IL37 Human

What is IL-37 and what are its primary functions in human immunity?

IL-37 is a member of the IL-1 family (also previously known as IL-1F7) discovered by computational cloning in 2000. It functions primarily as an immunosuppressive cytokine that inhibits innate immunity and inflammatory responses. IL-37 suppresses the production of pro-inflammatory cytokines (including IL-6, IL-1α, and TNF-α) in innate immune cells and inhibits the maturation of dendritic cells . Unlike most IL-1 family members that promote inflammation, IL-37 serves as a fundamental negative regulator of inflammation, making it a critical modulator in various inflammatory and autoimmune conditions.

Table 1: Publication Growth of IL-37 Research (2001-2021)

How does IL-37 differ from other members of the IL-1 family in structure and function?

Unlike most IL-1 family cytokines that are primarily pro-inflammatory, IL-37 exhibits distinct anti-inflammatory properties. Structurally, IL-37 maintains the β-trefoil fold characteristic of the IL-1 family, but its unique receptor requirements and signaling pathways set it apart functionally. IL-37 specifically requires IL-18Rα and IL-1R8 (SIGIRR) receptors to execute its anti-inflammatory program . Furthermore, IL-37 demonstrates both intracellular and extracellular mechanisms of action, with extracellular forms requiring the IL-1 family decoy receptor IL-1R8 . This dual functionality gives IL-37 a more complex regulatory role compared to other IL-1 family members.

What are the primary signaling pathways through which human IL-37 exerts its immunosuppressive effects?

IL-37 exerts its immunosuppressive effects through multiple signaling pathways. The primary mechanism involves binding to IL-18Rα and IL-1R8 (SIGIRR) receptors, which initiates anti-inflammatory signaling cascades . This receptor engagement is critical for IL-37's ability to suppress NF-κB activation, as evidenced by the high centrality of "NF-κB" in keyword co-occurrence analysis . Intracellularly, IL-37 can translocate to the nucleus and influence gene expression. The extracellular forms of IL-37 inhibit innate inflammation but require the IL-1 family decoy receptor IL-1R8, highlighting the complexity of IL-37 signaling networks in modulating immune responses through multiple pathways.

How is IL-37 expression regulated across different human tissues and disease states?

IL-37 expression varies significantly across tissues and is dynamically regulated in different disease states. Bibliometric analysis shows that "expression" is one of the most important terms associated with IL-37 research, with 165 co-occurrences . Increased levels of circulating IL-37 have been documented in patients with rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus . In rheumatoid arthritis patients specifically, there is elevated expression of synovial IL-1R8, which is essential for IL-37's anti-inflammatory effects. The regulation of IL-37 appears to be particularly responsive to inflammatory stimuli, suggesting a feedback mechanism where IL-37 increases during inflammation to help limit immune responses and prevent excessive tissue damage.

What are the most reliable methods for quantifying IL-37 expression in human clinical samples?

When quantifying IL-37 in human clinical samples, researchers should consider multiple complementary approaches to ensure reliable results. For protein detection, enzyme-linked immunosorbent assay (ELISA) remains the gold standard, though western blotting provides information about protein processing forms. For transcriptional analysis, quantitative PCR (qPCR) offers sensitive detection of IL-37 mRNA. Immunohistochemistry and flow cytometry are valuable for assessing cellular sources of IL-37 within tissues or blood samples.

Table 2: Recommended Methods for IL-37 Quantification

The bibliometric analysis indicates that "differential expression" (cluster #2) has been a significant research focus in IL-37 studies , highlighting the importance of comparative expression analysis between healthy and diseased states.

How should researchers design experiments to accurately assess IL-37's immunosuppressive functions?

Designing experiments to assess IL-37's immunosuppressive functions requires careful consideration of multiple factors. In vitro approaches should include:

• Dose-response experiments with recombinant IL-37 on relevant human immune cells (monocytes, macrophages, dendritic cells)

• Time-course studies to determine optimal pre-treatment or co-treatment schedules with inflammatory stimuli

• Comparison of effects on multiple inflammatory mediators (cytokines, chemokines, surface markers)

• Receptor blocking experiments to confirm IL-18Rα and IL-1R8 dependency

• Knockdown/knockout studies using siRNA or CRISPR-Cas9

For in vivo studies, transgenic mouse models expressing human IL-37 have proven valuable, as evidenced by the high citation of research showing protection from colitis in IL-37-expressing mice . When designing these experiments, researchers must include appropriate controls and consider how the timing of IL-37 administration relative to inflammatory stimuli affects outcomes.

What cell and animal models are most appropriate for investigating IL-37 mechanisms in different disease contexts?

The selection of appropriate models for IL-37 research depends on the specific disease context and research question. For cellular models, primary human monocytes, macrophages, and dendritic cells are preferred as they express the necessary receptors (IL-18Rα and IL-1R8) . The keyword analysis showing "dendritic cell" with high co-occurrence confirms their importance in IL-37 research .

For disease-specific studies, researchers should consider:

• Rheumatoid arthritis: Fibroblast-like synoviocytes (IL-37 induces apoptosis in these cells)

• Inflammatory bowel disease: Intestinal epithelial cells and colitis models

• Cardiovascular disease: Vascular endothelial cells and atherosclerosis models

What analytical approaches should be employed when studying genetic variations in IL-37 across human populations?

When investigating IL-37 genetic variations across populations, researchers should implement a comprehensive analytical framework:

• Study design considerations:

  • Account for population stratification using principal component analysis

  • Calculate adequate sample sizes based on expected effect sizes and allele frequencies

  • Include diverse populations (the research shows IL-37 studies span 50 countries)

• Genotyping approaches:

  • Targeted sequencing of IL-37 and receptor genes

  • Genome-wide association studies for broader genetic context

  • Haplotype analysis to identify linked polymorphisms

• Functional validation:

  • Reporter assays to assess promoter variants

  • Expression quantitative trait loci (eQTL) analysis

  • In vitro testing of variant IL-37 proteins

• Data analysis:

  • Control for multiple testing using Bonferroni or false discovery rate methods

  • Conduct gene-environment interaction analysis

  • Perform meta-analysis across cohorts

The focus on "pathogenesis" and "disease" in keyword co-occurrence suggests that genetic variation in IL-37 may significantly contribute to disease susceptibility or progression, warranting rigorous analytical approaches.

How does IL-37 function within the broader cytokine network to maintain immune homeostasis?

IL-37 operates within a complex cytokine network to maintain immune homeostasis through multiple mechanisms:

• Counter-regulation of pro-inflammatory cytokines: IL-37 suppresses the production of key inflammatory mediators including IL-6, IL-1α, TNF-α, and other cytokines

• Receptor cross-talk: The requirement for IL-18Rα suggests competitive inhibition with IL-18 signaling pathways, representing an important checkpoint in inflammation

• Cell-specific regulatory effects: IL-37 modulates dendritic cell maturation and function, affecting downstream T cell responses and adaptive immunity

• Feedback inhibition loops: Inflammatory stimuli that activate NF-κB pathways induce IL-37 expression, which then suppresses further NF-κB activation, creating a negative feedback loop

The co-citation analysis showing "related cytokine" as cluster #5 highlights the academic interest in understanding IL-37's position within broader cytokine networks. Researchers investigating this area should employ systems biology approaches that can capture the dynamic interplay between multiple cytokines simultaneously, rather than studying IL-37 in isolation.

What is the current understanding of IL-37's role in the pathogenesis of autoimmune diseases?

IL-37 plays complex roles in autoimmune disease pathogenesis, often serving as an endogenous brake on inflammation:

Table 3: IL-37 in Major Autoimmune Conditions

The elevated IL-37 levels in these conditions suggest activation of endogenous anti-inflammatory mechanisms attempting to control disease progression. This has led researchers to investigate IL-37 supplementation as a potential therapeutic strategy. The keyword co-occurrence showing "rheumatoid arthritis" as a significant term confirms the importance of this autoimmune condition in IL-37 research.

Methodologically, researchers studying IL-37 in autoimmune diseases should examine both systemic and local expression patterns, while also investigating how genetic variations in IL-37 or its receptors might influence disease susceptibility or severity.

How do post-translational modifications influence the biological activity of human IL-37?

Post-translational modifications (PTMs) critically influence IL-37's biological activity through several mechanisms:

• Proteolytic processing: Like many IL-1 family members, IL-37 requires specific proteolytic cleavage for full bioactivity. The processing of IL-37 by caspase-1 has been shown to enhance its anti-inflammatory properties.

• Phosphorylation: Potential phosphorylation sites may regulate IL-37's interaction with signaling components or influence its intracellular trafficking.

• Glycosylation: Glycosylation could affect IL-37's stability, receptor binding affinity, and circulation half-life.

• Nuclear localization: Modifications affecting nuclear translocation may determine IL-37's ability to influence gene transcription directly.

The co-citation of papers discussing "extracellular forms of IL-37" suggests that processing of IL-37 is important for its function. Researchers investigating IL-37 PTMs should employ mass spectrometry-based approaches to identify modification sites, followed by site-directed mutagenesis to assess functional consequences. Additionally, researchers should consider how inflammatory environments might alter the PTM profile of IL-37, potentially affecting its anti-inflammatory properties in disease states.

What are the key challenges and strategies in developing IL-37-based therapeutic interventions?

Developing IL-37-based therapeutic interventions presents several challenges that researchers must address:

• Delivery and formulation challenges:

  • Recombinant IL-37 has limited stability in circulation

  • Targeted delivery to specific tissues requires novel formulation approaches

  • Optimal dosing regimens remain undetermined

• Mechanistic considerations:

  • Dual intracellular and extracellular functions complicate therapeutic strategies

  • Receptor requirements (IL-18Rα and IL-1R8) vary across tissues

  • Timing of intervention is critical given the context-dependent effects

• Safety concerns:

  • Potential immunogenicity of recombinant IL-37

  • Risk of compromising immune responses to pathogens

  • Differential effects across various autoimmune conditions

Strategies to overcome these challenges include developing stabilized IL-37 variants, receptor-specific agonists, gene therapy approaches, and small molecule enhancers of endogenous IL-37 expression. The keyword analysis showing "inhibitor" as a term with high centrality suggests research interest in how IL-37 inhibits inflammatory processes, which could inform therapeutic strategies targeting similar pathways.

How should researchers reconcile contradictory findings regarding IL-37 expression patterns in various diseases?

Contradictory findings regarding IL-37 expression across diseases represent a significant challenge requiring systematic resolution approaches:

• Methodological assessment:

  • Evaluate differences in sample collection, processing, and storage

  • Compare detection methods (ELISA kits, antibodies, PCR primers)

  • Assess statistical approaches and sample sizes

• Contextual factors:

  • Disease heterogeneity and subtype classification

  • Treatment status of patients and medication effects

  • Disease duration and activity measures

  • Tissue-specific versus systemic expression patterns

• Analytical strategies:

  • Meta-analysis with random effects models to account for heterogeneity

  • Subgroup analysis based on methodological factors

  • Bayesian approaches incorporating prior knowledge

The cluster analysis identifying "differential expression" (cluster #2) as a significant research focus confirms that expression variability is a recognized aspect of IL-37 biology. Longitudinal studies examining IL-37 expression throughout disease progression could help clarify apparent contradictions observed in cross-sectional data.

What factors explain the variability in IL-37 responses observed across different human populations?

The variability in IL-37 responses across populations stems from multiple interacting factors:

• Genetic determinants:

  • Polymorphisms in IL-37 coding regions affecting protein function

  • Variations in promoter regions influencing expression levels

  • Receptor (IL-18Rα and IL-1R8) genetic diversity

  • Background genetic modifiers affecting signaling pathways

• Environmental influences:

  • Different pathogen exposure histories shaping immune responses

  • Dietary factors affecting inflammatory status

  • Environmental pollutants modulating cytokine networks

  • Microbiome composition variations

• Methodological considerations:

  • Standardization of assays across populations

  • Accounting for reference ranges in different ethnic groups

  • Controlling for comorbidities and medication use

The bibliometric analysis showing research contributions from 50 different countries/regions suggests recognition of population differences in IL-37 biology. Researchers should conduct cross-population studies with standardized protocols and consider genome-wide association approaches to identify genetic factors influencing IL-37 responses.

What methodological approaches should researchers employ when IL-37 data contradicts established immunological paradigms?

When IL-37 data contradicts established immunological paradigms, researchers should follow these methodological principles:

• Validation through multiple approaches:

  • Confirm findings using independent techniques

  • Replicate experiments in different model systems

  • Collaborate with independent laboratories for verification

• Critical examination of assumptions:

  • Review the foundational evidence of the challenged paradigm

  • Identify contextual factors that might explain apparent contradictions

  • Consider cell-type or tissue-specific effects

• Transparent reporting:

  • Document all methodological details thoroughly

  • Pre-register experimental protocols when possible

  • Report all results, including those that appear contradictory

• Conceptual integration:

  • Propose mechanistic models that reconcile contradictory findings

  • Develop testable hypotheses that could resolve the contradiction

  • Consider paradigm refinement rather than replacement

The discovery that IL-37 is "a fundamental inhibitor of innate immunity" itself represented a paradigm shift in understanding IL-1 family cytokines, which were typically considered pro-inflammatory. This historical context provides a model for how researchers might approach new findings that challenge current understanding of IL-37 biology.

What statistical and bioinformatic approaches are most appropriate for analyzing complex IL-37 clinical datasets?

Analyzing complex IL-37 clinical datasets requires sophisticated statistical and bioinformatic approaches:

• For observational clinical studies:

  • Multivariate regression models controlling for relevant confounders

  • Propensity score matching for case-control comparisons

  • Mediation analysis to assess causal pathways involving IL-37

• For longitudinal data:

  • Mixed-effects models accounting for repeated measures

  • Time-series analysis for temporal patterns

  • Joint modeling for longitudinal biomarkers and clinical outcomes

• For biomarker evaluation:

  • Receiver operating characteristic (ROC) curve analysis

  • Net reclassification improvement (NRI) assessment

  • Decision curve analysis for clinical utility

• For integrative analyses:

  • Network analysis of cytokine interactions

  • Machine learning for pattern recognition in complex datasets

  • Multi-omics integration approaches

The keyword co-occurrence of "disease activity" suggests that correlating IL-37 levels with clinical indices is a common approach. Researchers should ensure appropriate sample size calculations during study design and consider Bayesian approaches when prior knowledge about IL-37 can inform analysis.

What emerging research trends are shaping the future of IL-37 investigation?

Bibliometric analysis reveals several emerging trends shaping the future of IL-37 research:

• Expansion to diverse disease contexts:

  • The involvement of IL-37 in disorders beyond established autoimmune diseases

  • Cardiovascular diseases emerging as the largest cluster (#0) in co-citation analysis

  • Exploration of IL-37's role in metabolic disorders

• Mechanistic refinement:

  • Additional immunomodulatory mechanisms beyond established anti-inflammatory effects

  • Understanding the dual intracellular and extracellular functions

  • Receptor-independent activities

• Therapeutic applications:

  • "Suppression" continuing as an active research front in keyword burst analysis

  • Development of IL-37-based therapeutic interventions

  • Biomarker applications for disease monitoring

• Tissue-specific biology:

  • "Epidermal barrier" (cluster #8) representing newer research directions

  • Tissue-resident immune cell responses to IL-37

  • Organ-specific functions and expression patterns

Researchers should position new studies to build upon these emerging trends while introducing innovative methodological approaches to address the complex biology of IL-37.

Which unexplored aspects of IL-37 biology warrant further investigation?

Despite significant research progress, several aspects of IL-37 biology remain underexplored:

• Evolutionary biology and comparative immunology:

  • Why humans have IL-37 while mice naturally lack this gene

  • Evolutionary pressures that shaped IL-37 function

  • Comparative analysis across species with IL-37 homologs

• Regulatory networks:

  • Transcriptional and post-transcriptional regulation of IL-37

  • microRNA networks controlling IL-37 expression

  • Epigenetic modifications of the IL-37 locus in different contexts

• Cellular sources and targets:

  • Non-immune cell sources of IL-37

  • Cell-type specific responses to IL-37 signaling

  • The role of "mast cells" (cluster #6) in IL-37 biology

• Developmental aspects:

  • IL-37 expression during different developmental stages

  • Role in tissue repair and regeneration

  • Influence on immune system development

The separate clustering of "IL-1F5" (SIGIRR, cluster #9) from other clusters suggests that the relationship between IL-37 and its receptor components still has unexplored facets that warrant further investigation.

How might emerging technologies advance our understanding of IL-37's functions and therapeutic potential?

Emerging technologies promise to revolutionize our understanding of IL-37 biology:

• Single-cell technologies:

  • Single-cell RNA sequencing to identify specific cellular sources and responders

  • Single-cell proteomics to characterize IL-37 production at protein level

  • Spatial transcriptomics to map IL-37 expression in tissue contexts

• Advanced genetic engineering:

  • CRISPR-Cas9 base editing for precise modification of IL-37 and receptor genes

  • Inducible expression systems for temporal control of IL-37

  • Humanized mouse models with physiological IL-37 expression

• Structural and interaction biology:

  • Cryo-EM of IL-37-receptor complexes

  • Protein-protein interaction mapping using proximity labeling

  • Hydrogen-deuterium exchange mass spectrometry for conformational dynamics

• Computational approaches:

  • Machine learning for pattern recognition in IL-37-related datasets

  • Systems biology modeling of IL-37 in cytokine networks

  • Virtual screening for small molecule modulators of IL-37 activity

These technologies will enable researchers to address complex questions about IL-37 function with unprecedented resolution and precision, potentially accelerating therapeutic applications.

What interdisciplinary approaches could yield breakthrough insights into IL-37 biology?

Interdisciplinary approaches hold particular promise for advancing IL-37 research:

• Immunology + Systems Biology:

  • Network modeling of IL-37 within broader cytokine systems

  • Identification of emergent properties in inflammatory regulation

  • Multi-scale modeling from molecular to organism level

• Immunology + Cardiovascular Research:

  • The cluster analysis identifying "cardiovascular disease" as the largest cluster

  • Investigating IL-37's role in atherosclerosis and heart failure

  • Effects on vascular inflammation and endothelial function

• Immunology + Neuroscience:

  • Neuroimmune interactions mediated by IL-37

  • Role in neuroinflammatory and neurodegenerative conditions

  • Effects on microglial function and neuronal health

• Immunology + Microbiome Research:

  • IL-37's role in host-microbiota interactions

  • Effects on intestinal barrier function and mucosal immunity

  • Microbial regulation of IL-37 expression

• Immunology + Computational Drug Design:

  • Structure-based design of IL-37 mimetics or enhancers

  • AI-driven discovery of small molecule modulators

  • Modeling of pharmacokinetics and tissue distribution

These interdisciplinary approaches can address complex questions about how IL-37 functions in different physiological contexts and accelerate the translation of basic research findings into therapeutic applications.