IL1F10 Human

What is IL1F10 and what are its main biological functions?

IL1F10, officially known as Interleukin 1 Family Member 10, is a member of the IL-1 cytokine family that functions primarily as an anti-inflammatory mediator. Also widely known as IL-38, it was discovered in silico in 2001 and initially termed IL-1HY2 before being assigned the designation IL1F10 . The gene is located on chromosome 2 between two receptor antagonists of the IL-1 family, IL-1RN and IL-36RN, with which it shares protein sequence homologies of 41% and 43%, respectively .

IL-38 exhibits significant immunomodulatory activity, particularly in suppressing inflammatory and autoimmune conditions. It binds to the IL-36 receptor (IL-1R6) and IL-1R9 (on macrophages and γδ-T cells), inhibiting the production of pro-inflammatory cytokines such as IL-6 and IL-8 from LPS-stimulated peripheral blood mononuclear cells (PBMC) and macrophages . It also dampens Th17 responses, reducing inflammation in murine models of psoriasis and arthritis .

How does IL1F10 expression differ from other IL-1 family members?

IL1F10 stands apart from many other IL-1 family members due to its predominantly anti-inflammatory properties. While cytokines like IL-1β are pro-inflammatory, IL-38 more closely resembles IL-1Ra and IL-36Ra in function, acting as an antagonist in inflammatory pathways .

Unlike IL-1β, which is rapidly induced during acute inflammation, IL-38 shows stable expression under normal conditions and is not significantly induced during experimental endotoxemia in humans . This suggests a role in maintaining immune homeostasis rather than participating in acute inflammatory responses.

What are the primary cellular sources of IL1F10 in humans?

Research indicates that B cells are a major source of IL-38 in circulation. Gene expression studies have detected IL1F10 mRNA in isolated CD19+ B cells from peripheral blood mononuclear cells (PBMC), while it was not detectable in PBMC depleted of CD19+ B cells .

In vitro experiments have shown that IL-38 can be released from CD19+ B cells after stimulation with rituximab (an anti-CD20 antibody), suggesting a potential mechanism for its release into circulation .

How does IL1F10 expression change in disease states?

IL1F10 expression and circulating IL-38 concentrations show significant alterations in various disease states. In overweight individuals at high risk for cardiovascular disease, plasma IL-38 concentrations are significantly lower (approximately 3-fold) compared to healthy subjects, with the lowest levels observed in those with metabolic syndrome .

IL-38 levels correlate inversely with inflammatory markers including high-sensitivity C-reactive protein (hsCRP), IL-6, IL-1Ra, and leptin, consistent with its anti-inflammatory properties . These findings suggest that reduced IL-38 may contribute to the chronic low-grade inflammation observed in obesity and metabolic disorders.

Interestingly, in acute inflammatory conditions like ST-elevated myocardial infarction (STEMI), IL-38 plasma concentrations may be transiently elevated, possibly representing a response to limit inflammation and restore homeostasis .

What are the optimal methods for measuring IL1F10 protein levels in clinical samples?

For reliable measurement of IL-38 protein levels in clinical samples, enzyme-linked immunosorbent assay (ELISA) has been successfully employed in large-scale studies . When designing studies to measure IL-38:

• Sample collection considerations: Plasma samples appear to be suitable for IL-38 measurement. In healthy individuals, IL-38 concentrations remain stable over time, suggesting that single time-point measurements may be representative .

• Detection thresholds: Researchers should be aware that IL-38 may not be detectable in all subjects. In one study of healthy individuals, IL-38 was detectable (>16 pg/mL) in 72% of men and 64% of women .

• Temporal stability: For longitudinal studies, it's important to note that IL-38 concentrations appear stable over time in healthy individuals, with concentrations remaining consistent across four seasons in a subset of subjects studied .

• Cell isolation protocols: For cellular studies, CD19+ B cell isolation from PBMC using standard immunomagnetic separation techniques has been effective for examining IL1F10 expression and protein content .

What experimental approaches are most effective for studying IL1F10 function?

Several experimental approaches have proven valuable for investigating IL1F10 function:

• In vitro stimulation assays: Stimulation of isolated B cells with agents like rituximab (anti-CD20) can induce IL-38 release, providing a system to study regulation of secretion .

• Gene expression analysis: qPCR assessment of IL1F10 mRNA in isolated cell populations helps identify cellular sources and regulatory mechanisms .

• Protein detection in cell lysates and supernatants: Western blotting and ELISA of cellular compartments can determine whether IL-38 is primarily intracellular or secreted .

• Correlation studies with immune cell subsets: Flow cytometry combined with plasma IL-38 measurement has revealed associations between IL-38 levels and specific B cell populations, including memory B cells and plasmablasts .

• Human experimental models: The human endotoxemia model, while not showing changes in IL-38 itself, can be useful for studying the relationship between IL-38 and other inflammatory mediators .

How do IL1F10 levels correlate with age and inflammatory markers?

IL-38 concentrations show several important correlations with age and inflammatory markers:

• Age correlation: In healthy subjects, IL-38 concentrations correlate negatively with age, contrasting with pro-inflammatory cytokines like IL-6, IL-1Ra, and IL-18BP which increase with age .

• Inflammatory marker associations: In overweight subjects, IL-38 correlates inversely with:

  • High-sensitivity C-reactive protein (hsCRP)

  • IL-6

  • IL-1Ra

  • Leptin

These correlations suggest that lower IL-38 levels may contribute to age-related and obesity-related increases in systemic inflammation .

What is the relationship between IL1F10 and specific immune cell populations?

Research has revealed significant correlations between circulating IL-38 concentrations and specific immune cell populations:

• B cell associations: IL-38 plasma concentrations correlate positively with circulating memory B cells and plasmablasts, consistent with the identification of B cells as a major source of IL-38 .

• Stability of associations: These correlations between IL-38 and immune cell subsets appear to be stable characteristics of individuals, as IL-38 concentrations remain consistent over time within subjects .

The table below summarizes key correlations between IL-38 and various parameters:

How does IL1F10 contribute to metabolic inflammation and cardiovascular disease risk?

IL-38 appears to play a significant role in metabolic inflammation and cardiovascular disease risk through several mechanisms:

• Reduced levels in metabolic syndrome: Subjects with metabolic syndrome demonstrate significantly lower IL-38 concentrations compared to those without metabolic syndrome, suggesting that IL-38 deficiency may contribute to metabolic inflammation .

• Inverse relationship with inflammatory mediators: The negative correlation between IL-38 and inflammatory markers (hsCRP, IL-6) in overweight individuals suggests that inadequate IL-38 production might permit enhanced inflammatory responses .

• Relationship with IL-1β: While not reaching statistical significance in all studies, there appears to be a trend toward higher concentrations of IL-1β in subjects with low IL-38, consistent with IL-38's proposed role in suppressing IL-1β production .

• SNP associations: Single nucleotide polymorphisms associated with IL1F10 have been linked to serum CRP concentrations in genome-wide association studies, further supporting IL-38's role in modulating systemic inflammation .

• Response during acute cardiovascular events: In acute STEMI, IL-38 plasma concentrations may increase concurrently with hsCRP, possibly representing a compensatory anti-inflammatory response .

These findings suggest a model where chronic low concentrations of IL-38 may serve as a biomarker of cardiovascular disease risk, while acute increases during cardiovascular events may represent an attempt to limit inflammation and restore homeostasis .

What are the current hypotheses regarding IL1F10's molecular mechanisms of action?

Several mechanisms have been proposed for IL-38's anti-inflammatory effects:

• Receptor antagonism: IL-38 binds to the IL-36 receptor (IL-1R6), potentially functioning as a receptor antagonist similar to IL-1Ra and IL-36Ra, with which it shares structural homology .

• IL-1R9 binding: IL-38 also binds to IL-1R9 on macrophages, inhibiting IL-6 secretion by restraining JNK induction and reducing AP1 and NFκB activity .

• Suppression of Th17 responses: IL-38 can inhibit the IL-1R9 on γδ-T cells and thereby reduce Th17 responses, which may explain its beneficial effects in models of psoriasis and other autoimmune conditions .

• B cell-derived immunomodulation: As a B cell product, IL-38 may represent a previously unrecognized mechanism by which B cells contribute to immune regulation and homeostasis .

• Inhibition of pro-inflammatory cytokine production: Recombinant IL-38 has been shown to inhibit CRP and IL-1β production by PBMC from patients with hyperlipidemia, suggesting direct suppressive effects on inflammatory mediator production .

What are the key contradictions or knowledge gaps in current IL1F10 research?

Several important contradictions and knowledge gaps exist in the current understanding of IL1F10:

• Expression vs. protein levels: There appears to be a disconnect between IL1F10 mRNA expression and protein levels, particularly in keratinocytes versus B cells, where mRNA expression does not necessarily correlate with protein abundance .

• Acute vs. chronic responses: While IL-38 is reduced in chronic inflammatory conditions like obesity and metabolic syndrome, it may be elevated in acute situations like STEMI. The mechanisms underlying these differential responses remain unclear .

• Receptor interactions: Although IL-38 has been shown to bind to IL-36R and IL-1R9, the relative importance of these interactions in different tissues and disease states requires further investigation .

• Gender differences: Some studies suggest potential differences in IL-38 levels between males and females, but these have not reached statistical significance in all cohorts, warranting larger studies to clarify this question .

• Therapeutic potential: Despite promising anti-inflammatory properties, the therapeutic potential of recombinant IL-38 or strategies to enhance endogenous IL-38 production remains largely unexplored in human clinical settings.

• Regulation of expression: The factors controlling IL1F10 expression under normal and pathological conditions are incompletely understood, particularly the mechanisms leading to reduced expression in metabolic disorders .

What control groups should be included when studying IL1F10 in disease models?

When designing studies to investigate IL1F10 in disease models, researchers should consider several control groups:

How should researchers account for confounding factors when measuring IL1F10 in clinical studies?

Several potential confounding factors should be considered when designing clinical studies measuring IL1F10:

• Age effects: Statistical adjustment for age is essential given the significant negative correlation between IL-38 concentrations and age .

• Body mass index: BMI has a substantial impact on IL-38 levels and should be included as a covariate in analyses .

• Metabolic parameters: Factors such as metabolic syndrome status, glucose tolerance, and insulin sensitivity may influence IL-38 levels independently of BMI .

• Medication use: The potential impact of medications, particularly those with anti-inflammatory properties, on IL-38 levels should be considered and documented.

• Immune cell populations: Given the correlation between IL-38 and specific B cell subsets, variations in circulating immune cell populations may influence IL-38 measurements and should be assessed when possible .

• Acute inflammatory stimuli: As IL-38 does not appear to be acutely regulated during experimental endotoxemia, researchers should document any acute inflammatory events that might influence other cytokines without affecting IL-38, potentially confounding relationship analyses .

What are the most promising therapeutic applications of IL1F10 research?

Several promising therapeutic applications emerge from current IL1F10 research:

• Biomarker for cardiovascular risk: The inverse correlation between IL-38 and inflammatory markers in subjects at risk for cardiovascular disease suggests potential utility as a biomarker for risk stratification .

• Anti-inflammatory therapy: The anti-inflammatory properties of IL-38 make recombinant IL-38 or strategies to enhance endogenous IL-38 production potential therapeutic approaches for inflammatory and autoimmune conditions .

• Metabolic inflammation: The reduced IL-38 levels in subjects with metabolic syndrome suggest that IL-38 supplementation might help address the chronic inflammation associated with metabolic disorders .

• Personalized medicine: The stable individual differences in IL-38 levels suggest that IL-38 measurements might help identify patients most likely to benefit from specific anti-inflammatory interventions .

• B cell-targeted therapies: The identification of B cells as a major source of IL-38 suggests that therapies targeting B cells might have unanticipated effects on IL-38 levels and anti-inflammatory pathways that should be considered in their development .

What novel methodologies might advance our understanding of IL1F10 biology?

Several methodological approaches could significantly advance IL1F10 research:

• Single-cell analysis: Single-cell RNA sequencing of B cell populations could help identify the specific B cell subsets responsible for IL-38 production and the factors regulating this production.

• Tissue-specific expression studies: More comprehensive analysis of IL-38 expression across different tissues could clarify the relative contributions of various cellular sources to circulating and local IL-38 levels.

• Genetic association studies: Expanded genome-wide association studies focused on IL1F10 genetic variants and their associations with inflammatory and autoimmune conditions could provide insights into IL-38's role in disease susceptibility.

• Longitudinal studies in at-risk populations: Prospective studies measuring IL-38 levels in subjects at risk for cardiovascular events could establish its value as a predictive biomarker.

• Receptor binding and signaling analysis: More detailed characterization of IL-38's interactions with IL-36R, IL-1R9, and potentially other receptors would clarify its molecular mechanisms of action.

• Therapeutic trials: Early-phase clinical trials of recombinant IL-38 in inflammatory conditions could establish proof-of-concept for its therapeutic utility .