Fever in childbirth: a mini-review of epidural-related maternal fever.

Fever during childbirth, which is often observed in clinical settings, is characterized by a temperature of 38°C or higher, and can occur due to infectious and non-infectious causes. A significant proportion of non-infectious causes are associated with epidural-related maternal fever during vaginal delivery. Therapeutic interventions are required because fever has adverse effects on both mother and newborn. Effective treatment options for ERMF are lacking. As it is difficult to distinguish it from intrauterine infections such as chorioamnionitis, antibiotic administration remains the only viable option. We mentioned the importance of interleukin-1 receptor antagonist in the sterile inflammatory fever pathway and the hormonal influence on temperature regulation during childbirth, an important factor in elucidating the pathophysiology of ERMF. This review spotlighted the etiology and management of ERMF, underscoring recent advancements in our understanding of hypothalamic involvement in thermoregulation and its link to sterile inflammation. We propose to deepen the understanding of ERMF within the broader context of autonomic neuroscience, aiming to foster the development of targeted therapies.

Analysis of the Association of IL-1A, IL-1B and IL-1RN Polymorphisms with Peri-implantitis in a Portuguese Population.

PURPOSE: The aim of this study was to investigate whether genetic variations in cytokine genes involved in the pathogenesis of peri-implantitis, could be associated with its occurrence, an issue that remains controversial and may vary according to the population evaluated. MATERIAL AND METHODS: A cross-sectional analytical study was carried out on 102 Portuguese Caucasian individuals divided into two groups: 43 individuals with peri-implantitis and 59 individuals with peri-implant health. Samples from the buccal mucosa were obtained and genetic analysis was performed using the real-time polymerase chain reaction (PCR) technique for IL-1A and IL-1B and using PCR and restriction fragment length polymorphism analysis for IL-1RN. RESULTS: The IL-1A -889 C/T polymorphism showed a higher prevalence of the less common allele (T allele) in cases of peri-implantitis than in healthy cases (27.9% vs 16.9%, respectively), but without statistical significance (p = 0.060). For the IL-1B +3954 C/T and IL-1RN (variable number of tandem repeats) polymorphisms, the analysis revealed that the allele and genotype frequencies did not differ significantly between groups. There was a significant association between a history of periodontitis and peri-implantitis (p = 0.020). CONCLUSIONS: The genetic polymorphisms evaluated had no influence on the occurrence of periimplantitis in the population studied. Further research into genetic variations in different populations is needed to elucidate the role of genetic factors in the onset and progression of periimplant disease.

Low expression of interleukin-1 receptor antagonist correlates with poor prognosis via promoting proliferation and migration and inhibiting apoptosis in oral squamous cell carcinoma.

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

Case report: Novel compound heterozygous IL1RN mutations as the likely cause of a lethal form of deficiency of interleukin-1 receptor antagonist.

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

Potency assay to predict the anti-inflammatory capacity of a cell therapy product for macrophage-driven diseases: overcoming the challenges of assay development and validation.

BACKGROUND: Given the high level of product complexity and limited regulatory guidance, designing and implementing appropriate potency assays is often the most challenging part of establishing a quality control testing matrix for a cell-based medicinal product. Among the most elusive tasks are the selection of suitable read-out parameters, the development of assay designs that most closely model the pathophysiological conditions, and the validation of the methods. Here we describe these challenges and how they were addressed in developing an assay that measures the anti-inflammatory potency of mesenchymal stromal cells (MSCs) in an M1 macrophage-dominated inflammatory environment. METHODS: An in vitro inflammation model was established by coculturing skin-derived ABCB5+ MSCs with THP-1 monocyte-derived M1-polarized macrophages. Readout was the amount of interleukin 1 receptor antagonist (IL-1RA) secreted by the MSCs in the coculture, measured by an enzyme-linked immunosorbent assay. RESULTS: IL-1RA was quantified with guideline-concordant selectivity, accuracy and precision over a relevant concentration range. Consistent induction of the macrophage markers CD36 and CD80 indicated successful macrophage differentiation and M1 polarization of THP-1 cells, which was functionally confirmed by release of proinflammatory tumor necrosis factor α. Testing a wide range of MSC/macrophage ratios revealed the optimal ratio for near-maximal stimulation of MSCs to secrete IL-1RA, providing absolute maximum levels per individual MSC that can be used for future comparison with clinical efficacy. Batch release testing of 71 consecutively manufactured MSC batches showed a low overall failure rate and a high comparability between donors. CONCLUSIONS: We describe the systematic development and validation of a therapeutically relevant, straightforward, robust and reproducible potency assay to measure the immunomodulatory capacity of MSCs in M1 macrophage-driven inflammation. The insights into the challenges and how they were addressed may also be helpful to developers of potency assays related to other cellular functions and clinical indications.

Loss of interleukin 1 signaling causes impairment of microglia- mediated synapse elimination and autistic-like behaviour in mice.

In the last years, the hypothesis that elevated levels of proinflammatory cytokines contribute to the pathogenesis of neurodevelopmental diseases has gained popularity. IL-1 is one of the main cytokines found to be elevated in Autism spectrum disorder (ASD), a complex neurodevelopmental condition characterized by defects in social communication and cognitive impairments. In this study, we demonstrate that mice lacking IL-1 signaling display autistic-like defects associated with an excessive number of synapses. We also show that microglia lacking IL-1 signaling at early neurodevelopmental stages are unable to properly perform the process of synapse engulfment and display excessive activation of mammalian target of rapamycin (mTOR) signaling. Notably, even the acute inhibition of IL-1R1 by IL-1Ra is sufficient to enhance mTOR signaling and reduce synaptosome phagocytosis in WT microglia. Finally, we demonstrate that rapamycin treatment rescues the defects in IL-1R deficient mice. These data unveil an exclusive role of microglial IL-1 in synapse refinement via mTOR signaling and indicate a novel mechanism possibly involved in neurodevelopmental disorders associated with defects in the IL-1 pathway.

Inhibition of IL-1 Ameliorates Cardiac Dysfunction and Arrhythmias in a Murine Model of Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis often associated with cardiac sequelae, including arrhythmias. Abundant evidence indicates a central role for IL (interleukin)-1 and TNFα (tumor necrosis factor-alpha) signaling in the formation of arterial lesions in KD. We aimed to investigate the mechanisms underlying the development of electrophysiological abnormalities in a murine model of KD vasculitis. METHODS: Lactobacillus casei cell wall extract-induced KD vasculitis model was used to investigate the therapeutic efficacy of clinically relevant IL-1Ra (IL-1 receptor antagonist) and TNFα neutralization. Echocardiography, in vivo electrophysiology, whole-heart optical mapping, and imaging were performed. RESULTS: KD vasculitis was associated with impaired ejection fraction, increased ventricular tachycardia, prolonged repolarization, and slowed conduction velocity. Since our transcriptomic analysis of human patients showed elevated levels of both IL-1ß and TNFα, we asked whether either cytokine was linked to the development of myocardial dysfunction. Remarkably, only inhibition of IL-1 signaling by IL-1Ra but not TNFα neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFα neutralization significantly improved vasculitis and heart vessel inflammation. The treatment of L casei cell wall extract-injected mice with IL-1Ra also restored conduction velocity and improved the organization of Cx43 (connexin 43) at the intercalated disk. In contrast, in mice with gain of function of the IL-1 signaling pathway, L casei cell wall extract induced spontaneous ventricular tachycardia and premature deaths. CONCLUSIONS: Our results characterize the electrophysiological abnormalities associated with L casei cell wall extract-induced KD and show that IL-1Ra is more effective in preventing KD-induced myocardial dysfunction and arrhythmias than anti-TNFα therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.

Combining Classic and Novel Neutrophil-Related Biomarkers to Identify Non-Small-Cell Lung Cancer.

BACKGROUND: Recent studies have revealed that neutrophils play a crucial role in cancer progression. This study aimed to explore the diagnostic value of neutrophil-related biomarkers for non-small-cell lung cancer (NSCLC). METHODS: We initially assessed the associations between classic neutrophil-related biomarkers (neutrophil-to-lymphocyte ratio (NLR), absolute neutrophil counts (NEU), absolute lymphocyte counts (LYM)) and NSCLC in 3942 cases and 6791 controls. Then, we measured 11 novel neutrophil-related biomarkers via Luminex Assays in 132 cases and 66 controls, individually matching on sex and age (±5 years), and evaluated their associations with NSCLC risk. We also developed the predictive models by sequentially adding variables of interest and assessed model improvement. RESULTS: Interleukin-6 (IL-6) (odds ratio (OR) = 10.687, 95% confidence interval (CI): 3.875, 29.473) and Interleukin 1 Receptor Antagonist (IL-1RA) (OR = 8.113, 95% CI: 3.182, 20.689) shows strong associations with NSCLC risk after adjusting for body mass index, smoking status, NLR, and carcinoembryonic antigen. Adding the two identified biomarkers to the predictive model significantly elevated the model performance from an area under the receiver operating characteristic curve of 0.716 to 0.851 with a net reclassification improvement of 97.73%. CONCLUSIONS: IL-6 and IL-1RA were recognized as independent risk factors for NSCLC, improving the predictive performance of the model in identifying disease.

Clinical advances in biological therapy for generalized pustular psoriasis: a review.

INTRODUCTION: In 2022, U.S. Food and Drug Administration (FDA) approved the first biologics, intravenous spesolimab, for acute flare of generalized pustular psoriasis (GPP). The drug works by blocking IL-36 signaling, the key pathway of GPP. Among the known mutations causing GPP, IL36RN mutations are most common, and the presence of IL36RN mutations had been found to affect the clinical manifestations and treatment response of GPP. AREAS COVERED: Literature search was conducted in PubMed, Embase and ClinicalTrials.gov for relevant studies discussing biologic treatment for GPP with special emphasis on larger studies, pediatric group, pregnant women, and the influence of IL36RN mutation on the effectiveness of biologics. EXPERT OPINION: The approval of spesolimab for GPP flare treatment marks a new era. However, whether spesolimab will be placed as the treatment of choice remains unknown, considering its higher cost, lack of direct comparison with existing biologics, and uncertain effects on co-existing plaque-type psoriasis. However, the demonstration of numerically better efficacy for patients carrying pathogenic IL36RN mutations suggests the role of pharmacogenetics in the choices of GPP treatment. Future randomized studies are warranted to investigate the effectiveness and safety of biologics for GPP in pediatric and pregnant groups.

The efficacy and safety of interleukin-1 receptor antagonist in stroke patients: A systematic review.

Stroke is the leading cause of disability worldwide, yet there is currently no effective treatment available to mitigate its negative consequences. Pro-inflammatory cytokines, such as interleukin-1 (IL-1), are known to play a crucial role in exacerbating the aftermath of stroke. Thus, it is hypothesized that blocking inflammation and administering anti-inflammatory drugs at an optimal time and dosage may improve the long-term quality of life for stroke patients. This systematic review examines the effectiveness and safety of IL-1 receptor antagonist (IL-1Ra), commercially known as "anakinra," in clinical studies involving the treatment of stroke patients. A comprehensive literature search was conducted until October 2023 to identify relevant studies. The search yielded 1403 articles, out of which 598 were removed due to duplication. After a thorough review of 805 titles and abstracts, 797 articles were further excluded, resulting in 8 studies being included in this systematic review. The findings from all the included studies demonstrate that IL-1Ra is safe for use in acute ischemic and hemorrhagic stroke patients, with no significant adverse events reported. Additionally, biomarkers, clinical assessments, serious adverse events (AEs), and non-serious AEs consistently showed more favorable outcomes in IL-1Ra receiving patients. Stroke elevates the levels of several inflammatory cytokines, however, administration of IL-1RA directly or indirectly modulates these markers and improves some clinical outcomes, suggesting a potential therapeutic benefit of this intervention.

A rare cause of AA amyloidosis: Glomus tumor and treatment with anakinra-Case report and literature review.

Systemic AA amyloidosis is associated with poorly controlled chronic inflammatory disorders. Chronic infections and inflammatory arthritis are the most common causes; however, they can also rarely occur as a complication of neoplastic disorders. The development of AA amyloidosis secondary to paraganglioma, which is a rare type of tumor, has rarely been reported in the literature. In this case, an 85-year-old female patient with a glomus tumor in the neck, who has been followed up over 50 years, applied with complaints of loss of appetite, nausea, and diarrhea for 5-6 months. While evaluating the patient, who had high levels of acute phase reactants, amyloidosis was diagnosed by salivary gland biopsy. No other cause was found to explain amyloidosis. The patient, who could not tolerate treatment with colchicine and azathioprine, is successfully treated with the interleukin-1 inhibitor anakinra. A rare relationship, systemic AA amyloidosis, which is thought to have developed as a result of long-standing jugular paraganglioma, is presented in this article. In addition, publications showing an association between paragangliomas and amyloidosis were reviewed.

Impact of C-reactive protein levels and role of anakinra in patients with ST-elevation myocardial infarction.

BACKGROUND: Interleukin-1 blockade with anakinra reduces C-reactive protein (CRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). The effectiveness of anakinra according to the degree of systemic inflammation in STEMI has not been addressed. METHODS: We analyzed 139 patients from three Virginia Commonwealth University Anakinra Response Trial randomized clinical trials to assess whether CRP levels predicted HF hospitalization or death in patients with STEMI, and if CRP levels influenced the effects of treatment with anakinra. RESULTS: CRP cut-off levels for prediction of the composite of death or HF hospitalization for CRP at admission, 3 and 14 days were, respectively 6.45 mg/L (100% of sensitivity and 66.1% specificity), 26 mg/L (100% of sensitivity and 78% specificity) and 9.56 mg/L (100% of sensitivity and 80% specificity). More patients with elevated CRP levels died or had a HF hospitalization (5/47 [11%] vs 0/82 [0%], p = 0.004 for CRP at admission; 5/32 [15.6%] vs 0/92 [0%], p < 0.001 for day 3 and 5/26 [19%] vs 0/89 [0%], p < 0.001 for day 14). A greater number of patients treated with anakinra had low CRP levels at 3 and 14 days compared to placebo (Odds Ratio 0.11 [95% IC 0.04-0.28], p < 0.0001 and OR 0.35 [95% CI 0.14-0.86], p = 0.02, respectively). Anakinra significantly prevented death or HF hospitalization in patients with high inflammatory burden (p = 0.04 for admission, p = 0.24 for day 3, and p = 0.05 for day 14). CONCLUSION: Patients with elevated CRP had higher incidence of HF hospitalization or death. Anakinra reduced the number of patients with elevated CRP levels and prevented death or HF hospitalization in patients with elevated CRP levels.

Interleukin-1beta and inflammasome expression in spinal cord following chronic constriction injury in male and female rats.

Females represent a majority of chronic pain patients and show greater inflammatory immune responses in human chronic pain patient populations as well as in animal models of neuropathic pain. Recent discoveries in chronic pain research have revealed sex differences in inflammatory signaling, a key component of sensory pathology in chronic neuropathic pain, inviting more research into the nuances of these sex differences. Here we use the chronic constriction injury (CCI) model to explore similarities and differences in expression and production of Inflammatory cytokine IL-1beta in the lumbar spinal cord, as well as its role in chronic pain. We have discovered that intrathecal IL-1 receptor antagonist reverses established pain in both sexes, and increased gene expression of inflammasome NLRP3 is specific to microglia and astrocytes rather than neurons, while IL-1beta is specific to microglia in both sexes. We report several sex differences in the expression level of the genes coding for IL-1beta, as well as the four inflammasomes responsible for IL-1beta release: NLRP3, AIM2, NLRP1, and NLRC4 in the spinal cord. Total mRNA, but not protein expression of IL-1beta is greater in females than males after CCI. Also, while CCI increases all four inflammasomes in both sexes, there are sex differences in relative levels of inflammasome expression. NLRP3 and AIM2 are more highly expressed in females, whereas NLRP1 expression is greater in males.

Development and verification of a detection method for activity of neutralizing antibody in ELISA antibody positive serum of rats immunized with recombinant human interleukin-1 receptor antagonist / 中国生物制品学杂志

@#Objective To develop and verify a method for detecting the activity of neutralizing antibodies in ELISA antibody positive serum of rats immunized with recombinant human interleukin-1 receptor antagonist(rhIL-1Ra). Methods The SD rats were subcutaneously immunized with 3,20 and 100 mg/kg rhIL-1Ra injection respectively,10 rats in each group,half male and half female,twice a day at an interval of at least 4 h between each dose for 13 consecutive weeks. The blood samples were collected from the jugular vein of rats during the administration period and the recovery period. The serum samples were isolated and detected for the antibody titers by ELISA,and the samples positive for rhIL-1Ra antibody were purified by Protein A chromatographic column. Based on,D10G4·1 cells biological activity assay,a method for the detection of neutralizing antibody activity was developed and verified for the specificity,sensitivity and precision. The neutralizing antibody activity of rhIL-1Ra antibody positive serum determined by ELISA was detected by using the developed method.Results With the increase of doses,the serum antibody titers of rats in various dose groups gradually increased,and there were still antibodies in the recovery period,and the titer was still high. Rabbit anti-rhIL-1Ra monoclonal antibody showed obvious neutralizing effect on rIL-1Ra,while rabbit anti-rIFN-2b monoclonal antibody had no dose-effect relationship with rIL-1Ra. The sensitivity of the method was 171. 93 μg/mL;The CVs of precision verification were not more than 20%. The positive antibody sera detected by ELISA all had neutralizing effect on rhIL-1Ra injection,which was consistent with the results detected by ELISA. Conclusion The method developed in this study has good specificity and high sensitivity in the detection of serum neutralizing antibody activity in rats immunized with rhIL-1Ra,which can be used to detect the serum neutralizing antibody activity of animals with rhIL-1Ra repeated administration.

Elevated IL-1ß and Comparable IL-1 Receptor Antagonist Levels Are Characteristic Features of L-PRP in Female College Athletes Compared to Male Professional Soccer Players.

Autologous platelet-rich plasma (PRP) therapy has been becoming popular for the treatment of musculotendinous injuries among athletes. However, for individual and practical variations, clinical success is hardly predictable. To overcome this difficulty, we have been exploring possible criterion candidates for monitoring its clinical effectiveness. In this study, we focused on sex-based differences in young elite athletes and compared the biochemical compositions of their PRP. Leukocyte-rich PRP (L-PRP) was manually prepared from blood samples collected from male professional soccer players (mPSPs) (n = 25) and female college athletes (fCAs) (n = 36). Platelet-derived growth factor-BB (PDGF-BB), transforming-growth factor-ß1 (TGFß1), platelet factor-4 (PF4), interleukin-1ß (IL-1ß), and IL-1 receptor antagonist (IL-1RA) were quantified using an enzyme-linked immunosorbent assay. The levels of PDGF-BB, TGFß1, and PF4 in L-PRP were significantly higher in mPSPs than in fCAs. Conversely, IL-1ß and IL-1RA were detected at significantly and slightly higher levels, respectively, in fCAs than in mPSPs. Our findings suggest that, even though L-PRP from fCAs may have lower potential to induce cell growth and differentiation than that of mPSPs, due to the latter's higher capacity to control inflammation, it does not necessarily imply that PRP treatment in fCAs is less effective. Thus, these cytokine levels should be checked before PRP therapy.

Accuracy of generative artificial intelligence models in differential diagnoses of familial Mediterranean fever and deficiency of Interleukin-1 receptor antagonist.

With the increasing development of artificial intelligence, large language models (LLMs) have been utilized to solve problems in natural language processing tasks. More recently, LLMs have shown unique potential in numerous applications within medicine but have been particularly investigated for their ability in clinical reasoning. Although the diagnostic accuracy of LLMs in forming differential diagnoses has been reviewed in general internal medicine applications, much is unknown in autoinflammatory disorders. From the nature of autoinflammatory diseases, forming a differential diagnosis is challenging due to the overlapping symptoms between disorders and even more difficult without genetic screening. In this work, the diagnostic accuracy of the Generative Pre-Trained Transformer Model-4 (GPT-4), GPT-3.5, and Large Language Model Meta AI (LLaMa) were evaluated in clinical vignettes of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) and Familial Mediterranean Fever (FMF). We then compared these models to a control group including one internal medicine physician. It was found that GPT-4 did not significantly differ in correctly identifying DIRA and FMF patients compared to the internist. However, the physician maintained a significantly higher accuracy than GPT-3.5 and LLaMa 2 for either disease. Overall, we explore and discuss the unique potential of LLMs in diagnostics for autoimmune diseases.

Anakinra authorized to treat severe coronavirus disease 2019; Sepsis breakthrough or time to reflect?

Introduction: The European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) announced conditions for using recombinant human interleukin-1 receptor antagonist (rhIL-1ra) to treat hospitalized patients with Coronavirus disease 2019 (COVID-19) and risk for progression. These decisions followed publication of the suPAR-guided Anakinra treatment for Validation of the risk and early Management OF seveRE respiratory failure by COVID-19 (SAVE- MORE) phase 3 clinical trial that yielded positive results. Methods: We conducted a literature review and theoretical analysis of IL-1 blockade as a therapy to treat COVID-19. Using a stepwise analysis, we assessed clinical applicability of the SAVE-MORE results and evaluated conceptual support for interleukin-1 suppression as a suitable approach to COVID-19 treatment. This therapeutic approach was then examined as an example of inflammation-suppressing measures used to treat sepsis. Results: Anakinra use as a COVID-19 therapy seems to rely on a view of pathogenesis that incorrectly reflects human disease. Since COVID-19 is an example of sepsis, COVID-19 benefit due to anti-inflammatory therapy contradicts an extensive history of unsuccessful clinical study. Repurposing rhIL-1ra to treat COVID-19 appears to exemplify a cycle followed by inflammation-suppressing sepsis treatments. A landscape of treatment failures is interrupted by a successful clinical trial. However, subsequent confirmatory study fails to replicate the positive data. Discussion: We suggest further experimentation is not a promising pathway to discover game-changing sepsis therapies. A different kind of approach may be necessary.

Apolipoprotein B and interleukin 1 receptor antagonist: reversing the risk of coronary heart disease.

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

Interleukin Variants Are Associated with the Development and Progression of IgA Nephropathy: A Candidate-Gene Association Study and Meta-Analysis.

The interleukin-1 gene cluster encodes cytokines, which modulate mesangial cell proliferation and matrix expansion, both constituting central factors in the development and progression of immunoglobulin A nephropathy (IgAN). A candidate-gene study was performed to examine the association of polymorphisms of the interleukin-1 gene cluster with the risk of progressive IgAN. To gain deeper insights into the involvement of interleukin genes in IgAN, a meta-analysis of genetic association studies (GAS) that examine the association between interleukin variants and IgAN was conducted. Association study: The case-control study consisted of 121 unrelated Caucasians with sporadic, histologically diagnosed IgAN and of 246 age- and sex-matched healthy controls. Persistent proteinuria (>2 g/24 h) and/or impaired kidney function (serum creatinine > 1.5 mg/dL) defined progressive (n = 67) vs. non-progressive (n = 54) IgAN cases. Genotypes were assessed for two promoter-region single-nucleotide polymorphisms, C-899T (rs1800587) in IL1A and C-511T (rs16944) in IL1B, and for one penta-allelic variable-length tandem repeat polymorphism (VNTR 86 bp intron 2) in IL1RN. The association of these variants with the susceptibility of IgAN and the development of progressive IgAN (healthy status, IgAN, progressive IgAN) was tested using the generalized odds ratio (ORG) metric. Linkage disequilibrium and haplotype analysis were also performed. Meta-analysis: We included in the meta-analysis 15 studies investigating association between 14 interleukin variants harbored in eight different genes and IgAN. The ORG was used to evaluate the association between interleukin variants and IgAN using random effects models. The present case-control study revealed association of IL1B C-511T (rs16944) with the progression of IgAN (p = 0.041; ORG = 2.11 (1.09-4.07)). On haplotype analysis, significant results were derived for the haplotypes C-C-1 (p = 0.005; OR = 0.456 (0.261~0.797)) and C-T-2 (p = 0.003; OR = 4.208 (1.545-11.50)). Regarding association and meta-analysis results, variants in IL1B (rs1143627 and rs16944), IL1RN (rs928940, rs439154, and rs315951) and IL10 (rs1800871) were associated with IgAN based on either genotype or allele counts. Genetic variants and haplotypes in the IL1B, IL1RN, and IL10 genes might contribute to an increased risk for development and progression of IgAN.