Downregulation of type I interferon signalling pathway by urate in primary human PBMCs.

Type I interferons (IFN1s) mediate innate responses to microbial stimuli and regulate interleukin (IL)-1 and IL-1 receptor antagonist (Ra) production in human cells. This study explores interferon-stimulated gene (ISG) alterations in the transcriptome of patients with gout and stimulated human primary cells in vitro in relation to serum urate concentrations. Peripheral blood mononuclear cells (PBMCs) and monocytes of patients with gout were primed in vitro with soluble urate, followed by lipopolysaccharide (LPS) stimulation. Separately, PBMCs were stimulated with various toll-like receptor (TLR) ligands. RNA sequencing and IL-1Ra cytokine measurement were performed. STAT1 phosphorylation was assessed in urate-treated monocytes. Cytokine responses to IFN-ß were evaluated in PBMCs cultured with or without urate and restimulated with LPS and monosodium urate (MSU) crystals. Transcriptomics revealed suppressed IFN-related signalling pathways in urate-exposed PBMCs or monocytes which was supported by diminishment of phosphorylated STAT1. The stimulation of PBMCs with IFN-ß did not modify the urate-induced inflammation. Interestingly, in vivo, serum urate concentrations were inversely correlated to in vitro ISG expression upon stimulations with TLR ligands. These findings support a deficient IFN1 signalling in the presence of elevated serum urate concentrations, which could translate to increased susceptibility to infections.

Interleukin-1 Beta (IL1B) and Nerve Growth Factor (NGF): Key Players in Rabbit Reproductive Regulation.

Several seminal plasma components, besides NGF, are implicated as ovulation-inducing factors in mammals. This study investigated the IL1B and its receptor IL1R1 in the testis (T), male accessory glands, prostate (P) and seminal vesicles (SV), and uterus (U) of adult rabbits using immunohistochemistry (IHC) and quantitative reverse transcription PCR (RT-qPCR). We also assessed the presence of IL1B in seminal plasma through Western blotting (WB) and examined the interaction between IL1B and NGF in vitro by measuring their production with enzyme-linked immunosorbent assay (ELISA) in the presence of NGF and IL1B alone or with their respective receptor antagonists. IHC revealed IL1B system expression in all reproductive organs studied, with IL1B and IL1R1 localized to the germinative epithelium of the T and the epithelial cells of the accessory glands and U. IL1B gene transcript levels were significantly higher (p < 0.01) in the P and SV compared to the T, while IL1R1 levels were significantly higher (p < 0.001) in the P compared to the other tissues, while IL1R1 levels were three times higher (p < 0.001) in the P. WB confirmed the presence of IL1B in seminal plasma with a 30-35 kDa band. The in vitro study demonstrated that IL1B increased (p < 0.05) basal NGF production in the U, whereas NGF had no effect on IL1B production. These findings provide evidence of the expression of the IL1B/IL1R1 system in both male and female rabbit reproductive tracts and suggest that IL1B in seminal plasma may influence uterine endocrine activity. The results propose a potential role for IL1B in ovulation, in conjunction with NGF, supporting that ovulation may involve inflammatory-like processes.

Microglia regulate cortical remyelination via TNFR1-dependent phenotypic polarization.

Microglia are strongly implicated in demyelinating neurodegenerative diseases with increasing evidence for roles in protection and healing, but the mechanisms that control CNS remyelination are poorly understood. Here, we show that microglia-specific deletion of tumor necrosis factor receptor 1 (TNFR1) and pharmacological inhibition of soluble TNF (solTNF) or downstream interleukin-1 receptor (IL-1R) allow maturation of highly activated disease-associated microglia with increased size and myelin phagocytosis capacity that accelerate cortical remyelination and motor recovery. Single-cell transcriptomic analysis of cortex at disease onset reveals that solTNF inhibition enhances reparative IL-10-responsive while preventing damaging IL-1-related signatures of disease-associated microglia. Longitudinal brain transcriptome analysis through disease reveals earlier recovery upon therapeutic loss of microglia TNFR1. The functional relevance of microglia inflammatory polarization pathways for disease is validated in vivo. Furthermore, disease-state microglia producing downstream IL-1/IL-18/caspase-11 targets are identified in human demyelinating lesions. Overall, redirecting disease microglia polarization by targeting cytokines is a potential approach for improving CNS repair in demyelinating disorders.

Investigating the influence of inflammasome complex genes on Turner syndrome.

Turner syndrome (TS) is associated with an increased susceptibility to inflammatory and autoimmune diseases. This study investigates the association between genetic polymorphisms in the IL1B and NLRP3 genes, as well as the expression profiles of IL1B, NLRP3, and NLRP1, and the risk of inflammatory and autoimmune conditions in TS patients compared to healthy controls. The genetic association analysis included 92 TS patients (case) and 146 healthy controls (HC), evaluating IL1B rs16944, NLRP3 rs10754558 and rs4925659 using TaqMan genotyping assays. In addition, mRNA expression levels of IL1B, NLRP3, and NLRP1 were also compared in 17 TS patients and 17 healthy females (control group) using qPCR-based fluorogenic probes. The study found significant associations with the G allele of rs16944 (p = 0.001) and the GG genotype (p = 0.002) in TS patients, though these were not associated with inflammatory disorders in this group., On the other hand, rs4925659 exhibited a significantly higher frequency of the A allele (p = 0.02) and AA genotype (p = 0.0001) in HC, while the A allele and GA genotype were more common in the TS group (p = 0.0001). Expression analysis revealed a downregulation of IL1B and NLRP3 (fold change: FC = -6.78 and -15.73, respectively) and an upregulation of NLRP1 (FC = 21.5) in TS patients compared to HC. These results indicate a differential distribution of IL1B and NLRP3 polymorphisms in TS patients, and suggest that alterations in the expression of IL1B, NLRP3, and NLRP1 may contribute to an inflammatory imbalance in the Turner syndrome.

IL-1 receptor-associated kinase 3 (IRAK3) in lung adenocarcinoma predicts prognosis and immunotherapy resistance: involvement of multiple inflammation-related pathways.

Background: Lung cancer is a globally prevailing malignancy, and the predominant histological subtype is lung adenocarcinoma (LUAD). IL-1 receptor-associated kinase 3 (IRAK3) has been identified in connection with innate immune and inflammatory response. The aim of this study is to investigate the impact of IRAK3 on prognosis and immunotherapy efficacy in LUAD, which remains incompletely elucidated. Methods: Our study delved into multiple online databases to find out expression, methylation and prognostic potentials of IRAK3 in LUAD and other malignancies. We employed tissue microarrays to assess IRAK3 protein levels in our LUAD cohort [National Cancer Center (NCC), China] and explore prognostic values. The correlations between IRAK3 and immune infiltration based on The Cancer Genome Atlas (TCGA) data were analyzed by corresponding algorithms. The contribution of IRAK3 to immunotherapy response was explored through the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Both LinkedOmics database and gene set enrichment analysis (GSEA) were applied to investigate how IRAK3 influences the tumor immune microenvironment and regulates immunotherapy response. We applied single-cell RNA sequencing datasets for the investigation of IRAK3 expression across diverse immune cells. Moreover, we employed genomics of drug sensitivity in cancer (GDSC) databases to examine how IRKA3 expression correlates with different drug responses. Results: Compared with normal tissues, various tumor tissues had lower IRAK3 expression which could be regulated by its high methylation level. Reduced IRAK3 protein level was observed to correlate with advanced tumor stages and unfavorable prognosis among patients with LUAD, especially individuals with lymph node metastasis. Gene set enrichment analysis (GSEA) and tumor infiltration analysis proved that IRAK3 provoked immune infiltration. Macrophages/monocytes, CD4+ T cells, CD8+ T cells and neutrophils correlated significantly with IRAK3 expression. With TIDE algorithm, IRAK3 was verified to be related to poor immune checkpoint blockade (ICB) response. IRAK3 demonstrated positive associations with T-cell dysfunction score and immune checkpoint markers. Conversely, it exhibited negative correlations with microsatellite instability (MSI) and tumor mutation burden (TMB). High IRAK3 expression exacerbated cytotoxic T lymphocyte (CTL) dysfunction and predicted immunotherapy resistance by involvement of multiple inflammation-related pathways including IL-6/JAK/STAT3 signaling, inflammatory response and interferon-gamma (IFN-γ) response pathways. Additionally, elevated IRAK3 expression was predicted to be related with better responses to chemotherapeutic and molecular targeted drugs. Conclusions: Our findings indicated that IRAK3 could function as an independent prognostic predictor and an immunotherapeutic indicator in LUAD through involvement of multiple inflammation-related pathways.

Histological Improvement and Cytokine Levels Reduction in Patients with Oral Lichen Planus after Photobiomodulation Therapy.

Background: Oral lichen planus (OLP) is a mucocutaneous disease associated with the formation of symptomatic lesions in the mouth that are often refractory to treatment. An as-yet-unknown antigen triggers an inflammatory reaction in which various immune and non-immune cells release multiple cytokines that contribute to disease progression. The ability of photobiomodulation (PBM) to reduce the symptoms and signs of the disease has been shown, but little is known about its molecular and cellular effects. The aim of this study was to evaluate changes in pro-inflammatory cytokine levels and in histological findings in OLP patients treated with photobiomodulation therapy. Methods: Twenty OLP patients underwent PBM with diode laser (810 nm), (0.50 W, 30 s, 1.2 J/cm2), 3 times weekly for a month. Pain level and clinical scores of lesions were recorded before and after therapy. Salivary levels of IL-1ß, IL-6, and TNF-α in OLP patients were measured before and after PBM and compared with those of 10 healthy controls. Biopsies were taken at the beginning and end of treatment to assess pathomorphological changes. Results: PBM significantly reduced the level of pain and clinical scores of the lesions. Salivary levels of IL-1ß, IL-6, and TNF-α in OLP patients were significantly higher compared to those in healthy controls and decreased after therapy. 60% of the post-treatment OLP biopsies demonstrated histological improvement, characterized by inflammatory infiltrate reduction (50%), epithelial hyperplasia reduction (30%), epithelial thickening (15%), or epidermal-dermal attachment repair (5%). Conclusion: The effectiveness of PBM therapy in OLP patients was confirmed at the clinical, molecular, and histomorphological levels.

Anakinra-Dependent Recurrent Pericarditis: The Role of the R202Q Variant of the MEFV Gene.

Background: the role of the R202Q (c.605G>A, p.Arg202Gln) missense variant of the MEFV gene has been debated as either a benign polymorphism or a potentially pathogenic mutation. We report and discuss here the case of a young female with corticosteroid-dependent recurrent pericarditis carrying the homozygous R202Q variant, exhibiting distinctive clinical features possibly influenced by this genetic variant. Methods: a 30-year-old woman with a previous diagnosis of cancer and recent respiratory infection presented with severe pleuritic chest pain, hypotension, tachycardia, and fever. Initial diagnostic evaluation indicated cardiac tamponade, and emergent pericardiocentesis was performed. Despite initial treatment with NSAIDs, colchicine, and corticosteroids, the patient experienced multiple recurrences. Genetic testing identified homozygous R202Q variant in the MEFV gene. Given the corticosteroid dependency and recurrent nature of her condition, IL-1 inhibitor anakinra was introduced, leading to significant improvement, although tapering below 150 mg per week failed to prevent recurrences. Results: the introduction of anakinra resulted in rapid symptom relief and resolution of pericardial effusion. However, attempts to taper or discontinue anakinra led to pericarditis recurrences. Ultimately, a maintenance dose of 50 mg every three days was established, which maintained remission for 18 months without recurrence. Despite multiple tapering attempts, further reduction in anakinra dosage was unsuccessful without triggering relapses. Conclusions: the R202Q variant, although typically considered benign, may contribute to an autoinflammatory phenotype resembling familial Mediterranean fever. This case underscores the potential pathogenicity of the homozygous R202Q variant in recurrent pericarditis and its responsiveness to IL-1 inhibition. In patients with corticosteroid-dependent recurrent pericarditis, genetic testing for the R202Q variant should be considered when anti-IL-1 drugs cannot be withdrawn. Further studies are warranted to elucidate the variant's role in pericardial inflammation and guide personalized treatment strategies.

Interleukin-1 Receptor-Associated Kinase 1 in Cancer Metastasis and Therapeutic Resistance: Mechanistic Insights and Translational Advances.

Interleukin-1 Receptor Associated Kinase 1 (IRAK1) is a serine/threonine kinase that plays a critical role as a signaling transducer of the activated Toll-like receptor (TLR)/Interleukin-1 receptor (IL-1R) signaling pathway in both immune cells and cancer cells. Upon hyperphosphorylation by IRAK4, IRAK1 forms a complex with TRAF6, which results in the eventual activation of the NF-κB and MAPK pathways. IRAK1 can translocate to the nucleus where it phosphorylates STAT3 transcription factor, leading to enhanced IL-10 gene expression. In immune cells, activated IRAK1 coordinates innate immunity against pathogens and mediates inflammatory responses. In cancer cells, IRAK1 is frequently activated, and the activation is linked to the progression and therapeutic resistance of various types of cancers. Consequently, IRAK1 is considered a promising cancer drug target and IRAK1 inhibitors have been developed and evaluated preclinically and clinically. This is a comprehensive review that summarizes the roles of IRAK1 in regulating metastasis-related signaling pathways of importance to cancer cell proliferation, cancer stem cells, and dissemination. This review also covers the significance of IRAK1 in mediating cancer resistance to therapy and the underlying molecular mechanisms, including the evasion of apoptosis and maintenance of an inflammatory tumor microenvironment. Finally, we provide timely updates on the development of IRAK1-targeted therapy for human cancers.

Strobilanthes sarcorrhiza root phenolic extract prevent diabetic nephropathy in mice by regulating NF-κB/IL-1ß signaling and glycerophospholipid metabolism.

Strobilanthes sarcorrhiza, a folk medicine from China, is known to treat kidney deficiency and lumbago. However, its protective effects and mechanisms against diabetic nephropathy (DN) remain unclear. This study aimed to investigate the effects and mechanisms of Strobilanthes sarcorrhiza root phenolic extract (CTS) on streptozotocin (STZ)-induced DN in mice. Firstly, the constituents in CTS were characterized by UPLC-QTOF-MS. Thirty-three constituents were identified, including 12 phenylethanoid glycosides and their derivatives, 14 phenylpropanoid glycosides derivatives, 6 polyphenols derivatives, and 1 other constituent. Then, utilizing the identified constituents of CTS, network pharmacology was used to anticipate potential pathways against DN. Thirty-two out of thirty-three constituents showed anti-DN activity; their mechanism of action was significantly linked to tumor-, glycosylation-, metabolism-related pathways, etc. Furthermore, the effectiveness of CTS against DN and its in vivo mechanism was assessed by combining immunohistochemistry, untargeted metabolomics, biochemical evaluation, and histopathological examination. The findings showed that CTS improved blood glucose and lipid levels in diabetic mice, reduced serum levels of ALT, CREA, UREA, IL-1ß, and IL-17, decreased pathological damage and fibrosis in kidney tissue, and lowered the protein expression of VEGF, Laminin, TNF-α, and NF-κB in kidney tissue. Metabolomics results indicated that CTS alleviated DN mainly by regulating glycerophospholipid metabolism. To the best of our knowledge, this study is the first to report that Strobilanthes sarcorrhiza attenuates DN, potentially through the inhibition of the NF-κB pathway, leading to a reduction in the inflammatory response and fibrosis of renal tissue. These findings suggest that Strobilanthes sarcorrhiza could be a promising therapeutic agent for DN.

Redundancy in Innate Immune Pathways That Promote CD8+ T-Cell Responses in AAV1 Muscle Gene Transfer.

While adeno-associated viral (AAV) vectors are successfully used in a variety of in vivo gene therapy applications, they continue to be hampered by the immune system. Here, we sought to identify innate and cytokine signaling pathways that promote CD8+ T-cell responses against the transgene product upon AAV1 vector administration to murine skeletal muscle. Eliminating just one of several pathways (including DNA sensing via TLR9, IL-1 receptor signaling, and possibly endosomal sensing of double-stranded RNA) substantially reduced the CD8+ T-cell response at lower vector doses but was surprisingly ineffective at higher doses. Using genetic, antibody-mediated, and vector engineering approaches, we show that blockade of at least two innate pathways is required to achieve an effect at higher vector doses. Concurrent blockade of IL-1R1 > MyD88 and TLR9 > MyD88 > type I IFN > IFNaR pathways was often but not always synergistic and had limited utility in preventing antibody formation against the transgene product. Further, even low-frequency CD8+ T-cell responses could eliminate transgene expression, even in MyD88- or IL-1R1-deficient animals that received a low vector dose. However, we provide evidence that CpG depletion of vector genomes and including TLR9 inhibitory sequences can synergize. When this construct was combined with the use of a muscle-specific promoter, transgene expression in muscle was sustained with minimal local or systemic CD8+ T-cell response. Thus, innate immune avoidance/blockade strategies by themselves, albeit helpful, may not be sufficient to prevent destructive cellular responses in muscle gene transfer because of the redundancy of immune-activating pathways.

Analysis of the role of IL-1 family and related genes in head and neck squamous cell carcinoma.

OBJECTIVE: The Interleukin-1 (IL-1) family plays an important regulatory role in the development of tumors, but its function is still unclear in head and neck squamous cell carcinoma (HNSCC). Analyzing the IL-1 family can help to understand the tumor mechanism. METHODS: Using GEPIA2, UALCAN, cBioprotocol and HPA databases, the IL-1 family and related genes (IL-1α, IL-1ß, IL1RN, IL1R1, IL1R2, IL1RL1, IL1RL2, IL1RAP, IL1RAPL1, IL1RAPL2, IL1F10, IL18, IL18BP, IL18R1, IL18RAP, IL36A, IL36B, IL36G, IL36RN, IL33, IL37, SIGIRR, CASP1, AIM2) were analyzed for their expression and prognostic relevance in HNSCC. The Kaplan-Meier, log-rank test and Spearman correlation were used to analysis. RESULTS: In tumors, IL-1α, IL-1ß, IL1R1, IL1RL1, IL1F10, IL33, CASP1, and AIM2 are highly expressed, while IL1RN, IL1RAPL1, IL1RAPL2, IL18BP, IL18R1 and IL18RAP are poorly expressed. IL-1α, IL1RAP, and IL1RAPL2 were prognostic risk factors in at least two databases, while IL18RAP, IL36A, and SIGIRR were prognostic protective factors. SIGIRR was confirmed in all three databases. Compared to HPV- tumors, IL18RAP and SIGIRR are highly expressed in HPV+ tumors. In addition, IL-1α, IL-1ß, IL1RL2, IL1RAP were negatively correlated with CD8A/B expression, while IL1R2, IL18R1, IL18RAP, IL33, SIGIRR, CASP1, AIM2 were positively correlated with CD8A/B expression. CONCLUSION: The differential expression of the IL-1 family and related genes affects the microenvironment changes and survival prognosis of HNSCC patients. Among them, IL-1α, IL1RAP, IL18RAP, and SIGIRR may affect the prognosis of patients by affecting local CD8+ T cell infiltration in the tumor.

Impacts of linseed oil diet on anxiety and memory extinction after early life stress: A sex-specific analysis of mitochondrial dysfunction, astrocytic markers, and inflammation in the amygdala.

Early exposure to stressors affects how the organism reacts to stimuli, its emotional state throughout life, and how it deals with emotional memories. Consequently, it may affect susceptibility to psychopathology later in life. We used an animal model of early stress by maternal separation to study its potential impact on the extinction of aversive memories and anxiety-like behavior in adulthood, as well as its effects on mitochondrial functionality, inflammatory and astrocytic markers in the amygdala. We also assessed whether a diet enriched with linseed oil, known for its high content in omega-3 fats, could be used to attenuate the behavioral and neurochemical effects of early stress. Litters of Wistar rats were divided into controls (intact) or subjected to maternal separation (MS). They were subdivided into two groups receiving isocaloric diets enriched in soy or linseed oils at weaning. In adulthood, the animals were exposed to the open field and the elevated plus maze, to evaluate exploratory activity and anxiety-like behavior. They were also trained in a context of fear conditioning, and afterward subjected to an extinction session, followed by a test session to evaluate the extinction memory. Amygdalae were evaluated for inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumor-necrose factor (TNF)-alpha), mitochondrial functionality, and astrocyte markers (glial fibrillary acidic protein - GFAP, S100B, and glutamine synthetase activity). MS induced anxiety-like behavior in the elevated plus-maze, which was reversed by a diet enriched in linseed oil offered from weaning. When testing the memory of an extinction session of fear conditioning, MS animals showed more freezing behavior. MS males receiving a linseed oil-enriched diet had lower functional mitochondria in the amygdala. In addition, MS led to increased inflammatory cytokines, particularly IL-1beta, and the diet enriched in linseed oil further increased these levels in MS animals. MS also increased S100B levels. These results point to a higher emotionality presented by MS animals, with higher levels of inflammatory cytokines and S100B. While a diet enriched in linseed oil attenuated anxiety-like behavior, it further altered amygdala IL-1beta and reduced mitochondria functionality, particularly in males. MS also increased glutamine synthetase activity in the amygdala, and this effect was higher when the animals received a diet enriched in linseed oil, particularly in females. In conclusion, these results point to MS effects on emotional behavior, and neurochemical alterations in the amygdala, with sex-specific effects. Although a diet enriched in linseed oil appears to be able to reverse some of MS behavioral effects, these results must be considered with caution, since biochemical parameters could be worsened in MS animals receiving a linseed oil-enriched diet. This knowledge is important for the understanding of mechanisms of action of strategies aiming to reverse early stress effects, and future studies are warranted to determine possible interventions to promote resilience.

Transcriptome Analysis of Porphyromonas gingivalis Lipopolysaccharide-Induced Early Gene Expression in Human Gingival Keratinocytes.

AIM: Porphyromonas gingivalis lipopolysaccharide (PgLPS) is a significant virulence factor and a driver of early innate immune responses in epithelial cells. The presence of PgLPS in immediate proximity to gingival epithelium induces significant inflammatory responses. In primary human gingival keratinocytes (HGK), we utilized transcriptome analysis to elucidate the change in early gene expression induced by PgLPS. METHODS: HGK cell cultures were treated with PgLPS (4 h), and RNA was extracted and prepared for RNA sequence (RNAseq) analysis. Differentially expressed genes (DEGs) were identified, and potential interactions between these genes were subsequently examined using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analytic approaches to identify significantly enriched pathways. Expression of genes associated with relevant pathways was evaluated using real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR). RESULTS: RNAseq analysis identified 25 DEGs, and GO and KEGG analytic approaches showed related genes expressed in two general pathways. First, pathways broadly related to urokinase and coagulation included the genes PLAU, PLAUR, and SerpinB2. In RT-qPCR analysis, these genes were induced by PgLPS over time (4-24 h), and these data were consistent with PgLPS induction of cell migration. Second, interleukin-1 (IL-1) receptor binding and cytokine-activity pathways were also enriched. Genes associated with these pathways included IL36G, IL1B, IL1RN, and CXCL14. RT-qPCR analysis confirmed PgLPS induction of genes associated with the IL-1family. When expression of IL1B and IL36G genes was examined in relation to their respective antagonists, only IL36G gene expression was increased. CXCL14 gene expression was reduced over time, and this was consistent with RNAseq analysis. CONCLUSIONS: Genes associated with significantly enriched GO and KEGG pathways are relevant to aspects of periodontal disease (PDD) pathogenesis. First, PgLPS induced expression of PLAU, PLAUR, and SerpinB2, and these changes were consistent with an increase in cell migration that was found. Second, both IL36G and IL1B gene expression was significantly induced, but only IL36G in relation to its selective antagonist (IL36RN) was increased. These data support that early upregulation of IL36G may serve as an alarmin that can drive early innate immune inflammatory responses in HGK. Further in vivo testing of these findings is ongoing.

Fluctuation trend of inflammatory indexes related to gestational diabetes mellitus from second trimester to third trimester of pregnancy.

OBJECTIVE: This study aims to assess the prognostic and diagnostic value of inflammatory indexes related to gestational diabetes mellitus (GDM) from the second trimester to the third trimester of pregnancy. MATERIALS AND METHODS: In this study, we randomly selected 65 pregnant women diagnosed with GDM at our hospital from December 2022 to June 2023 to form the GDM group (n = 65). Additionally, 65 pregnant women at the same gestational weeks without GDM were selected as the Normal group (n = 65). We collected gestational information and serum samples at 24 and 36 weeks of gestation from the participants. The levels of NLRP3, IL-1Ra, and TBP-2 were determined using enzyme-linked immunosorbent assay (ELISA) to explore their changes during pregnancy. Further, this study analyzed the changes in the levels of NLRP3, IL-1Ra, and TBP-2 at 24 and 36 weeks of gestation in GDM patients and their correlation with gestational diabetes mellitus. RESULTS: The study showed that pre-pregnancy body mass index (BMI), neonatal weight, gestational hypertension, and macrosomia are significantly associated with the occurrence of GDM (P < 0.05). Statistical analysis comparing the normal and GDM groups found no significant changes in the levels of NLRP3, IL-1Ra, and TBP-2 with the progression of gestation in the normal group. In contrast, in the GDM group, the levels of IL-1Ra in serum samples at 24 and 36 weeks were significantly increased (P < 0.05) while the levels of NLRP3 and TBP-2 were significantly reduced (P < 0.05). At 36 weeks, there was a positive correlation between the levels of NLRP3, IL-1Ra, and TBP-2. Compared to the normal group, the overall levels of NLRP3, IL-1Ra, and TBP-2 in the GDM group were lower (P < 0.05) and the weight of the newborns was significantly correlated with these three indicators (P < 0.05), specifically newborn weight increased with the levels of NLRP3 and TBP-2 but decreased with the increase of IL-1Ra (P < 0.05). Multifactorial logistic regression analysis further revealed that NLRP3 is an independent factor influencing GDM (P < 0.05). ROC curve analysis of the NLRP3 level at 24 weeks of gestation found that NLRP3 has a good value in predicting GDM (AUC = 0.720, 95%CI 0.630-0.809, P < 0.001) and the combined prediction of NLRP3, IL-1Ra, and TBP-2 also showed a good predictive value for GDM. CONCLUSION: The changes in NLRP3, IL-1Ra, and TBP-2 persisted throughout the 24 to 36 weeks of gestation, playing an important role in predicting the occurrence of GDM and the weight of the newborn.

Pilot Study of IL-1 Antagonist Anakinra for Treatment of Endometriosis.

Purpose: To evaluate the impact of an interleukin-1 (IL-1) antagonist anakinra (Kineret®) on endometriosis-related quality of life (QoL), pain, and inflammatory biomarkers. Methods: This was a single-site, randomized, double-blinded, placebo-controlled, cross-over pilot clinical study of patients recruited at an academic specialty clinic. Eligible participants were females aged 18-45 years with menstrual cycles every 24-32 days. Subjects had moderate to severe dysmenorrhea and either a surgical diagnosis of endometriosis or an endometrioma on imaging. Subjects were randomly assigned in a double-blind fashion to receive either the study drug or placebo administered as daily injections during the first 3 periods and then the alternate intervention for the next 3 periods. Results: Fifteen subjects completed the 6 menstrual cycle study. After each period, they completed the Endometriosis Health Profile-30 (EHP-30) QoL questionnaire and an assessment of dysmenorrhea using a 0-100 Visual Analogue Scale (VAS). All domains of the EHP-30 showed a trend towards improvement, with significant improvements in powerlessness (54.5 vs 63.3, p = 0.04) and self-image (58.1 vs 66.7, p = 0.03) on the study drug compared to placebo. The mean dysmenorrhea VAS also trended toward improvement with a score of 37.5 during active treatment and 42.6 with placebo (p = 0.26). No difference in menstrual cycle length was detected (29.3 days vs 27.7 days, p = 0.56). There were significant differences in multiple inflammatory biomarkers between the study drug and placebo, including BDNF, IL-1, and IL-6 among certain groups. Conclusion: With all EHP-30 domains and the dysmenorrhea VAS showing either a statistical improvement or trend towards improvement, there is justification for a larger study. As no impact on menstrual cycles was detected, anakinra may be a particularly impactful option for women desiring fertility. Additional evaluation is needed on the role of anakinra on inflammatory markers given significant reductions were identified in multiple biomarkers.

Endometriosis is a common gynecologic disease afflicting millions of patients. Anakinra is an IL-1 antagonist currently used for treatment of rheumatoid arthritis which has been found to improve quality of life measures for patients with endometriosis. Anakinra also reduces levels of biomarkers known to be associated with endometriosis-related inflammation. More study is needed on the role of anakinra in improving endometriosis symptoms.

Long-Standing Chronic Recurrent Pericarditis Managed With Advanced Diagnostic and Therapeutic Methods.

A 65-year-old woman with a history of idiopathic pericarditis presented with chronic recurrent pericarditis. Because of the inability to taper off anakinra without recurrent flares, she transitioned to rilonacept, which led to symptom abatement. Her positive response to rilonacept therapy correlated with an improvement in inflammatory changes noted on cardiac magnetic resonance imaging.

Case Series Analysis of Late-Onset Atopic Dermatitis: Unraveling Clinical Variants.

Atopic Dermatitis (AD), recognized as one of the most prevalent chronic inflammatory skin disorders among children, is characterized by skin barrier dysfunction and immune system abnormalities. Historically viewed as a childhood condition, recent findings underscore a notable prevalence of AD in adults, prompting a critical examination of this demographic. Diagnosis hinges largely on subjective clinical assessments due to the absence of universally accepted biomarkers. Consequently, efforts are underway to identify dependable biomarkers to enhance diagnostic precision. This paper underscores the scarcity of AD diagnoses in adults despite its pediatric prominence, emphasizing the need for heightened awareness and tailored diagnostic approaches in adult populations. Severity scores such as SCORing Atopic Dermatitis (SCORAD) and dermatological life quality index (DLQI) play pivotal roles in evaluating disease severity and its impact on quality of life, guiding the development of personalized treatment strategies for adult AD patients. In this study, we aim to present four compelling cases of adult-onset atopic dermatitis, each offering unique insights into this increasingly recognized phenomenon. What makes these cases particularly noteworthy is the absence of any prior atopic history in two out of four patients, challenging the conventional understanding of AD as a condition predominantly linked to childhood. Moreover, the clinical presentation in all four cases was markedly atypical, underscoring the elusive nature of adult-onset AD diagnosis. In our investigation, interleukin 4 (IL-4), interleukin 13 (IL-13), and Immunoglobulin E (IgE) were utilized as diagnostic biomarkers for our patient cohort. Given the established pivotal roles of IL-4 and IL-13 in AD pathogenesis, elevated serum levels of these biomarkers, although not universally endorsed, hold potential for diagnostic utility. Furthermore, heightened levels of IgE, indicative of allergic responses and inflammation inherent to the condition, emphasize its significance as a key biomarker and therapeutic target in AD management.

Interleukin-1ß modulates lymphoid differentiation of Flt3-positive multipotent progenitors after transplantation.

Myeloablative pre-conditioning facilitates the differentiation of transplanted hematopoietic stem and progenitor cells (HSPCs). However, the factors in the stress environment that regulate HSPC behavior remain elusive. Here, we investigated the mechanisms that shaped the cell fates of transplanted murine multipotent progenitors (MPPs) expressing the Fms-related receptor tyrosine kinase 3 gene (Flt3). Using lineage tracing, clonal analysis, and single-cell RNA sequencing (RNA-seq), we showed that the myeloablative environment increased lymphoid priming of Flt3+ MPPs and that their efficient B cell output required intact interleukin 1 (IL-1) signaling. The Flt3+ MPPs with short-term exposure to IL-1ß underwent a myeloid-biased to lymphoid-biased cell fate switch and produced more lymphoid-biased progeny with a stronger B lymphopoiesis capacity in vitro. Correspondingly, a brief exposure to IL-1ß facilitated the B cell output of transplanted Flt3+ MPPs in vivo. Together, our study demonstrated an unrecognized function of IL-1ß in promoting B lymphopoiesis and highlighted a latent effect of IL-1ß in regulating MPP cell fate dynamics.

Assessing the causal relationship between CRP, IL-1α, IL-1ß, and IL-6 levels and intervertebral disc degeneration: a two-sample Mendelian randomization study.

Growing research has suggested an association between chronic inflammation and Intervertebral disc degeneration (IVDD), but whether there is a causal effect remains unknown. This study adopted two-sample Mendelian randomization (MR) approach to explore the etiological role of chronic inflammation in IVDD risk. Here, summary statistics for C-reactive protein (CRP), interleukin (IL)-1 α , IL-1 ß , IL-6 expression and IVDD were obtained from genome-wide association studies (GWAS) of European ancestry. MR analyses were conducted by using inverse variance weighted (IVW), Wald Ratio, weighted median, and MR-Egger method. Sensitivity analyses were conducted to assess the robustness of the results. The MR analyses suggested a lack of causal association of CRP, IL-6 , and IL-1 α levels on IVDD (CRP-IVDD: odds ratio [OR] = 0.97, 95% confidence interval [CI] 0.86-1.09, P = 0.583; IL-6-IVDD: OR = 1.04, 95% CI 0.86-1.27, P = 0.679; IL-1 α -IVDD: OR = 1.09, 95%CI 1.00-1.18, P = 0.058). However, there was a sign of a connection between genetically elevated IL-1 ß levels and a decreased IVDD incidence (OR = 0.87, 95%CI 0.77-0.99, P = 0.03). Our findings suggest a connection between IL-1 ß levels and the risk of IVDD. However, due to the support of only one SNP, heterogeneity and pleiotropy tests cannot be performed, the specific underlying mechanisms warrant further investigation.

Decoding paradoxical links of cytokine markers in cognition: Cross talk between physiology, inflammaging, and Alzheimer's disease- related cognitive decline.

Recent research has revolutionized our understanding of memory consolidation by emphasizing the critical role of astrocytes, microglia, and immune cells in through cytokine signaling. Cytokines, compact proteins, play pivotal roles in neuronal development, synaptic transmission, and normal aging. This review explores the cellular mechanisms contributing to cognitive decline in inflammaging and Alzheimer's disease, highlighting the paradoxical effects of most studied cytokines (IL-1, IL-6, TNF-α) in brain function, which act as a double-edged sword in brain physiology, acting both as facilitators of healthy cognitive function and as a potential contributor to cognitive decline.