TT (HRa 0.41; 95%CI=0.22–0.75; p = 0.004) and concomitant immunosuppressants (HRa 0.46; 95%CI=0.27–0.77; p = 0.003) as protection from IFX failure. However, no association between HLA-DQA1 * 05 allele and persistence of IFX therapy was found, with similar failure rates among carriers and non-carriers (52.8% vs. 47.4%, respectively; p = 0.544). ConclusionsSNPs rs10929587-TT in ADAM17, rs10489629-TT in IL23R and rs3794271-CC in SLCO1C1, together with no previous bowel surgery and concomitant immunosuppression, were identified as protection from failure to IFX.

Influence of adalimumab on interleukin 12/23 signalling pathways in human keratinocytes treated with lipopolysaccharide A.

The interleukin-12/23 (IL-12/23) signalling pathway plays an important role in the pathogenesis of psoriasis. In addition, even molecularly targeted therapy has been reported to lose adequate response to treatment. To determine the expression patterns of mRNAs and miRNAs related to IL-12/23 signalling pathways in the human keratinocyte culture exposed to liposaccharide A (LPS) and then adalimumab in comparison with untreated cells. Human, adult, low-Calcium, high-Temperature keratinocyte (HaCaT) cultures were exposed to 1 µg/ml LPS for 8 h, and then adalimumab was added to the cultures at a concentration of 8 µg/ml and incubated for 2, 8, and 24 h. We used mRNA and miRNA microarray, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay techniques. STAT1, STAT3, STAT5, IL-6, IL-6R, SOCS3, and JAK3 genes differentiated HaCaT cultures with the drug from controls regardless of the time the cells were exposed to the drug. The addition of adalimumab to a culture previously exposed to LPS resulted in silencing of SOCS3 and IL-6 expression compared to the control, while for the other transcripts they were found to be overexpressed compared to the control culture. The assessment indicated the strongest connections between JAK3 and hsa-miR-373-5p (target score 96); SOCS3, STAT5, and hsa-miR-1827 (target score 96). Our study indicates that adalimumab has the strongest modulating effect on mRNA and miRNA expression of JAK/STAT and IL-6-dependent IL-12/23 pathways.

Clinical Value of IL6R Gene Variants as Predictive Biomarkers for Toxicity to Tocilizumab in Patients with Rheumatoid Arthritis.

Tocilizumab is a first-line biologic disease-modifying anti-rheumatic drug (bDMARD) that inhibits the interleukin-6 (IL-6) pathway by antagonizing the IL-6 receptor (IL-6R). Tocilizumab is widely used to treat rheumatoid arthritis (RA), a prevalent autoimmune disease that can cause irreversible joint damage and disability. Although many bDMARDs have been developed for RA, there is a lack of validated biomarkers which could guide personalized medicine strategies. To evaluate whether single-nucleotide polymorphisms (SNPs) in the IL6R gene could predict tocilizumab toxicity in patients with RA, we conducted a retrospective cohort study of 88 patients treated with tocilizumab. Six SNPs previously described in the IL6R gene were genotyped (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625). Using parametric tests, we studied the association between the SNPs and hepatotoxicity, infection, hypersensitivity, gastrointestinal, hematological, and dyslipidemia adverse events (AEs). We found associations between dyslipidemia and rs4845625 and between hematological AEs and rs11265618 and rs4329505. No further associations were found for the remaining SNPs and other AEs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for toxicity to tocilizumab in patients with RA.

Investigation of the Relationship between IL-6, IL-6R and CXCL5 Polymorphisms and Obesity in Denizli Province of Turkey

Obesity and its effects on increasing morbidity and mortality have reached the level of an epidemic with a high frequency in modern populations. IL-6 released from adipose tissue is known to trigger the chronic inflammation in obesity. CXCL5, which mediates the activation and migration of neutrophils, has been found at high levels in obese subjects. In our study, we aimed to investigate the possible effects of IL-6, IL-6R and CXCL5, polymorphisms and haplotypes on the development of obesity. We studied IL-6, rs2069827 (-1363, G/T), rs1800797 (-597, G/A), rs1800796 (-572, G/C) and rs1800795 (-174, G/C), IL-6R rs4845617 (-183, G/A), rs2228145 (+48892, A/C) and CXCL5 rs352046 (-156, G/C) polymorphic sites in 60 obesity patients and 59 healthy controls. For genotyping we used PCR-RFLP based approach. The IL-6 rs1800796, rs1800795 and IL-6R rs4845617 G allelles could be the possible genetic factors responsible for obesity. We found similar results in female obese group. The results indicated that there was no association between obesity and other SNPs (rs2069827, rs1800797, and rs1800795 and rs2228145) and CXCL5, rs352046. The results of IL-6 and IL-6R haplotype analysis by global differentiation test showed that haplotypes may have different distributions between obese and controls. Our results showed that polymorphisms and possible haplotypes in IL-6 and IL-6R genes, which have an important role in inflammation, may affect the development of obesity. This study points out the necessity of investigating the possible effects of gene polymorphisms of other cytokines and their receptors in the development of obesity in larger populations.

IL6R gene polymorphisms and their relation to chronic obstructive pulmonary disease susceptibility in theChinese population.

Background: This work was designedto explore the correlation between IL6R polymorphisms and chronic obstructive pulmonary disease (COPD) susceptibility. Methods: Agena MassARRAY was used to genotype five SNPsof IL6R in 498 patients with COPD and 498 controls. Genetic models and haplotype analysis were used to assess the associations between SNPs and COPD risk. Results: Rs6689306 and rs4845625 increase the risk of COPD. Rs4537545, rs4129267 and rs2228145 were related to a decreased risk of COPD in different subgroups. Haplotype analysis revealed that GTCTC, GCCCA and GCTCA contributed to a reduced risk of COPD after adjustment. Conclusion: IL6R polymorphisms are significantly associated with COPD susceptibility.

Somatic Mutations Alter Interleukin Signaling Pathways in Grade II Invasive Breast Cancer Patients: An Egyptian Experience.

This study aimed to investigate the impact of somatic mutations on various interleukin signaling pathways associated with grade II invasive breast cancer (BC) in Egyptian patients to broaden our understanding of their role in promoting carcinogenesis. Fifty-five grade II invasive BC patients were included in this study. Data for somatic mutations in 45 BC patients were already available from a previous study. Data for somatic mutations of 10 new BC patients were included in the current study. Somatic mutations were identified using targeted next-generation sequencing (NGS) to study their involvement in interleukin signaling pathways. For pathway analysis, we used ingenuity variant analysis (IVA) to identify the most significantly altered pathways. We identified somatic mutations in components of the interleukin-2, interleukin-6, and inter-leukin-7 signaling pathways, including mutations in JAK1, JAK2, JAK3, SOCS1, IL7R, MCL1, BCL2, MTOR, and IL6ST genes. Interestingly, six mutations which were likely to be novel deleterious were identified: two in the SCH1 gene, two in the IL2 gene, and one in each of the IL7R and JUN genes. According to IVA analysis, interleukin 2, interleukin 6, and interleukin 7 signaling pathways were the most altered in 34.5%, 29%, and 23.6% of our BC group, respectively. Our multigene panel sequencing analysis reveals that our BC patients have altered interleukin signaling pathways. So, these results highlight the prominent role of interleukins in the carcinogenesis process and suggest its potential role as promising candidates for personalized therapy in Egyptian patients.

Exploring the association between Th17 pathway gene polymorphisms and pulmonary tuberculosis.

Th17 cells play a key role in immunity against Mycobacterium tuberculosis (MTB), and this study aimed to explore the association of Th17 pathway gene polymorphisms with pulmonary tuberculosis (PTB) susceptibility in a Chinese population. A total of 10 single nucleotide polymorphisms in Th17 pathway genes (IL-17A gene rs2275913, rs3748067, rs8193036, rs3819024, IL-17F gene rs7741835, rs763780, IL-21 gene rs907715, rs2055979, IL-23R gene rs11805303, and rs7518660) were genotyped in 456 PTB patients and 466 controls using SNPscan technique. The IL-23R rs11805303 CC genotype, C allele frequencies were significantly lower in PTB patients than in controls, and the rs11805303 variant was significantly associated with the reduced risk of PTB in a recessive model. There were no significant associations between IL-17A, IL-17F, and IL-21 gene variations and PTB risk. In IL-17A gene, rs2275913, rs3748067, and rs3819024 variants were associated with drug resistance in PTB patients. In IL-17F gene, rs7741835 variant affected drug resistance, and rs763780 variant was associated with hypoproteinemia in PTB patients. In addition, the lower frequencies of the TT genotype, T allele of rs2055979 were found in PTB patients with drug-induced liver injury. Haplotype analysis showed that IL-23R CG haplotype frequency was significantly lower in PTB patients than in controls, while the TG haplotype frequency was higher. In conclusion, IL-23R rs11805303 polymorphism may contribute to the genetic underpinnings of PTB in the Chinese population, and the IL-17A, IL-17F, and IL-21 genetic variations are associated with several clinical manifestations of PTB patients.

BAX 335 Hemophilia B Gene Therapy Phase 1/2 Clinical Trial: Long-Term Safety and Efficacy Follow-up

Background: BAX 335 is an adeno-associated virus serotype 8 (AAV8)-based clotting factor IX (FIX) Padua (R338L) gene therapy for the treatment of hemophilia B. A phase 1/2 safety and efficacy study dosed 8 participants with BAX 335 between 2013 and 2015 (NCT01687608). Infusions with BAX 335 were generally well tolerated; however, 7 of 8 participants did not achieve significant levels of durable transgene expression despite the use of glucocorticoids and resumed FIX replacement by 52 weeks (Konkle et al, Blood 2021;137:763-74). A root-cause analysis identified CpG content in the vector as a potential immunogenic trigger for the innate immune response, resulting in loss of expression. One participant demonstrated high levels of durable FIX expression, with detectable FIX activity levels between 0.1 and 0.4 IU/mL after 4 years and was found to have a missense variant in the IL6R gene. This study is the longest ongoing clinical gene therapy trial using a FIX R338L transgene. Aims: (1) To report long-term safety and participant disposition; (2) to describe persistence of endogenous FIX R338L transgene expression; and (3) to report long term persistence of neutralizing anti-capsid antibodies. Methods: Eight adult male participants with hemophilia B (FIX activity ≤2%) received BAX 335 in 1 of 3 intravenous dose cohorts (2.0 x 1011, 1.0 x 1012, or 3.0 x 1012 vector genomes/kg). The primary study objective was to assess the safety of BAX 335. Secondary assessments included the kinetics of plasma FIX activity, the need for exogenous FIX replacement, and systemic immune responses to BAX 335 and vector transgene protein. FIX clotting activity was measured using the one-stage clotting assay at the central laboratory. Serum neutralizing antibodies against the AAV8 and AAV2 capsids were measured to Year 5 following BAX 335 infusion using an in vitro transduction inhibition assay. Laboratory and in-person assessments were conducted for the first 5 years after BAX 335 infusion (one unscheduled visit was made at 7.2 Years). This was followed by annual liver ultrasound scans and telephone questionnaires assessing health status with the aim of completing 15 years of follow-up per participant. The study was approved by the institutional review boards of all participating sites, and all participants provided written informed consent. Results: Of 8 participants enrolled (aged 20-69 years), 2 discontinued from the study approximately 1 and 3 years after receiving BAX 335 infusion, and another participant withdrew consent 2 weeks prior to the data cutoff of May 6, 2022. Data from the 6 participants who had >5 years of long-term safety follow-up were included in this analysis. At data cutoff, 176 adverse events (AEs) were reported in all 8 dosed participants, most (72%) occurred in Years 1 and 2. In total, 6 serious adverse events (SAEs) were reported in 3 participants, of these 2 SAEs (post-procedural hemorrhage, arthritis) were reported after the interim analysis reported by Konkle et al. 2021. None were considered to be related to BAX 335 and all resolved. Although long-term hemostatic protection from bleeds was not observed in most of the participants in this analysis, 1 participant had continued FIX activity (Figure 1), with a most recent value of 0.078 IU/mL at 7.2 years after BAX 335 infusion. This participant has neither experienced any bleeds nor needed FIX replacement therapy after the second week of vector infusion. No FIX inhibitors have been observed. At Year 5, AAV neutralizing antibodies persisted at high titers in most participants (reciprocal of serum dilution: AAV2, <5 to 10,240; AAV8, 80 to 40,960). Conclusions: No additional BAX 335-related AEs, malignancy or thrombosis were reported in this long-term follow-up analysis of a phase 1/2 study. One participant achieved persistent FIX transgene activity in the circulation for 7.2 years and remains free from bleeding and the need for FIX replacement therapy. This is the longest duration of FIX R338L expression reported. Consistent with other studies, AAV neutralizing antibodies remained persistent at titers that would limit re-dosing with current AAV platforms. Future studies should explore patient-specific factors that may predict persistent transgene expression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Serum Levels of IL-6 Are Associated with Suicide Attempt but Not with High Lethality Suicide Attempts: A Preliminary Case-Control Study.

Suicide attempts are an emerging health problem around the world. Increased levels of IL-6 have been associated with suicidal behavior. Therefore, the aims of this study were to evaluate the serum levels of IL-6 in individuals with suicide attempts and a comparison group and to associate the IL-6 levels with the lethality of the suicide attempt. Additionally, we associated the rs2228145 polymorphism of the IL6R gene with suicide attempts or with the IL-6 serum levels. Suicide attempts and their lethality were evaluated using the Columbia Suicide Severity Rating Scale. The serum concentrations of IL-6 were measured by the ELISA technique in individuals with suicide attempts and then compared to a control group. The rs2228145 polymorphism of the IL6R gene was analyzed by real-time polymerase chain reaction. We found elevated serum levels of IL-6 in the suicide attempt group when compared to the control group (F = 10.37, p = 0.002). However, we found no differences of the IL-6 levels between high and low lethality. The IL6R gene polymorphism rs2479409 was not associated with suicide attempts. Our data suggest that IL-6 serum is increased in individuals with suicide attempts.

Serum levels and genetic variations of cytokines in two canine breeds (Ibizan hound and boxer) in the Mediterranean region, in terms of Leishmania infantum infection

Leishmaniosis, endemic to the Mediterranean area and considered to be the most important zoonosis in Europe, is caused by Leishmania infantum, an intracellular protozoan parasite transmitted by sandflies Phlebotomus. On the one hand, the Ibizan hound, a canine breed native of the Mediterranean region has been described to present a great resistance to the leishmaniosis parasitic infection. On the other hand, other breeds, including boxer, present high prevalence, and severity of the infection. In this study, serum levels of cytokines related to immune response together with the genetic variants found in genes encoding these cytokines have been interrogated in dogs of these two canine breeds (Ibizan hound and boxer) living in the Mediterranean region. A total of 59 apparently healthy dogs were sampled with their corresponding epidemiological data. Serum levels of cytokines were interrogated by ELISA commercial kits and the genetic analysis was carried out with the commercial CanineHD BeadChip and subsequent bioinformatic analysis. The results showed higher levels of IFN-γ, IL-2, and IL-18 and lower levels of IL-8 in Ibizan hound dogs compared to boxer ones. Genomic analysis revealed several genetic variants fixed in the Ibizan hound samples, including IFNG, IL2, IL6R, and IL12RB1 genes, which could explain these differences.

Galactomyces Ferment Filtrate Potentiates an Anti-Inflammaging System in Keratinocytes.

Skincare products play a crucial role in preventing the dry skin induced by various causes. Certain ingredients can help to improve the efficacy of skincare products. Galactomyces ferment filtrate (GFF) is such a functional ingredient. Its use originated from the empirical observation that the hands of sake brewers who deal with yeast fermentation retain a beautiful and youthful appearance. Consequently, skincare products based on GFF are widely used throughout the world. Recent studies have demonstrated that GFF activates an aryl hydrocarbon receptor (AHR) and upregulates the expression of filaggrin, a pivotal endogenous source of natural moisturizing factors, in epidermal keratinocytes. It also activates nuclear factor erythroid-2-related factor 2 (NRF2), the antioxidative master transcription factor, and exhibits potent antioxidative activity against oxidative stress induced by ultraviolet irradiation and proinflammatory cytokines, which also accelerate inflammaging. GFF-mediated NRF2 activation downregulates the expression of CDKN2A, which is known to be overexpressed in senescent keratinocytes. Moreover, GFF enhances epidermal terminal differentiation by upregulating the expression of caspase-14, claudin-1, and claudin-4. It also promotes the synthesis of the antiinflammatory cytokine IL-37 and downregulates the expression of proallergic cytokine IL-33 in keratinocytes. In addition, GFF downregulates the expression of the CXCL14 and IL6R genes, which are involved in inflammaging. These beneficial properties might underpin the potent barrier-protecting and anti-inflammaging effects of GFF-containing skin formulae.

IL-6 signaling in acute exercise and chronic training: Potential consequences for health and athletic performance.

The cytokine interleukin-6 (IL-6) is involved in a diverse set of physiological processes. Traditionally, IL-6 has been thought of in terms of its inflammatory actions during the acute phase response and in chronic conditions such as rheumatoid arthritis and obesity. However, IL-6 is also an important signaling molecule during exercise, being acutely released from working muscle fibers with increased exercise duration, intensity, and muscle glycogen depletion. In this context, IL-6 enables muscle-organ crosstalk, facilitating a coordinated response to help maintain muscle energy homeostasis, while also having anti-inflammatory actions. The range of actions of IL-6 can be explained by its dichotomous signaling pathways. Classical signaling involves IL-6 binding to a cell-surface receptor (mbIL-6R; present on only a small number of cell types) and is the predominant signaling mechanism during exercise. Trans-signaling involves IL-6 binding to a soluble version of its receptor (sIL-6R), with the resulting complex having a much greater half-life and the ability to signal in all cell types. Trans-signaling drives the inflammatory actions of IL-6 and is the predominant pathway in disease. A single nucleotide polymorphism (rs2228145) on the IL-6R gene can modify the classical/trans-signaling balance through increasing the levels of sIL-6R. This SNP has clinical significance, having been linked to inflammatory conditions such as rheumatoid arthritis and type 1 diabetes, as well as to the severity of symptoms experienced with COVID-19. This review will describe how acute exercise, chronic training and the rs2228145 SNP can modify the IL-6 signaling pathway and the consequent implications for health and athletic performance.

Correlation between childhood tuberculosis and abundance of T cell gene transcription and impaired T cell function

Purpose: To investigate the relationship amongst childhood tuberculosis, abundance of T cell gene transcription and impairment of T cell function.&#x0D; Methods: A total of 329 pediatric patients treated for tuberculosis in Central Hospital of Zibo, Zibo, China from 2017 to 2019 were enrolled in the study. Among them, 167 cases of tuberculosis-hospitalized children were assigned to the TB group. Additionally, 162 well- and adequately-treated patients with a previous history of tuberculosis were selected as the control group. The abundance of continuous gene transcripts in the peripheral blood of the children was analyzed. The RNA profiles were analyzed via microarray, while interferon (IFN) level was measured by enzyme linked immunosorbent assay (ELISA). The T cell proliferation was determined by thymidine assay.&#x0D; Results: Within 6 months of the commencement of treatment, the differentially expressed transcripts returned the expression in children in the control group. The abundance of Talipes equinovarus, atrial septal defect, robin sequence, and the persistence of the left superior vena cava (TARP) gene transcription in the TB group was lower than in the control group on days 30, 120 and 180 (p &lt; 0.05), while IL1R2 gene transcription abundance in the TB group was higher than in the control group on days 30, 120 ,180 (p &lt; 0.05). The proliferation of T cells and IFNγ in tuberculosis children (TB group) were lower than in healthy controls (p &lt; 0.05). In this study, a total of 129 genes were found to have significant differences in expression, and hence it is speculated that changes in RNA abundance altered the immune pathway.&#x0D; Conclusion: The reduced abundance of T cell gene transcription and renovated T cell function in children with tuberculosis are related to acquired immunodeficiency. The results of this study provide a theoretical basis for the clinical diagnosis and treatment of tuberculosis in children.

Role of IL6R Genetic Variants in Predicting Response to Tocilizumab in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this therapy. Identifying genetic biomarkers as predictors of TCZ response could be a key to providing a personalized medicine strategy. We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict TCZ response in patients with RA. We retrospectively included 88 RA patients treated with TCZ. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Responses to treatments were assessed at six months using three variables: a quantitative improvement in Disease activity score including 28 joints (DAS28), a satisfactory European League Against Rheumatism (EULAR) response, and low disease activity (LDA) achievement. The three response variables studied were associated with genetic variant rs4845625, and no association was found with the other five SNPs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for TCZ response.

P06.02.B Advanced CAR-T cell against orthotopic glioblastoma mouse model

Abstract Background The adoptive and engineered chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in treating hematologic cancers; however, this success has yet to be extrapolated to solid tumors such as glioblastoma multiforme (GBM). The purpose of this study was to evaluate the survival efficacy using advanced CAR-T cells in orthotopic GBM mouse model. Material and Methods Advanced CAR-T cell, which reprograms the patient’s T-cells with a transgene encoding part of interleukin-7 receptor-α (ΔIL7Rα) domain in addition to the CD3ζ signaling domain and 4-1BB costimulatory domain in the advanced CAR gene to exhibit excellent in vivo persistence and anti-tumor effect of advanced CAR-T cells. In addition to the advanced CAR gene, TGF-beta converter is introduced, which converts the inhibitory signal of TGF-beta, an immunosuppressive cytokine overexpressed in the hostile tumor microenvironment, into the activation signal of the cytokine IL-18 in advanced CAR-T cells.DAY9 NSG mice bearing orthotopically xenografted GBM cell lines (1 × 105 U251MG expressing IL13Rα2) were randomized to 8 experimental groups. Each experimental group was intravenously injected with only once with different subtype advanced CAR-T cells (Td ~ 47.3% of 5 × 106) and monitored for survival. Results Among treatment groups, mice treated with advanced CAR-T cells of TGF-β converter subtype demonstrated a statistically significant increase in survival (p=0.042, 95%CI, 0.375-0.981) compared with other subtypes. In DAY9 orthotopic GBM mouse model, we showed that a single I.V. injection of advanced CAR-T cells targeting IL13Rα2-specific tumor achieved survival benefit. Conclusion This study is the first report to show statistically significant survival benefit in DAY9 orthotopic GBM mouse model using a single I.V. injection of advanced CAR-T cells, yet merits further clinical trials in real world of clinical setting.

Mapping autophagosome contents identifies interleukin-7 receptor-α as a key cargo modulating CD4+ T cell proliferation

CD4+ T cells are pivotal cells playing roles in the orchestration of humoral and cytotoxic immune responses. It is known that CD4+ T cell proliferation relies on autophagy, but identification of the autophagosomal cargo involved is missing. Here we create a transgenic mouse model, to enable direct mapping of the proteinaceous content of autophagosomes in primary cells by LC3 proximity labelling. Interleukin-7 receptor-α, a cytokine receptor mostly found in naïve and memory T cells, is reproducibly detected in autophagosomes of activated CD4+ T cells. Consistently, CD4+ T cells lacking autophagy show increased interleukin-7 receptor-α surface expression, while no defect in internalisation is observed. Mechanistically, excessive surface interleukin-7 receptor-α sequestrates the common gamma chain, impairing the interleukin-2 receptor assembly and downstream signalling crucial for T cell proliferation. This study shows that key autophagy substrates can be reliably identified in this mouse model and help mechanistically unravel autophagy’s contribution to healthy physiology and disease.