Recombinant Human Interleukin-1 receptor-like 2 (IL1RL2), partial (Active)

Protein Characteristics and Nomenclature

IL1RL2, also known by several alternative names including CD121b, IL1RB, and Interleukin-1 receptor type 2 (IL-1R-2), functions as a non-signaling receptor for several interleukin-1 family cytokines, including IL1A, IL1B, and IL1RN . The protein exists in both membrane-bound and secreted forms, with distinct functional properties depending on its localization. The membrane-bound form contains a transmembrane domain that anchors it to the cell surface, while the secreted form acts as a soluble decoy in the extracellular environment.

The recombinant form of human IL1RL2 is typically produced as a human fragment protein with expression regions spanning approximately 14-343 amino acids . When produced as an Fc chimera (fusion protein), it has a theoretical molecular weight of approximately 63.1 kDa . The amino acid sequence contains immunoglobulin-like domains in its extracellular portion that are critical for ligand recognition and binding, which contribute to its specificity for IL-1 family cytokines.

Expression and Production Systems

Recombinant IL1RL2 is predominantly expressed in mammalian cell systems to ensure proper folding and post-translational modifications essential for biological activity. HEK293 cells are commonly used as the expression system of choice, capable of producing the protein with greater than 95% purity and endotoxin levels below 1 EU/μg . This high-quality production is crucial for research applications requiring biologically active proteins with minimal contaminants.

The manufacturing process typically involves protein expression followed by multiple purification steps to remove cellular debris and contaminants. The final product is often formulated in a physiologically compatible buffer such as PBS (pH 7.4) and may be lyophilized for extended storage stability . For research applications, the protein is generally characterized by SDS-PAGE to confirm its molecular weight and purity, and functional assays to verify its biological activity, particularly its ability to bind IL-1 family cytokines.

Decoy Receptor Activity

The primary function of IL1RL2 is to act as a decoy receptor that regulates IL-1 signaling pathways. Unlike typical signaling receptors, IL1RL2 competitively binds to IL1B and prevents its interaction with the signaling receptor IL1R1 . By sequestering IL1B, IL1RL2 effectively reduces the concentration of this potent pro-inflammatory cytokine available for receptor activation, thereby dampening inflammatory responses before they can be initiated.

IL1RL2 demonstrates preferential binding to IL1B while showing relatively lower affinity for IL1A and IL1RN . This selective binding profile allows for nuanced regulation of different IL-1 family cytokines, focusing its inhibitory effect on IL1B, which is one of the most potent pro-inflammatory cytokines. This mechanism represents a natural checkpoint in the inflammatory cascade that helps maintain immunological homeostasis without requiring energy-intensive signaling processes.

Complex Formation with Co-receptors

Beyond simple ligand sequestration, IL1RL2 exhibits more sophisticated regulatory behavior through its interaction with the IL-1 receptor accessory protein (IL1RAP). After binding to IL1B, IL1RL2 can non-covalently associate with IL1RAP, forming a non-signaling complex that further modulates cellular responses . This interaction is significant because it diverts IL1RAP from participating in signaling complexes with IL1R1, providing an additional level of control over IL-1 pathway activation.

The secreted form of IL1RL2 demonstrates particularly important regulatory activity in the extracellular environment. When secreted IL1RL2 binds to IL1B, it recruits secreted IL1RAP with high affinity . This complex formation appears to be the dominant mechanism for IL1B neutralization by soluble receptors. The coordinated action of these soluble factors creates an effective buffer system that can rapidly respond to and neutralize excess IL1B, preventing excessive inflammatory signaling that could contribute to tissue damage or chronic inflammation.

Research Tool Applications

Recombinant human IL1RL2 serves as a valuable research tool in immunology and inflammation studies. Its high purity and low endotoxin content make it suitable for sensitive applications including SDS-PAGE analysis, functional ELISAs, and cell-based assays . The protein's consistent quality and defined properties enable researchers to investigate IL-1 signaling pathways, receptor-ligand interactions, and mechanisms of inflammatory regulation with reproducible results.

The biological activity of recombinant IL1RL2 is typically evaluated through its ability to bind human IL-1 family cytokines. With an ED50 (effective dose for 50% response) typically less than 50 μg/ml in functional binding assays, the protein demonstrates reliable activity suitable for quantitative experimental applications . This characteristic makes it valuable for developing screening assays, validating therapeutic candidates, and investigating the fundamental biology of cytokine-receptor interactions.

Functional Studies and Assay Development

In fundamental research, recombinant IL1RL2 enables detailed investigation of cytokine-receptor interactions and their consequences for cellular responses. The protein can be used in binding assays to determine affinity constants, in competition assays to study receptor preferences, and in cell-based systems to examine the biological effects of manipulating IL-1 signaling pathways. These applications contribute significantly to our understanding of basic immunological mechanisms.

For pharmaceutical research and therapeutic development, recombinant IL1RL2 provides a platform for screening potential modulators of IL-1 signaling. By establishing assays that measure IL1RL2 binding to its ligands or its interaction with co-receptors, researchers can identify compounds that might enhance or inhibit these interactions . Such assays represent critical early steps in drug discovery programs targeting IL-1 mediated inflammatory conditions. Additionally, the protein serves as a valuable positive control in assays designed to characterize novel anti-inflammatory agents.

Role in Inflammatory Disorders

The IL-1 signaling system that IL1RL2 helps regulate has been implicated in numerous inflammatory diseases. By controlling IL1B activity, which is a master regulator of inflammation, IL1RL2 may influence the pathogenesis and progression of conditions characterized by dysregulated IL-1 signaling. The protein's natural regulatory role suggests potential therapeutic strategies that could mimic or enhance this function for treating inflammatory disorders.

While the search results don't directly link IL1RL2 to specific diseases, research on the related receptor IL1RL1 provides context for the importance of this receptor family in inflammatory conditions. IL1RL1 has been genetically associated with asthma, particularly asthma with features of T-H2-like inflammation . Given the functional similarities within the receptor family, IL1RL2 may have comparable relevance to inflammatory disorders, though the specific associations require further investigation.

Potential Therapeutic Applications

The natural anti-inflammatory mechanism of IL1RL2—acting as a decoy receptor that captures and neutralizes pro-inflammatory cytokines—provides a biological model for potential therapeutic interventions. Recombinant forms of IL1RL2 or molecules designed to mimic its activity could theoretically be developed as anti-inflammatory agents for conditions characterized by excessive IL-1 signaling, similar to how other recombinant cytokine receptors have been developed as therapeutics.

While not directly addressing IL1RL2, the search results mention research on recombinant human IL-2 (rhIL-2) for correcting NK cell phenotype and function , demonstrating the principle that recombinant cytokine pathway components can have therapeutic applications. This parallel suggests potential avenues for exploring IL1RL2-based therapeutic approaches. The development of such therapies would require extensive preclinical validation followed by clinical trials to establish safety and efficacy in specific disease contexts.

Emerging Research Areas

Several promising research directions could advance our understanding of IL1RL2 biology and applications. These include investigation of its role in additional disease contexts beyond those currently established, development of more sophisticated recombinant forms with enhanced stability or activity, and exploration of structure-based design of mimetic molecules that could recapitulate the protein's regulatory functions in a more targeted manner.

The genetic aspects of IL1RL2 function represent another important area for investigation. Research on IL1RL1 has shown that single nucleotide polymorphisms (SNPs) are associated with receptor expression levels and markers of T-H2-like inflammation . Similar genetic studies of IL1RL2 could reveal important associations with disease susceptibility or therapeutic response, potentially leading to personalized treatment approaches based on individual genetic profiles.

Translational Research Opportunities

Translating basic knowledge about IL1RL2 into clinical applications presents several opportunities. The development of IL1RL2-based therapeutics or molecules that enhance its natural regulatory function could provide new treatment options for inflammatory conditions. Additionally, research into the relationship between IL1RL2 expression or function and disease phenotypes could yield biomarkers for disease stratification or treatment response prediction.

Collaborative research between basic scientists, immunologists, and clinicians will be essential for advancing IL1RL2 from a research tool to a clinically relevant target. Such interdisciplinary approaches could accelerate the discovery of novel therapeutic applications and improve our understanding of how IL1RL2 contributes to inflammatory disease mechanisms. As research technologies continue to advance, our ability to manipulate and study this important regulatory protein will similarly progress, opening new avenues for both basic discovery and therapeutic innovation.