Receptor Density Is Key to the Alpha2/Beta Interferon Differential Activities

Abstract

Multiple type I interferons (IFN-␣A persistent question in the field of helically bundled cytokines concerns the molecular basis of intracellular signal activation following binding to cognate cell surface receptors. Typically, cytokine-induced dimerization of the receptor subunits is thought to trigger catalytic transactivation of the associated Jak tyrosine kinases. Phosphorylation of critical receptor tyrosine motifs by the activated Jak proteins allows recruitment and activation of downstream Stat effectors (25,34). A clear distinction can be made between the short homodimeric Jak2-activating receptors, such as the growth hormone or the erythropoietin receptors, and the more complex heteromeric receptors. Among these latter is the type I interferon (IFN) receptor, a prototypic class 2 receptor, made of two subunits, each associated with a different Jak enzyme (29). IFNAR2 contains extracellularly two fibronectin III domains forming a well-defined cytokine binding module. The cytoplasmic region of IFNAR2 is 250 amino acids long, interacts with Jak1, and contains two principal Tyr-based Stat recruitment motifs (24,35). IFNAR1 is made of a large ectodomain of four fibronectin III domains, not all involved in ligand binding, and a 100-amino-acid-long cytoplasmic region complexed with Tyk2 and subjected to ligand-induced ubiquitination driving receptor proteolysis (13,14).A large array of IFNs (over a dozen ␣ subtypes and one ␤ subtype) bind to this ubiquitously expressed receptor complex to induce rapid gene expression programs that elicit measurable antiviral responses and cell growth inhibition as well as cell context-specific functional changes (4, 31). Several studies have reported on differential activities of type I IFNs, but no unique function has ever been attributed to a given subtype (see references in reference 29). Thus, a differential can be defined as a lack of correlation between two specific activities. For instance, depending on the cell system, IFN-␣2 and IFN-␤ can exhibit equivalent antiproliferative potency or over a 100-fold difference in antiproliferative potency and nearly equipotency in antiviral activity. Since no overt differences are observed in the structure or stoichiometry of the ligand-receptor complex formed with different subtypes, the concordant view points to the way each IFN subtype engages the available receptors. Indeed, kinetic measurements of the interaction of IFN-␣2 and IFN-␤ with receptor ectodomains have shown substantial differences. IFNAR2 represents the high-affinity subunit, toward which IFN-␣2 exhibits nanomolar binding affinity and IFN-␤ exhibits ϳ100 pM binding affinity. Conversely, IFNAR1 is the low-affinity subunit, toward which IFN-␣2 exhibits micromolar affinity and IFN-␤ ϳ50 nM affinity (19,22). The contribution of the individual and combined affinities on ternary complex formation by either IFN subtype have been thoroughly studied (10,26). However, how these dynamic parameters influence receptor function and translate into activation of Jak, recruitment of...

IFN‐α subtypes: distinct biological activities in anti‐viral therapy

“…The authors show that murine IFN-a1, IFN-a2, IFN-a4 and IFN-a5 induced a tyrosine phosphorylation of STAT1, whereas tyrosine phosphorylation of STAT3 was only induced in response to IFN-a1. For IFN-a subtypes, it was also suggested that the quantity of the receptor on the surface of a specific target cell correlates with different biological activities of the subtypes indicating that abundant IFNAR expression might compensate for the weak binding affinity of certain IFN-a subtypes (Moraga et al, 2009). In addition to the varying binding affinities, differences in tissue-specific expression of the IFN-a subtypes or the receptor may influence biological activities.…”

Relationship between interleukin-1 type 1 and 2 receptor gene polymorphisms and the expression level of membrane-bound receptors

“…36 It is known that the activity of specific mediators (i.e., cytokines) depends on the density of their receptor on cells. 21,22 Thus, it may be assumed that individuals with the above SNP genotypes in the IL1R1 gene may be more susceptible to the action of IL-1 due to their increased expression of the signal transductioncapable IL-1 type 1 receptors. Our study demonstrated that individuals with the homozygous TT genotype in SNP rs2234650:C.T in the IL1R1 gene have a lower percentage of cells expressing IL1R1 on the intact CD14 1 monocyte population.…”

“…It is known that differences in expression of cytokine receptors can be caused by gene polymorphisms. 20,22 Polymorphisms in cytokine genes and their receptors have been the focus of intensive investigations for the last 15 years. Prior studies have found associations of specific polymorphisms with the predisposition to certain diseases, with their clinical course and outcome, as well as with appropriate therapies.…”

“…It is therefore important to know not only the percentage of cells expressing these membrane-bound receptors but also the density of these receptors on the cells. 21,22 Differing expression levels of IL-1 receptors type 1 and 2 have previously been shown in T-lymphocyte populations. 23 Moreover, prior studies have examined the association of polymorphisms in the IL-1 receptor genes with different diseases.…”

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

“…Both the IFN−αs and IFN−βs bind a single heterodimeric receptor (IFNAR composed of both IFNAR1 and IFNAR2 subunits), expressed by almost all cells in human and mouse [20][21][22][23]. Furthermore, levels of IFNAR2 in the liver have been shown to be a predictive biomarker of response to IFN treatment in chronic hepatitis C patients [24].…”