IL 31 Human

What is IL-31 and how is it structurally characterized?

IL-31 is a member of the gp130/IL-6 cytokine family, predominantly produced by activated CD4+ T cells (particularly Th2 cells), mast cells, macrophages, dendritic cells, eosinophils, and basophils. Unlike other members of this family, IL-31 does not engage gp130 directly .

Structurally, IL-31 is characterized as a short-chain cytokine with a four α-helix bundle structure. The human IL-31 gene is located on chromosome 12q24.31, encoding a 164 amino acid precursor that yields a 141 amino acid mature polypeptide . Despite sharing structural similarities with other four-helical bundle cytokines, IL-31 has no apparent sequence homology to these proteins .

Human and mouse IL-31 share only 31% amino acid identity, and there is no cross-species activity – mouse IL-31 cannot interact with human IL-31 receptors and vice versa . This species specificity must be considered when designing experimental models.

What receptor complex mediates IL-31 signaling?

IL-31 signals through a heterodimeric receptor complex consisting of:

• IL-31 Receptor A (IL-31RA): A unique gp130-like receptor chain specific to IL-31

• Oncostatin M Receptor beta (OSMRβ): A receptor subunit shared with oncostatin M (OSM)

The functional activity of IL-31 depends on the expression of both receptor components, as blocking either receptor type decreases IL-31-mediated cellular responses . These receptors are expressed on multiple cell types, including T cells, dorsal root ganglia (DRG) neurons, keratinocytes, dendritic cells, eosinophils, basophils, and macrophages .

The OSMRβ component increases IL-31 binding affinity to IL-31RA, facilitating optimal signal transduction . This heterodimeric receptor arrangement allows IL-31 to exert effects on both immune cells and non-immune cells, explaining its diverse biological functions.

What signaling pathways are activated by IL-31?

Binding of IL-31 to its heterodimeric receptor complex activates multiple intracellular signaling pathways:

• JAK/STAT pathway: The primary signaling cascade activated by IL-31, leading to activation of STAT1, STAT3, and STAT5 transcription factors

• PI3K/AKT pathway: Contributes to cell survival, proliferation signals, and modulation of inflammatory gene expression

• MAPK pathway: Activates ERK, p38, and JNK components, regulating cellular responses including proliferation, differentiation, and cytokine production

The relative engagement of these pathways varies depending on cell type and physiological context. For example, in sensory neurons, IL-31 signaling induces a transcriptional program leading to nerve elongation and branching, whereas in immune cells, the same signaling pathways may promote cytokine production and inflammatory responses .

How does IL-31 contribute to pruritus pathophysiology?

IL-31 serves as a crucial mediator in the neuro-immune axis linking immune activation with pruritus development through multiple mechanisms:

• Direct neuronal activation: IL-31 receptors are expressed on dorsal root ganglia (DRG) neurons that mediate itch sensation . IL-31 upregulates IL-31RA expression in these neurons, creating a feed-forward mechanism that enhances sensitivity to the cytokine .

• Neuronal remodeling: IL-31 induces a transcriptional program in sensory neurons leading to nerve elongation and branching, creating extensive axonal networks in the superficial epidermis with expanded receptive fields for itch stimuli .

• Keratinocyte-neuron communication: IL-31 stimulates keratinocytes to produce leukotriene LTB4, which acts on sensory neurons to amplify itch signaling, creating dual pathways (direct neuronal activation and indirect via keratinocytes) .

• Temporal characteristics: IL-31-mediated pruritus has a later onset compared to histamine-mediated pruritus, explaining why antihistamines are often ineffective in IL-31-dominant conditions .

• Sensitization mechanisms: IL-31 contributes to increased sensitivity to minimal stimuli in conditions like atopic dermatitis, potentially maintaining itch sensation even after the initial inflammatory trigger resolves .

These mechanisms explain why IL-31-mediated pruritus can be particularly severe and persistent in conditions such as atopic dermatitis and bullous pemphigoid.

What diseases show significant IL-31 involvement?

IL-31 has been implicated in various disease states, with strongest evidence for:

Atopic Dermatitis (AD):

• IL-31 is a major promoter of pruritus and scratching behavior

• Promotes epidermal cell proliferation and skin thickening via remodeling during chronic Th1-mediated phase

• IL-31 levels correlate with disease chronicity and pruritus severity

Bullous Pemphigoid (BP):

• Eosinophils are major sources of IL-31 in this condition

• IL-31 levels correlate with disease activity and pruritus intensity

Mastocytosis:

• Increased IL-31 levels relating to disease severity, serum tryptase levels, and percentage of bone marrow infiltration by mast cells

• Mast cells are the main source of IL-31 in both skin and bone marrow

Allergic Respiratory Diseases:

• IL-31 is implicated in allergic rhinitis and asthma

• Produced by Th2 clones, eosinophils, and mast cells involved in allergic airway inflammation

• IL-4 promotes IL-31 production through autocrine mechanisms in these conditions

How do Th2 cytokines regulate IL-31 expression and function?

IL-31 functions within a complex cytokine network with bidirectional relationships to other Th2 cytokines:

IL-4/IL-13 Interactions:

• IL-4 stimulates Th1 clones to express IL-31 through autocrine mechanisms

• IL-4 and IL-13 increase IL-31RA expression on macrophages through STAT6 signaling pathway

• Macrophages stimulated with IL-4 and IL-13 show increased IL-31RA expression, which can be blocked by antibodies against IL-4R

• IL-31 can enhance production of IL-4 and IL-13 from basophils, creating a positive feedback loop

Microenvironmental Factors:

• The variety of IL-31 expression depends on the microenvironment, with factors such as exposure to allergens, pathogens, and UV radiation modifying production by immune and non-immune cells

• In allergic asthma models, Th2 cytokines serve as main triggers of IL-31RA expression and play crucial roles in Th2-mediated IL-31/IL-31RA connections

This complex cytokine network creates feedback loops that can amplify and sustain Th2-mediated inflammation, establishing a self-perpetuating cycle of inflammation and pruritus in conditions like atopic dermatitis.

What methodological approaches are optimal for measuring IL-31 in experimental and clinical settings?

Several methodological approaches can be employed to measure IL-31 expression in experimental and clinical samples:

Systemic Level Detection:

• Enzyme-Linked Immunosorbent Assay (ELISA) for quantifying circulating IL-31 levels in serum/plasma

• Multiplex immunoassays for simultaneous detection of IL-31 alongside other cytokines

• Flow cytometry-based cytokine bead arrays for high-throughput analysis

Tissue Analysis:

• Immunohistochemistry to visualize IL-31 localization in tissue sections

• Immunofluorescence for co-localization studies with other markers

• In situ hybridization to detect IL-31 mRNA in tissue sections

Cellular Expression:

• Flow cytometry to identify intracellular IL-31 in specific cell populations

• RT-PCR for IL-31 mRNA quantification

• Western blotting for IL-31 protein detection in cellular extracts

Experimental Considerations:

• When studying IL-31 in tissue samples, multiple complementary techniques should be employed

• Control for cross-reactivity with other cytokines

• Consider appropriate positive controls (e.g., stimulated T cells known to produce IL-31)

• Account for potential degradation of the cytokine in stored samples

• Validate findings using functional assays when possible

What therapeutic approaches target IL-31 signaling?

Several therapeutic strategies targeting IL-31 signaling have emerged:

Direct IL-31 Pathway Targeting:

• Nemolizumab (CIM331): Anti-IL-31 receptor A monoclonal antibody

  • Demonstrated efficacy in clinical trials for atopic dermatitis

  • Shows promising safety profile comparable to other biological drugs

  • Primarily reduces pruritus intensity

Indirect Modulation:

• Omalizumab (anti-IgE): Reduces serum IL-31 levels in chronic spontaneous urticaria

• Dupilumab (anti-IL-4Rα): By blocking IL-4/IL-13 signaling, may indirectly reduce IL-31 production

• JAK inhibitors: Target downstream signaling pathways activated by IL-31

Future Directions:

• Development of new antibodies against IL-31 for both humans and animals

• Bispecific antibodies targeting multiple cytokines in the pruritus pathway

• Combined approaches targeting both IL-31 and its neuronal effects

• Personalized therapy based on IL-31 pathway biomarkers

The search for new therapeutic options is particularly important as treatment for IL-31-mediated conditions "has proven to be prolonged and specific for each patient" .

What experimental models are available for studying IL-31 biology?

Several experimental models can be used to investigate IL-31 biology:

In Vitro Models:

• Primary human cell cultures (T cells, keratinocytes, sensory neurons)

• Co-culture systems (e.g., keratinocytes with sensory neurons)

• Human cell lines expressing IL-31 receptors

• Reporter cell lines measuring IL-31-induced activation of specific signaling pathways

Transgenic Mouse Models:

• IL-31 overexpressing mice (develop severe pruritus, alopecia, and skin lesions)

• DOCK8-deficient mice (produce large amounts of IL-31 from CD4+ T cells)

• Transgenic mice with CD4+ T cell-specific deletion of EPAS1 (transcription factor involved in IL-31 induction)

Ex Vivo Human Models:

• Human skin biopsies from patients with IL-31-associated conditions

• Peripheral blood mononuclear cells from patients and healthy controls

• Dorsal root ganglia cultures

Key Experimental Considerations:

• Species differences (31% homology between human and mouse IL-31)

• Lack of cross-species activity between human and mouse IL-31/receptors

• Appropriate controls for each model system

• Physiologically relevant IL-31 concentrations

Researchers should note that mice models have limitations given the species specificity of IL-31, making translational studies challenging.