IL 17B Human

What is the structural relationship between IL-17B and other IL-17 family members?

IL-17B belongs to the six-member IL-17 cytokine family (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E/IL-25, and IL-17F). While all family members share some structural homology, IL-17B shows distinct receptor binding preferences that influence its functional outcomes. Cytokine signals from IL-17 family members propagate via heterodimeric complexes composed of IL-17R subunits, with IL-17RA serving as a common subunit for multiple family members . Structure-function studies indicate that specificity is determined by high-affinity interactions between the cytokine and a second receptor subunit, with IL-17B utilizing both IL-17RA and IL-17RB .

What are the primary cellular sources of IL-17B in humans?

Unlike IL-17A (primarily produced by Th17 cells) and IL-25 (epithelial cells), IL-17B exhibits a distinct tissue expression pattern. Research indicates that IL-17B is expressed in various tissues including pancreas, small intestine, and stomach, suggesting a potential role in mucosal immunity. The cell-specific expression patterns of IL-17B in humans remain partially characterized, representing an important area for future investigation. Current evidence suggests that IL-17B expression is restricted to specific tissue microenvironments, which may explain its context-dependent immunological effects .

What methodological approaches are recommended for measuring IL-17B protein levels in human samples?

For accurate quantification of human IL-17B protein levels, sandwich immunoassay techniques provide reliable results. The methodology involves:

• Using plates pre-coated with IL-17B-specific capture antibodies

• Adding the biological sample and detection antibodies conjugated with electrochemiluminescent labels (e.g., MSD SULFO-TAG)

• Following a series of incubation and wash steps

• Using a SECTOR Imager to measure emitted light intensity

A typical protocol includes:

• Sample dilution (2-fold in appropriate diluent)

• Blocking step (1 hour with Blocker A solution)

• Sample incubation (2 hours)

• Detection antibody incubation (2 hours)

• Final washing and reading steps

This approach allows detection of IL-17B with high sensitivity and specificity while minimizing cross-reactivity with other IL-17 family members .

How does IL-17B functionally compare to IL-25 in regulating human type 2 immune responses?

When designing experiments to compare these cytokines, researchers should:

• Utilize purified recombinant proteins at equimolar concentrations

• Include appropriate receptor-blocking antibodies to confirm specificity

• Assess dose-response relationships across multiple cell types

• Examine temporal dynamics of signaling activation

• Consider combination studies with other cytokines (particularly IL-33) to assess context-dependent effects

These approaches will help distinguish the unique contributions of IL-17B to type 2 immune regulation beyond those mediated by IL-25 .

What explains the contradictory pro- and anti-inflammatory effects reported for IL-17B in different experimental systems?

The seemingly contradictory roles of IL-17B (both pro- and anti-inflammatory) likely reflect context-dependent functions influenced by:

• Tissue-specific factors: IL-17B functions may vary between tissue microenvironments due to differential expression of receptor components and downstream signaling molecules.

• Species differences: Reports from rodent models show divergent effects compared to human systems, suggesting important evolutionary divergence in IL-17B biology.

• Concentration-dependent effects: IL-17B stimulates significant induction of TNF-α and IL-1β in monocytes but limits production of IL-6, at least in vitro . This selective cytokine modulation suggests concentration-dependent thresholds for various inflammatory pathways.

• Differential receptor expression: Varying expression levels of IL-17RA and IL-17RB across cell types may contribute to contradictory outcomes.

• Opposing angiogenic effects: Unlike IL-17A which promotes endothelial cell migration and tubule formation, IL-17B exhibits antiangiogenic properties, inhibiting these processes with minimal impact on endothelial cell growth .

When investigating these contradictions, researchers should carefully control for these variables and consider employing systems biology approaches to map the complete signaling network across different cellular contexts .

What evidence supports a causal role for IL-17B in inflammatory bowel disease pathogenesis?

Mendelian randomization (MR) studies provide compelling genetic evidence for IL-17B's causal role in inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). Recent two-sample MR analyses demonstrated:

• IL-17B is significantly associated with increased risk of UC (OR: 1.26, 95% CI, 1.09-1.46, P < 0.01) but not Crohn's disease (CD) .

• This association persists after correction for outliers using MR-PRESSO analysis, supporting the robustness of these findings .

• Multivariable MR analyses suggest that IL-17B's effects on UC may be mediated primarily through IL-17RB, revealing a potential mechanistic pathway .

• Power statistics for the effect of IL-17B on UC were initially 0.67 but improved to 0.93 when using more relaxed criteria for selecting instrumental variables, supporting the reliability of this causal relationship .

These findings contrast with the causal effects of other IL-17 family members: IL-17C and IL-17RC showed significant associations with CD but not UC, while IL-17E and IL-17RB, like IL-17B, were associated with UC risk . This pattern suggests distinct contributions of different IL-17 cytokines to IBD subtypes, with IL-17B specifically linked to UC pathogenesis.

What methodological considerations are crucial when designing experiments to investigate IL-17B signaling cross-talk with other cytokine pathways?

When investigating IL-17B's signaling cross-talk with other cytokine pathways, researchers should implement the following methodological approaches:

• Sequential stimulation designs: Pre-treat cells with IL-17B followed by stimulation with other cytokines (particularly IL-33) at varying time intervals to assess priming effects versus co-stimulation.

• Receptor expression profiling: Quantify IL-17RA and IL-17RB expression levels before and after cytokine stimulation to identify potential receptor modulation mechanisms.

• Pathway inhibitor studies: Use specific inhibitors of downstream signaling molecules to dissect shared versus distinct pathways between IL-17B and other cytokines.

• Genetic approaches: Employ CRISPR-Cas9 to create receptor subunit knockouts or signaling molecule deletions to determine pathway dependencies.

• Transcriptomic and proteomic analyses: Implement time-course omics approaches to map global changes following IL-17B stimulation alone or in combination with other cytokines.

• In vitro versus ex vivo comparisons: Validate findings from cell lines in primary human cells to ensure physiological relevance.

Evidence shows that IL-17B can augment IL-33-driven type 2 responses, indicating significant cross-talk between these pathways . This interaction may be particularly relevant in allergic and parasitic conditions where type 2 immune responses predominate.

How do genetic variants affecting IL-17B expression or function impact human disease susceptibility?

Genetic studies employing Mendelian randomization approaches have revealed important insights into how IL-17B genetic variants influence disease susceptibility:

• Protein quantitative trait loci (pQTL) affecting IL-17B levels show causal associations with inflammatory bowel disease, particularly ulcerative colitis (UC) .

• The genetic instrumental variables selected for IL-17B demonstrated robust F statistics (>20), indicating strong genetic instruments free from weak instrument bias .

• Genetic variants affecting IL-17B appear to have disease-specific effects, influencing UC but not Crohn's disease, suggesting pathway specificity in different IBD subtypes .

• Multivariable MR analyses indicate that genetic effects of IL-17B on UC may operate primarily through modulation of IL-17RB functionality .

When investigating such genetic associations, researchers should:

• Consider pathway-level analyses rather than focusing solely on individual genes

• Account for potential pleiotropic effects of genetic variants

• Validate findings across different population cohorts

• Integrate genomic data with functional studies to establish biological mechanisms

These genetic insights provide a foundation for personalized medicine approaches targeting the IL-17B pathway in susceptible individuals .

What are the optimal experimental controls when studying IL-17B in human immunological research?

When designing rigorous experiments to study IL-17B in human immunology, researchers should implement the following control strategies:

• Receptor specificity controls:

  • Include IL-17RA and IL-17RB blocking antibodies separately and in combination

  • Use receptor-deficient cell lines (CRISPR-modified) as negative controls

  • Compare responses to other IL-17 family members that share receptor components (e.g., IL-25)

• Reagent validation controls:

  • Confirm recombinant IL-17B bioactivity using established bioassays

  • Test multiple commercial sources of IL-17B to rule out source-specific effects

  • Include heat-inactivated IL-17B to control for potential contaminants

• Cell-type specific controls:

  • Compare responses in receptor-expressing versus non-expressing cells

  • Include positive control stimuli known to activate similar pathways

  • Use dose-response studies to establish specificity thresholds

• Genetic controls:

  • When using genetic approaches to study IL-17B effects, include appropriate control loci

  • For Mendelian randomization studies, test for pleiotropy using MR-Egger regression and MR-PRESSO approaches

  • Perform leave-one-out sensitivity analyses to ensure results aren't driven by individual genetic variants

These control strategies will enhance experimental rigor and reproducibility when investigating IL-17B biology .

How can researchers address discrepancies between in vitro and in vivo findings related to IL-17B function?

Addressing discrepancies between in vitro and in vivo IL-17B findings requires systematic methodological approaches:

• Physiological concentration ranges:

  • Determine physiological IL-17B concentrations in relevant tissues

  • Conduct dose-response experiments spanning sub-physiological to supra-physiological ranges

  • Compare in vitro concentrations to those achievable in vivo

• Microenvironmental context:

  • Develop complex co-culture systems that better recapitulate tissue microenvironments

  • Incorporate extracellular matrix components in 3D culture systems

  • Consider oxygen tension differences between standard culture conditions and in vivo settings

• Temporal dynamics:

  • Implement time-course experiments rather than single time-point measurements

  • Use inducible expression systems to model acute versus chronic exposure

  • Consider pulsatile versus continuous exposure paradigms

• Translational validation approaches:

  • Validate key in vitro findings using ex vivo human tissue samples

  • Employ humanized mouse models where appropriate

  • Correlate experimental findings with human genetic association data

• Systems biology integration:

  • Combine experimental data with computational modeling to predict context-dependent outcomes

  • Account for feedback loops and compensatory mechanisms present in vivo

  • Integrate multi-omic datasets to comprehensively map response networks

These approaches help reconcile apparently contradictory findings regarding IL-17B's pro- versus anti-inflammatory properties in different experimental systems .

What are the most promising therapeutic applications targeting the IL-17B pathway in human disease?

Based on current evidence, the most promising therapeutic applications targeting the IL-17B pathway include:

• Ulcerative colitis interventions: Mendelian randomization studies provide strong genetic evidence for IL-17B's causal role in UC but not CD, suggesting potential for UC-specific therapies . Therapeutic approaches could include:

  • Monoclonal antibodies targeting IL-17B

  • Small molecule inhibitors of IL-17B/IL-17RB interaction

  • Receptor antagonists blocking IL-17RB signaling

• Type 2 inflammatory disorders: Given IL-17B's role in promoting type 2 cytokine secretion from innate lymphoid cells and Th2 cells , therapeutic targeting might benefit:

  • Allergic asthma

  • Atopic dermatitis

  • Eosinophilic esophagitis

• Combined pathway blockade: The finding that IL-17B can augment IL-33-driven type 2 responses suggests potential benefit from dual pathway inhibition in certain inflammatory contexts.

• Targeted angiogenesis modulation: IL-17B's antiangiogenic properties could be exploited in conditions where aberrant angiogenesis contributes to pathology.

Future therapeutic development should consider the tissue-specific and context-dependent functions of IL-17B to maximize efficacy while minimizing unintended consequences .

What are the critical knowledge gaps that should be prioritized in future IL-17B research?

Despite significant advances, several critical knowledge gaps remain in our understanding of human IL-17B biology:

• Cell-specific expression patterns:

  • Which human cell populations produce IL-17B under physiological and pathological conditions?

  • How is IL-17B expression regulated at transcriptional and post-transcriptional levels?

  • What are the stimuli that induce IL-17B production in different cellular contexts?

• Signaling mechanisms:

  • What are the precise downstream signaling pathways activated by IL-17B in different cell types?

  • How does IL-17B signaling interact with other inflammatory pathways?

  • What explains the context-dependent pro- versus anti-inflammatory effects?

• Receptor biology:

  • How do IL-17RA and IL-17RB cooperate to transduce IL-17B-specific signals?

  • Are there additional co-receptors or accessory molecules involved?

  • What regulates receptor expression and turnover in response to ligand binding?

• Disease relevance:

  • Beyond IBD, what other human diseases involve dysregulated IL-17B signaling?

  • How do environmental factors modulate IL-17B expression and function?

  • What is IL-17B's role in host-microbiome interactions?

• Biomarker potential:

  • Can circulating IL-17B levels serve as biomarkers for disease activity or treatment response?

  • Are there genetic polymorphisms in the IL-17B pathway that predict disease susceptibility or severity?

Addressing these knowledge gaps through systematic research will advance both basic understanding and translational applications of IL-17B biology .