Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

IL-1 Receptor Family

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101687

Synonyms

Historical Background

The family of IL-1 receptors (IL-1R) belongs to the large superfamily of TIR domain-containing receptors, key molecules of innate immunity, which is the fast and non-specific type of immune response to pathogens and other stressful events (Boraschi and Tagliabue 2013; Dinarello 2013). The TIR superfamily encompasses Toll-like receptors (TLR), which are the main sensors of exogenous molecules (in general microbial components) and the IL-1R family, which bind endogenous inflammation-related cytokines.

The two families differ in their extracellular ligand-binding domains, which are different and specific for groups of ligands, with the IL-1R family being immunoglobulin (Ig) domain-bearing receptors, while the TLR family encompasses receptors with a leucine-rich repeat (LRR) domain. On the other hand, receptors of the TIR superfamily are characterized by the presence of a common sequence, the Toll-IL-1 Receptor (TIR) domain, in the intracellular receptor tail, which is responsible for a largely shared signaling pathway.

The Ig domain-bearing receptors include ten members of the IL-1R family and an IL-1R-similar single domain soluble protein, all of which share similar amino acid sequence, gene structure, and predicted three-dimensional fold.

These receptors have been known with different names over the years, until a unifying nomenclature has been proposed and largely adopted (Boraschi and Tagliabue 2013).

A summary of the information regarding the human receptors is reported in Table 1.
IL-1 Receptor Family, Table 1

IL-1R family members

Name

Other names

Ligands

Accession number

Gene (hu)

Chr. (hu)

Functions

IL-1R1

IL-1RI, CD121a

IL-1α, IL-1β, IL-1Ra, IL-38

UniProtKB: P14778

Extra accession: Q587I7

www.ncbi.nlm.nih.gov/protein/P14778.1

IL1R1

2q12

It initiates and amplifies the immune and inflammatory response upon binding the agonist ligands IL-1α and IL-1β; inhibited upon binding the antagonist ligand IL-1Ra; the coreceptor is IL-1R3. Binding of mature IL-38 has been also described. Soluble form, from proteolytic cleavage of membrane receptor, has IL-1 inhibitory function

IL-1R2

IL-1RII, CD121b

IL-1α, IL-1β, IL-1Ra (low affinity), pro-IL-1β (by soluble form), pro-IL-1α (intracellularly)

UniProtKB: P27930

Extra accession: D3DVJ5, Q6LCE6, Q9UE68

www.ncbi.nlm.nih.gov/protein/P27930.1

IL1R2

2q12

It binds IL-1β and less efficiently IL-1α and IL-1Ra; decoy receptor, it captures IL-1 but does not initiate signal transduction. Soluble form, from either proteolytic cleavage or alternative splicing, also has IL-1 inhibitory function

IL-1R3

IL-1RAcP

No ligand, accessory chain, it binds to dimeric complexes IL-1/IL-1R1, IL-1/IL-1R2, IL-33/IL-1R4, IL-36/IL-1R6

UniProtKB/Swiss-Prot: Q9NPH3

Extra accession: B1NLD0, D3DNW0, O14915, Q86WJ7

www.ncbi.nlm.nih.gov/protein/Q9NPH3.2

IL1RAP

3q28

Coreceptor for IL-1R1, IL-1R4, and IL-1R6, it is responsible for signaling after binding of IL-1 (α or β), IL-33, IL-36 (α, β, or γ). It can also form inactive complexes with IL-1R2 bound to IL-1. Soluble form, from alternative splicing, has inhibitory function

IL-1R3b

IL-1RAcPb

No ligand, function unknown

  

2q12

Possibly coreceptor for IL-1R1 in the brain, mediates IL-1α and IL-1β p38 and Src phosphorylation, while it seems unable to recruit MyD88 and IRAK-4

IL-1R4

T1, ST2, ST2L, DER4, Fit-1

IL-33

UniProtKB/Swiss-Prot: Q01638

Extra accessions: A8K6B3, Q53TU7, Q8NEJ3, Q9ULV7, Q9UQ44

www.ncbi.nlm.nih.gov/protein/Q01638.4

IL1RL1

2q12

It binds IL-33 using IL-1R3 as coreceptor. Soluble form, from alternative splicing, has IL-33 inhibitory function

IL-1R5

IL-18Rα

IL-1Rrp

IL-1Rrp1

CD218a

IL-18, IL-37

UniProtKB/Swiss-Prot: Q13478

Extra accessions: B2R9Y5, Q52LC9

www.ncbi.nlm.nih.gov/protein/Q13478.1

IL18R1

2q12

It binds IL-18 using IL-1R7 as coreceptor. It binds to IL-37 without recruiting IL-1R7. Soluble form has been described, of unknown function

IL-1R6

IL-1Rrp2

IL-1RL2

IL-36R

IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-38

UniProtKB/Swiss-Prot: Q9HB29

Extra accessions: Q13525, Q45H74, Q53TU8, Q587I8

www.ncbi.nlm.nih.gov/protein/Q9HB29.2

IL1RL2

2q12

It binds IL-36α, β, and γ, using IL-1R3 as coreceptor; activation of NFκB and MAPKs. Binding of IL-36Ra does not recruit IL-1R3 and forms an inactive complex with inhibitory role. Binding to full length IL-38 has been reported, leading to inflammatory or anti-inflammatory activation depending on dose

IL-1R7

IL-18Rβ

IL-18RAcP

AcPL

CD218b

No ligand, accessory chain, it binds to dimeric complex IL-18/IL-1R5

UniProtKB/Swiss-Prot: O95256

Extra accessions: B2RPJ3, Q3KPE7, Q53TT4, Q53TU5

www.ncbi.nlm.nih.gov/protein/O95256.1

IL18RAP

2q12

Coreceptor for IL-1R5, it is responsible for signaling after binding of IL-18. Soluble form has been described, of unknown function

IL-1R8

TIR8

SIGIRR

No ligand known, inhibitory chain, it inhibits signaling of IL-1R1, IL-1R4, IL-1R6. It contributes to anti-inflammatory signaling of IL-37 bound to IL-1R5

UniProtKB/Swiss-Prot: Q6IA17

Extra accessions: Q3KQY2, Q6UXI3, Q9H733

www.ncbi.nlm.nih.gov/protein/Q6IA17.3

SIGIRR

11p15.5

Orphan receptor; negative regulator of TLR4/IL-1R signaling; responsible for anti-inflammatory homeostatic signaling at the mucosal level. It has been suggested to take part to the anti-inflammatory activity of IL-37 (interacting with IL-1R5), of IL-36Ra in the brain and glial cells, and of IL-38 interacting with IL-1R6

IL-1R9

IL-1RAPL

IL-1RAPL1 TIGIRR-2

IL-1R8

IL-38 only known ligand; possibly involved in IL-38-independent neuronal regulation in cognitive functions

UniProtKB/Swiss-Prot: Q9NZN1

Extra accession: A0AVG4, Q9UJ53

www.ncbi.nlm.nih.gov/protein/Q9NZN1.2

IL1RAPL1

Xp22-p21.3

Orphan receptor, predominantly expressed in neurons, mutations/deletions involved in X-linked mental retardation, and other neurological conditions; it does not activate NFκB, ERK, and p38, but it can activate JNK. It does not use IL-1R3 or IL-1R7 as coreceptors. Involved in the regulation of neuronal functions. It binds mature IL-38 and induces anti-inflammatory activity in human macrophages, whereas binding of full length IL-38 increases inflammation. Gene homology with IL-18BP suggests it can be a brain-specific receptor for IL-18, although previous data show lack of classical activation by IL-18

IL-1R10

TIGIRR

TIGIRR-1

IL-1RAPL2

IL-1R9

No ligand known, unknown functions

UniProtKB/Swiss-Prot: Q9NP60

Extra accession: Q2M3U3, Q9NZN0

www.ncbi.nlm.nih.gov/protein/Q9NP60.1

IL1RAPL2

Xq22

Orphan receptor, abundantly expressed in the brain but present also in other organs. It does not activate JNK, ERK, p38, or NFκB. It does not use IL-1R3 or IL-1R7 as coreceptors. Gene homology with IL-18BP suggests it can be a brain-specific receptor for IL-18, although previous data show lack of classical activation by IL-18

IL-18BP

Tadekinig-α

IL-18, binding of IL-37 hypothesized but not demonstrated

UniProtKB: O95998

Extra accession: B3KUZ0, B7WPK4, O95993, O96027, Q9NZA9, Q9UBR7

www.ncbi.nlm.nih.gov/protein/O95998.2

IL18BP

11q13.4

Soluble single Ig-domain protein with homologies with IL-1R2, IL-1R8, and IL-1R9. It can capture IL-18 thereby inhibiting its activity

IL-1R1

IL-1R1 is the binding chain of the receptor for the inflammatory cytokines IL-1α and IL-1β. As all the receptors of the family, IL-1R1 works in complex with an accessory chain, unable to bind the ligand but necessary for signal transduction. Upon agonist ligand binding to IL-1R1, the receptor ectodomain changes its structure and allows interaction with the accessory chain IL-1R3, to form a trimeric complex. Approximation of the intracellular TIR domains of IL-1R1 and IL-1R3 initiates signal transduction and cell activation. IL-1R1 can also bind an antagonist ligand, another member of the IL-1 family, the IL-1 receptor antagonist IL-1Ra. Upon IL-1Ra binding, the structure of the ligand-binding domain of IL-1R1 does not change sufficiently for allowing recruitment of IL-1R3. Thus, the trimeric complex will not form and no activation will occur. IL-1R1 is a plasma membrane receptor, but it can also be found as soluble receptor (sIL-1R1) in biological fluids, as result of a metalloproteinase-mediated shedding from receptor expressing cells. sIL-1R1 is a soluble inhibitor, as it can capture IL-1 thereby preventing its interaction with the plasma membrane receptor. Thus, sIL-1R1 may act as anti-inflammatory molecule by inhibiting IL-1 activity. However, since the sIL-1R1 can also bind the IL-1 inhibitor IL-1Ra, this dampens its anti-inflammatory effect.

Some studies showed that immobilized IL-1R1 can efficiently bind mature IL-38 (another member of the IL-1 family) and, to a much lesser extent, also the full-length IL-38 (Mora et al. 2016). An excellent review summarizes the features of IL-1R1 initiated receptor complexing and activation/inhibition (Thomas et al. 2012).

IL-1R2

The second receptor of the IL-1R family is another receptor for IL-1 with potent anti-inflammatory capacity (Boraschi and Tagliabue 2013; Garlanda et al. 2013; Peters et al. 2013; Bonecchi et al. 2016). At variance with IL-1R1, IL-1R2 binds preferentially IL-1β (highly inflammatory and abundantly produced relative to IL-1α), while having much lower affinity for IL-1α and for IL-1Ra. Upon binding IL-1, similarly to IL-1R1, also IL-1R2 changes conformation and recruits the accessory chain IL-1R3 into a trimeric complex. However, IL-1R1 has a short intracytoplasmic tail that does not contain the TIR domain, making it unable to initiate signaling. Thus, IL-1R2 is an inhibitor of IL-1 activity in two ways, because it captures IL-1β (thereby preventing its interaction with IL-1R1) and because it can also sequester IL-1R3 into an inactive complex. Also in the case of IL-1R2, a soluble form is produced by proteolytic cleavage on the ectodomain from the surface of receptor-expressing cells (although a soluble form of IL-1R2 has been reported being generated by alternative splicing). Similar with the plasma membrane receptor, also sIL-1R2 is a potent inhibitor of IL-1β, more effective than sIL-1R1 because it does not bind IL-1Ra. In addition, the anti-inflammatory efficacy of sIL-1R2 includes its capacity to bind pro-IL-1β, the precursor form of IL-1β. Pro-IL-1β is not found in the extracellular space except in the case of necrotic cell death, in situations of tissue damage. In these circumstances, the ability of sIL-1R2 to capture this precursor and prevent its cleavage dampens the uncontrolled production of the inflammatory cytokine by extracellular enzymes, thereby contributing to contain inflammation and additional damage. An intracellular form of IL-1R2 has been described having the same capacity of capture and inhibition of cleavage for pro-IL-1α. Eventually, it has been shown that sIL-1R2 is also able to bind to the soluble form of IL-1R3, and that this complex has higher affinity for IL-1α and IL-1β, while still unable to bind IL-1Ra.

IL-1R3

The accessory chain IL-1R3 is a non-binding chain of the IL-1R family (Boraschi and Tagliabue 2013; Towne et al. 2004; Wesche et al. 1997). It serves as coreceptor for IL-1R1 and allows the initiation of signaling upon engagement within a complex with agonist-ligated IL-1R1 leading to the approximation of the two TIR domains present in the cytoplasmic tails of IL-1R1 and IL-1R3. IL-1R3 is promiscuous in its accessory function, as it serves as accessory chain also for other receptor complexes, namely those for IL-33 (with IL-1R4) and for IL-36 (with IL-1R6). As mentioned above, IL-1R3 can also form inactive receptor complexes with IL-1R2. As for the other receptors, IL-1R3 is also present in soluble form, generated by alternative splicing. It has been suggested that this soluble receptor may take the place of membrane IL-1R3 and form inactive complexes. Also, sIL-1R3 can form high affinity complexes with sIL-1R2 in capturing IL-1α and IL-1β.

A long form of IL-1R3 has been described, IL-1R3b, which is expressed only in central neurons. From a number of studies in mice, it seems that IL-1R3b can function as accessory chain for IL-1R1 and mediate some central effects of both IL-1α and IL-1β, which are distinct from those described for classical IL-1 activation with usage of the canonical IL-1R3 (Gosselin et al. 2013).

IL-1R4

Similar with IL-1R1, the receptor chain for the anti-inflammatory cytokine IL-33, IL-1R4, upon ligand binding forms a trimeric complex with the accessory chain IL-1R3 and initiates signal transduction. IL-1R4 is able to bind both the long and the “mature” forms of IL-33. Three splice variants of IL-1R4 had been described, the classical transmembrane receptor, a shorter protein also located on the plasma membrane but missing the intracellular domain, and a soluble form. On mast cells, the IL-1R4/IL-33/IL-1R3 complex can interact with c-Kit (which constitutively interacts with IL-1R3) upon c-Kit activation by its ligand SCF. This multireceptor interaction leads to the amplification of IL-33-induced mast cell activation. The soluble form of IL-1R4 binds IL-33 thereby inhibiting its activity. Increase in the circulating levels of sIL-1R4 is considered predictive of cardiovascular problems, given the cardioprotective role of IL-33. Comprehensive reviews were recently published summarizing the features and functional role of IL-1R4 and its ligand IL-33 (Martin 2013; Martin and Martin 2016).

IL-1R5

IL-1R5 is the ligand binding chain of the receptor for IL-18 (Boraschi and Tagliabue 2013; Novick et al. 2013). IL-1R5 binds IL-18 with low affinity, and the binding is stabilized, and affinity increased, once the accessory chain IL-1R7 enters the complex, thereby initiating signal transduction. Some studies suggest that IL-1R7 can also bind another cytokine of the IL-1 family, IL-37, which has anti-inflammatory activity. Binding of IL-37 does not antagonize IL-18, and therefore IL-37 is not an IL-18 receptor antagonist. It seems that binding of IL-37 to IL-1R5 does not recruit the accessory protein IL-1R7, whereas there is evidence that the anti-inflammatory effects of IL-37 require the presence of IL-1R8 (Nold-Petry et al. 2015). Whether IL-1R8 physically interacts with the complex IL-37/IL-1R5 is however not known. A soluble form of IL-1R5 has been detected in serum of patients with inflammatory diseases, presumably generated by alternative splicing (Booker and Grattan 2014), but neither its physiological nor its pathological role are known (Takei et al. 2011). Silencing of IL-1R5 (fibroblasts from IL-1R5 KO mice, in vitro silencing in human blood monocytes) seems to enhance the inflammatory responses to IL-1α and LPS, implying a homeostatic anti-inflammatory role of IL-1R5 (Nold-Petry et al. 2009).

IL-1R6

IL-1R6 is the ligand-binding chain for the IL-1F inflammatory cytokines IL-36α, IL-36β, and IL-36γ (Boraschi and Tagliabue 2013). The IL-36/IL-1R6 complex recruits the promiscuous accessory protein IL-1R3 in order to initiate signal transduction and cell activation. A fourth ligand, IL-36Ra, acts as a receptor antagonist, similarly to IL-1Ra. Another ligand, full length IL-38, was described able to bind IL-1R6 and induce decrease of inflammatory activation at low doses and increase at high doses (van de Veerdonk et al. 2012). IL-1R6 is associated with the inflammatory effects of IL-36 in skin, synovial fibroblasts, articular chondrocytes, dendritic cells and T cells, and its activity and regulation closely reflect those of IL-1R1 with IL-1. In the brain, regulation of IL-1R6 appears to be very different. IL-1R6 is present on glial cells (not in neurons) and is not activated by IL-36, possibly because it does not recruit IL-1R3. Soluble forms of IL-1R6 have not been reported.

IL-1R7

IL-1R7 is the unique accessory chain of the IL-18 receptor complex (Boraschi and Tagliabue 2013; Novick et al. 2013). IL-1R7 forms a signaling complex with IL-1R5 bound to IL-18, by stabilizing the complex and bringing about the necessary approximation of the intracellular TIR domains of the two receptor chains. IL-1R7 does not seem to form a trimeric complex with IL-1R5 bound to IL-37 (formal receptor binding data are not available) since the classical IL-18-related effects are not induced by IL-37. A soluble form of IL-1R7 has also been found in serum of patients with inflammatory diseases and in different organs, possibly derived from alternative splicing, whose role is not known (Takei et al. 2011).

IL-1R8

IL-1R8 is an anomalous member of the IL-1R family, as it presents a short extracellular portion encompassing a single Ig domain (Garlanda et al. 2013; Molgora et al. 2016). Because of its truncated extracellular domain, IL-1R8 has no ligand capacity. Intracellularly, IL-1R8 is longer than the other receptors of the family and displays an anomalous TIR domain that does not allow signaling upon approximation to the TIR domain of other receptors. Thus, IL-1R8 acts as inhibitor of IL-1R-initiated signaling and subsequent cell activation. The inhibitory activity of IL-1R8 has been described for several TIR receptors, i.e. for TLR as well as IL-1R. In inhibiting IL-1R signaling, it has been reported that IL-1R8 interacts both with the extracellular domain of the target receptor and with its intracellular domain. It is not known whether this interaction occurs with the ligated ligand-binding chains before recruitment of the accessory chain (which may therefore become unable to bind) or whether IL-1R8 interacts with the either one of the chains within a formed trimeric receptor complexes favoring their uncoupling. Physiologically, IL-1R8 has a protective role at the mucosal sites, by preventing excessive inflammatory activation in response to the abundant bacterial flora and subsequent tissue damage. In these sites, IL-1R8 is downregulated when inflammation must take place, and in chronic inflammatory diseases. Inhibition of IL-1R family members by IL-1R8 has been reported for the IL-1/IL-1R1/IL-1R3 and for the IL-33/IL-R4/IL-1R3 complexes, and suggested for the IL-18/IL-1R5/IL-1R7 complex. In the case of the IL-37/IL-1R5 complex, the role of IL-1R8 seems to be that of acting as accessory chain for anti-inflammatory activation (Nold-Petry et al. 2015). In all these cases, binding of IL-1R8 to the ligand/receptor complexes has not been demonstrated; therefore how IL-1R8 modulates the activation of IL-1RF members is still largely unknown. Only in the brain (not in the periphery) it has been reported that the anti-inflammatory activity of IL-36Ra requires the presence of IL-1R8 (Costelloe et al. 2008).

IL-1R9

IL-1R9, as IL-1R10, is preferentially expressed in the brain (Boraschi and Tagliabue 2013). Until now, IL-1R9 is considered an orphan receptor because it is not activated by IL-1 family cytokines in combination with any other IL-1R chains. The intracellular domain of IL-1R9 is longer than that of other IL-1R family members and is involved in regulating a series of neuronal functions. Mutations in IL-1R9 gene are associated with mental retardation, autism, schizophrenia, and cognitive anomalies, possibly based on alterations in the ability of IL-1R9 to stabilize glutaminergic synapses. A recent study has shown that genes coding for IL-1R9 and IL1R10 are evolutionarily related to the gene encoding IL-18BP. This suggests that IL-1R9 may be an alternative receptor for IL-18 in the CNS, i.e. an anatomical location where IL-18 is active and IL-1R5 is not expressed (Booker and Grattan 2016). Given the similarity of IL-1R9 with IL-1R10, the hypothesis that IL-1R10 may act as alternative IL-18 receptor in the CNS could be extended also to IL-1R9 (Booker and Grattan 2016). Another very recent study has identified mature IL-38 as possible ligand of IL-1R9 on human macrophages, yielding anti-inflammatory activity (Mora et al. 2016).

IL-1R10

IL-1R10 has significant homology with IL-1R9 and, in addition to the brain, is significantly expressed also in other organs (Boraschi and Tagliabue 2013). Similar with IL-1R9, IL-1R10 is an orphan receptor, since it cannot be activated by cytokines of the IL-1 family. The receptor is characterized by a longer intracellular domain, similar with that of IL-1R8. This may lead to hypothesize that IL-1R10 might have inhibitory functions. At present, however, no functional role has been described for this receptor. A recent study has shown that both the genes encoding IL-1R9 and IL-1R10 are evolutionarily related to the gene coding for IL-18BP, thereby suggesting that also IL-1R10 may be an alternative receptor for IL-18 in the CNS, which is an anatomical area where IL-18 is active and IL-1R5 is not expressed (Booker and Grattan 2016).

IL-18BP

IL-1BP is not a true member of the IL-1R family, although its sequence has similarities with some domains of several members of the family (IL-1R2, IL-1R8, IL-1R9). IL-18BP is a soluble protein displaying a single Ig domain, which binds with high affinity to the receptor-binding site of IL-18, thereby preventing its interaction with membrane IL-1R5 and acting as IL-18 inhibitor (Boraschi and Tagliabue 2013; Novick et al. 2013). Human IL-18BP comes in four isoforms, of which only two are able to bind and neutralize IL-18. The role of the inactive isoforms is unknown. IL-18BP is present at measurable levels in circulation and is often enhanced in a wide range of autoimmune and inflammatory diseases, so that it may be considered as a marker of inflammation. There are reports suggesting that IL-18BP could also bind IL-37 and that upon such binding the IL-18-inhibitory capacity of IL-18BP is increased, possibly because the IL-18BP/IL-37 complex may capture membrane IL-1R7, thus inhibiting the formation of the active IL-18/IL-1R5/IL-1R/ complex. At present, there is no formal confirmation of these findings.

Summary

The IL-1R family encompasses a number of transmembrane proteins that act in pairs (one ligand-binding chain and one accessory chain) for initiating ligand-dependent inflammatory cell activation. Some of the receptors have anti-inflammatory/inhibitory activity, mainly by interfering with the formation of an active receptor complex. The soluble forms of the receptors, which are receptor ectodomains released upon proteolytic cleavage, are additional anti-inflammatory molecules acting at a longer range.

We can summarize the composition and function of the IL-1RF as follows.

Five, maybe six receptor chains can bind IL-1F ligands to form active complexes:
  • IL-1R1 binds IL-1α, IL-1β, IL-1Ra, and IL-38.

  • IL-1R4 binds IL-33.

  • IL-1R5 binds IL-18 and IL-37.

  • IL-1R6 binds IL-36α, IL-36β, IL-36γ, IL-36Ra, and IL-38.

  • IL-1R9 and IL-1R10 might possibly bind IL-18 in the brain.

  • IL-1R9 binds IL-38.

Two, maybe three types of accessory chains have been described:
  • IL-1R3 functions as accessory chain for IL-1R1 (when the ligands are IL-1α and IL-1β), IL-1R4 (with IL-33 as ligand) and IL-1R6 (when the ligands are IL-36α, IL-36β, and IL-36γ).

  • IL-1R3b (a longer form of IL-1R3) is the accessory chain for IL-1R1 in neurons.

  • IL-1R7 is the accessory chain of IL-1R5 (when the ligand is IL-18).

Inactive ligand-receptor interactions and inactive receptor complexes may form as follows:
  • IL-1R1 can bind IL-1Ra and is blocked by it.

  • IL-1R2 can bind agonist IL-1α and IL-1β and block them.

  • IL-1R2 can bind agonist IL-1α and IL-1β and recruit IL-1R3 thereby blocking it.

  • IL-1R8 can bind to the IL-1R1/IL-1α or β /IL-1R3 complex and block signal transduction.

  • IL-1R8 can bind to the IL-1R5/IL-18/IL-1R7 complex and block signal transduction.

  • IL-1R8 can bind to the IL-1R4/IL-33/IL-1R3 complex and block signal transduction.

  • IL-1R8 can bind to the IL-1R8/IL-36/IL-1R3 complex and block signal transduction.

  • IL-18BP can bind to IL-18 and prevent its interaction with IL-1R5.

  • IL-1R6 can bind IL-36Ra and is blocked by it, possibly in the presence of IL-1R8.

Eventually receptor complexes with anti-inflammatory activity have been described:
  • IL-1R4 binds IL-33, recruits IL-1R3, and initiates an anti-inflammatory activation pathway.

  • IL-1R5 binds IL-37 and initiates an anti-inflammatory activation pathway that requires the presence of IL-1R8.

  • IL-1R1, IL-1R6, and IL-1R9 bind IL-38 and dampen inflammation.

In summary, the potent inflammatory activity of several cytokines of the IL-1 family requires a number of mechanisms for controlling it, in order to prevent unwanted tissue damage. By restricting them to those that involve receptors, we can list at least six of them:
  • Receptor antagonists. Two cases are known, the antagonist of IL-1R1 (IL-1Ra) and the antagonist of IL-1R6 (IL-36Ra). These cytokines block the receptor-binding site and prevent binding of the agonist cytokines.

  • Decoy receptors. One case is known, IL-1R2, which can capture agonist IL-1α and IL-1β thereby preventing their binding to IL-1R1.

  • Soluble decoys. Several soluble decoys are known, which can capture agonist ligands at longer range: sIL-1R1 captures IL-1α and IL-1β but also the antagonist IL-1Ra; sIL-1R2 captures IL-1α, IL-1β, and pro-IL-1β (but not IL-1Ra) and its binding affinity is increased by complexing with sIL1R3; sIL-1R4 can capture IL-33; sIL-1R5 can capture IL-18 together with sIL-1R7. We can also consider IL-18BP as a soluble decoy, although IL-18BP is not a bona fide IL-18 receptor.

  • Block of immature ligands. One case is known, that of IL-1R2 that can bind the precursor forms of IL-1α (intracellularly) and IL-1β (extracellularly) and shield them from protease cleavage and subsequent generation of the mature active cytokines.

  • Coreceptor competition. Capture of the accessory chain IL-1R3 by IL-1R2 bound to IL-1α or IL-1β is the major example of coreceptor competition. It is notable that the sequestration of IL-1R3, which is a promiscuous accessory chain, has effect not only on IL-1-dependent activation but also on effects mediated by IL-33 and IL-36, which use the same coreceptor. Another type of coreceptor competition may be considered that of IL-1R8, which interferes with the formation of active signaling receptor complexes for IL-1, IL-18, IL-33, and IL-36, although it is not clear whether this interference consists in preventing the recruitment of IL-1R3 or it occurs at some other level.

  • Negative signaling. Some receptor complexes may form that deliver inhibitory or anti-inflammatory signals. IL-1R8 has been claimed able to form negative-signaling complexes with IL-1R6 bound to IL-36Ra and with IL-1R5 bound to IL-37. IL-1R6 and IL-1R9 each can bind IL-38 and initiate an anti-inflammatory activity. In addition, IL-1R4 (the IL-33 receptor) together with IL-1R3 initiates an anti-inflammatory pathway.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Protein BiochemistryNational Research CouncilNaplesItaly