INTERLEUKIN-1 FAMILY: LIGANDS & RECEPTORS

• Introduction
• Novel IL-1 Ligands
• References

Introduction

The term IL-1 is generally used to describe IL-1 alpha and IL-1 beta, both of which exercise the same biological effects. Along with IL-1ra and IL-18, these molecules play important roles in both innate and adaptive immunity.

Figure 1. Schematic representation of phylogenetic relationship of IL-1 family members.8,14

Although IL-1 is considered a prototypical proinflammatory cytokine, the functions of IL-1 are not restricted to inflammation. IL-1 also plays a key role in many other biological functions such as hematopoiesis, fever, appetite control and bone metabolism, among others. The effects of IL-1 are exerted via binding specific cell surface receptors. The first IL-1 receptor was described in 1988, but it was not until seven years later that the accessory molecule IL-1RAcP was characterized as a signal transducing subunit for the IL-1 receptor complex. Since this time, the IL-1 family of ligands and receptors has expanded significantly. The following mini-review will briefly highlight the new additions to this family and also present the unified nomenclature that has been proposed for both the IL-1 ligands and receptors (please refer to references 1-4 for additional reviews on IL-1 ligands and receptors).

Novel IL-1 Ligands

Until recently, there were four members of the IL-1 ligand family: IL-1 alpha, IL-1 beta, IL-1ra and IL-18. Six additional members of this family have since been described based on conservation of amino acid (aa) sequence, identity of gene structure and three- dimensional structure. All of the new genes map to the region of chromosome 2 between the IL-1 beta and IL-1ra loci,³ thus suggesting that each of the new IL-1 family members arose from a common ancestral gene that later became duplicated (Figure 1). Each gene codes for a protein that contains a single structural domain formed from 12 beta strands connected by loop regions arranged in a beta-trefoil structure. Similar to IL-1 beta and IL-1ra, the new IL-1 family members differ most from each other within these loop regions. As with so many cytokines, the novel IL-1 family members have been described by several groups using their own nomenclature, thus resulting in a number of different names for the same molecule. Table 1 presents a simplified nomenclature that has been proposed for the IL-1 family ligands.⁵ The numeric order reflects the date of publication for each gene. The biological activities of the new IL-1 ligands have not been clearly identified as of yet. Further studies need to be performed in order to identify whether they are agonists or antagonists, which receptors they bind, and if they possess any of the characteristic activities so far ascribed to IL-1 alpha and IL-1 beta.

IL-1F5

IL-1F5^6-11 contains 155 aa, lacks a signal sequence and glycosylation sites, and produces a 17 kDa band upon immunoprecipitation. IL-1F5 is highly expressed in keratinocytes, psoriatic skin, placenta, uterus, brain, thymus, heart, kidney, monocytes, B cells and dendritic cells. In binding studies, IL-1F5 does not co-precipitate with IL-1R1, R3, R4, R5, R6, or R7 Fc fusions.⁸ The degree of sequence similarity between IL-1F5 and IL-1ra indicates that it may be a novel IL-1 receptor antagonist. Although the similarity with IL-1ra over the entire sequence is 52%, it is only 24% within the loop regions. Molecular modeling predicts that the loop structures (between strands 4 and 5 and between strands 7 and 8) are important determinants of the agonist properties of IL-1. Without functional studies and based on structure alone, however, it is very difficult to predict whether IL-1F5 has agonist or antagonist functions. Functional studies have focused on the inflammatory properties of IL-1 by using T cells, fibroblasts and endothelial cells to determine if IL-1F5 can mimic or antagonize IL-1 activity. So far, none have provided a definitive answer. Either IL-1F5 is an antagonist for an as yet untested agonist, or the IL-1F5 receptor(s) are not present on the cell types tested to date.

Table 1.

IL-1F6

This new member of the IL-1 family has been described by only one group.⁸ It is expressed in spleen, lymph node, tonsil, bone marrow, monocytes, B cells and T cells. IL-1F6 is unique, as it is the only new IL-1 family member synthesized by T cells. In binding studies, IL-1F6 does not co-precipitate with IL-1R1, R3, R4, R5, R6, or R7 Fc fusions.⁸ IL-1F6 is most closely related to IL-1F7 and IL-1F8.⁸

IL-1F7

IL-1F7 is expressed in most tissues, with relatively high levels in testis, thymus and uterus. IL-1F7 is one of the first examples of a mature cytokine of the IL-1 family to form homodimers.¹² It is also the only novel IL-1 family member to possess a pro domain¹⁰ (similar to IL-18, IL-1 alpha and IL-1 beta), yet it has more aa identity with IL-1ra than any of the agonists. Both IL-1 betaand IL-18 are cleaved by caspase-1 to generate the mature agonist form. Caspase-1 and, to a lesser extent, caspase-4 cleave pro-IL-1F7.¹² It is difficult to speculate whether this molecule is an agonist or antagonist, however, without functional data. Pan et al.¹³ have shown that IL-1F7 binds IL-18a (IL-1R5), although this binding did not elicit a functional response. Additionally, Kumar et al.12 have demonstrated both pro and mature forms of IL-1F7 bind IL-18a , but not IL-1 R1 or IL-1 R4. Unlike IL-18, IL-1F7 does not induce IFN-gamma secretion in KG-1 cells and cells and neither the pro or mature form of IL-1F7 binds IL-18BP.¹²

IL-1F8

IL-1F8 has been cloned by two groups.^8,10 Like IL-1 and IL-18, the IL-1F8 protein lacks a hydrophobic leader sequence, but unlike these molecules, it also lacks a pro domain.⁸ It is expressed in tonsil, bone marrow, heart, placenta, lung, testis, colon, monocytes and B cells. IL-1F8 is most closely related to IL-1F6 based on aa sequence alignment.⁸ A receptor for IL-1F8 remains to be identified.

IL-1F9

Keratinocytes are the main producers of IL-1F9. Production is greatly increased by stimulation with IL-1 beta and TNF-alpha, but not IL-4 or IFN-gamma.⁹ In contrast, Kumar et al.¹⁰ demonstrated an up- regulation of keratinocyte IL-1F9 by IFN-gamma. IL-1F9 is also up-regulated in models of contact hypersensitivity infection with HSV-1¹⁰ and in psoriasis,⁹ suggesting that IL-1F9 plays a role in immunity and inflammation of the skin. IL-1F9 does not bind IL-1R1, IL-1R4 or IL-1 R5, but induces NF-kappaB activation in IL-1R6 transfected cells.⁹ The addition of IL-1F5 to this reaction inhibits the effect, suggesting IL-F9 and IL-1F5 are the agonist and antagonist (respectively) for IL-1R6. Although IL-1F9 does not contain a hydrophobic leader sequence or a pro form, it is secreted as a 20 kDa molecule.

IL-1F10

Although IL-1F10 binds to soluble IL-1R1 (albeit with a lower affinity than IL-1 beta or IL-1ra), the functional significance of this is unclear. Accessory proteins may affect the binding affinity of IL-1F10 to sIL-1R1. Similar to other novel IL-1 family members, IL-1F10 is expressed in skin, but it is also expressed on activated B cells in tonsil. The DNA sequence demonstrates the conserved intron placement of the IL-1 family genes and corresponds to a 152 aa protein with a predicted molecular mass of 17 kDa.¹⁴

IL-1 Receptors

An extended IL-1 receptor (IL-1 R) family, currently comprising at least 9 family members, regulates IL-1 activity (see Table 1).⁹ All family members possess three immunoglobulin (Ig)-like domains in their extracellular region, while SIGIRR (single Ig domain-containing IL-1 R-related molecule), an IL-1 R family subtype, contains only one Ig domain.⁴ With the exception of IL-1 R2, all family members also have an intracellular TIR (Toll-like receptor/IL-1 R signaling) domain.⁴ A noticeably unique feature of IL-1 R8, IL-1 R9 and SIGIRR is the addition of a carboxy-terminal tail.⁴ Six of the IL-1 R family members (IL-1 R1, R2, R4, R5, R6 and R7) are clustered and localized to chromosome 2.⁴ IL-1 R3 is located on chromosome 3, SIGIRR is located on chromosome 11, and IL-1 R8 and IL-1 R9 are located on the X chromosome.⁴

IL-1 R1

IL-1 exerts its biological effects via binding a complex containing the type I IL-1R (IL-1RI, IL-1 R1). The two amino terminal Ig-like domains of IL-1 R1 are held rigid by disulfide bonds and the Ig-like domain nearest the cell surface is on a more flexible tether. The interaction of IL-1 R1 with IL-1 beta appears to occur via IL-1 R1 wrapping itself around the ligand and interacting with it in two places, a large contact area on the first two Ig domains and a smaller contact area on the membrane proximal domain. IL-1 R3 is then recruited to form the active, signaling complex. IL-1ra interacts with IL-1 R1 similarly, but this complex fails to recruit IL-1 R3.⁴

IL-1 R2

Although structurally similar to IL-1 R1, IL-1 R2 differs markedly within its cytoplasmic domain. The short cytoplasmic tail of IL-1R2 does not contain the TIR domain found within other IL-1 receptors. IL-1 R2 can be enzymatically cleaved at the cell surface to release a soluble IL-1 binding protein that regulates the activity of IL-1.¹⁵ Once solubilized, IL-1 R2 also demonstrates 2000-fold less affinity for IL-1ra, consistent with the idea that IL-1ra and soluble IL-1 R2 may cooperate in regulation of IL-1 activity.¹⁶

IL-1 R3

IL-1 R3 (IL-1R AcP) has no affinity on its own for either IL-1 alpha or IL-1 beta. It is recruited to the IL-1/IL-1 R1 complex, binds with high affinity and subsequently induces signal transduction. A soluble version of this receptor can be derived from alternatively spliced mRNA.¹⁷ Although the physiological role of this moiety is unclear, it may serve to block IL-1 signaling by binding and therefore blocking membrane-bound IL-1 R3 access to the IL-1/IL-1R1 membrane complex.¹⁸

IL-1 R4

Also known as ST2, IL-1 R4 does not bind any of the known IL-1 family ligands, but serves as a Th2 cell-specific marker that mediates Th2 effector functions.¹⁹ It is a primary response gene induced by growth stimulation. Alternative splicing generates two variants; a soluble protein (ST2) and a type I membrane bound protein (ST2L). IL-1 R4 expression in lymph node-negative breast cancer patients is a predictor of relapse-free survival.²⁰ Soluble IL-1 R4 can be found in serum. In severe asthma attacks, serum levels of soluble IL-1 R4 are elevated.²¹

IL-1 R5

Given the close relationship of IL-18 with IL-1, it is not surprising that the IL-18 receptor complex is remarkably similar to the IL-1 receptor complex (see reference 4 for a review). IL-1R5 (previously known as IL-1 Rrp or the IL-18 R alpha chain) binds IL-18 with relatively low affinity, then recruits IL-1 R7 (previously known as AcPL or the IL-18 R beta chain) to form the active signaling complex. IL-1 and IL-18 appear to signal using the same adapter molecules of MyD88, TRAF6 and IRAK. IL-1 R5 also binds IL-1F7.

IL-1 R6

IL-1 R6 binds IL-1F9 and mediates NF-?B activation.¹⁰ It also binds IL-1F5, an antagonist of NF-kB activation. IL-1 R6 is expressed in lung epithelium, brain vasculature, kidney, testes, monocytes, keratinocytes, fibroblasts and endothelial cells. Expression of this receptor and its ligands is increased in psoriatic lesions, suggesting they may be involved in local inflammatory responses.

IL-1 R7

This molecule, originally named AcPL, is the signaling component of the IL-18 R complex (see reference 4 for a review). Recruitment of IL-1 R7 can increase the low affinity binding of IL-18 to IL-1 R5. Both chains are required for IL-18 signal transduction.

IL-1 R8

IL-1 R8 is expressed in brain structures involved in the hippocampal memory system and is involved in a non-specific form of X-linked mental retardation, thus suggesting a role for this receptor in cognitive functions.²²

IL-1 R9

This receptor is most closely related to IL-1 R8; both genes are located on the X chromosome and the proteins share approximately 64% aa identity.²³ They also share the feature of large intron size, thus indicating the genes span large areas of the chromosome. IL-1 R9 is predominantly expressed in the skin and liver. A ligand for IL-1 R9, however, has not been identified to date.

SIGIRR

SIGIRR (Single Ig Domain containing IL-1 Receptor-Related molecule) represents a subtype of the IL-1 receptor family, due to it lacking the usual three Ig domains within its extracellular portion.²⁴ The intracellular C-terminus contains an additional 100 aa beyond the TIR domain, which is also found in the cytoplasmic tails of IL-1 R8, IL-1 R9 and other Toll-like receptor family members. SIGIRR is widely expressed and present in all cells and tissues tested thus far. The potential ligand(s) and associated signaling mechanism(s) for this receptor are unknown at this time. The gene for SIGIRR maps to chromosome 11 and, as such, is not localized with other members of the IL-1R family.

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