Quick Facts of IL-1R

• Interleukin-1 receptor (IL-1R) is a cytokine receptor which binds interleukin 1 (IL-1) which is a cytokine.

• There are two types of IL-1 receptor, termed type I and type II receptors, each with three extracellular immunoglobulin (Ig)-like domains but limited sequence similarity (28%) and different pharmacological characteristics.

• IL-1R contains three Ig domains and, together with the highly homologous IL-1R accessory protein (IL-1RAcP), forms a receptor complex for IL-1 alpha, IL-1 beta  and IL−1 receptor antagonist (IL-1RA). Of the three Ig-like domains, domains 1 and 2 are tightly linked, while domain 3 is completely separate and connected by a flexible linker.

• Both the receptors exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors.

• Both of them bind to the Interleukin-1 alpha, interleukin-1 beta and Interleukin-1RA which are cytokines that participate in the regulation of immune responses, inflammatory reactions, and haematopoiesis. Interleukin-1 (IL-1) exerts pleiotropic effects on a variety of tissues through binding to its receptor. interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kappaB(NF-kappaB).

• IL1RB is the beta subunit of the receptor and is known also as IL1R2. The human gene encoding the beta subunit was cloned by McMahan et al (1991). In the nomenclature of CD antigens, this receptor has been given the designation CD121b.

• IL1R2 is structurally incapable of signalling and functions as a decoy receptor, binding and inhibiting the effect of IL1. IL1R2 can reduce the number of signalling complexes consisting of IL1R1, IL1RAcP, and IL1, by binding to IL1RAcP and thus has the ability to modulate the responsiveness of cells to IL1 . The type I receptor is primarily responsible for transmitting the inflammatory effects of IL-1 while type II receptors may act as a suppressor of IL-1 activity by competing for IL-1 binding.

• Also opposing the effects of IL-1 is the IL-1RA.The IL-1RA binds IL1 and transduces IL1 signals in cooperation with the co-receptor IL1RAcP to initiate an inflammatory response. In the nomenclature of CD antigens, this receptor has been given the designation CD121a. The human gene encoding the alpha subunit was been cloned by Sims et al (1989).

• All the IL-1 receptors appear to be well conserved in evolution, and map to the same chromosomal location.

• Cells may produce soluble variants of the IL1 receptors (designated sIL1R1, sIL1R2), which can compete with membrane-bound receptors for ligand binding. They can act as molecular sinks and scavengers for free ligand and can play a regulatory role by modulating ligand availability.

• IL-1 Family Receptors:

The IL-1R family consists of members that are characterized by the presence of extracellular immunoglobulin-like (Ig) domains and by an intracellular TIR domain.They are:

-IL-1ra/IL-1F3
-IL-1 Rrp2/IL-1 R6
-IL-1 RI
-IL-18 R alpha/IL-1 R5
-IL-1 RII
-IL-18 R beta/IL-1 R7
-IL-1 RAcP/IL-1 R3
-SIGIRR
-IL-1 RAPL1/IL-1 R8
-ST2/IL-1 R4
-IL-1 RAPL2/IL-1 R9

• The IL-18 receptor (IL-18R), following binding to IL-18, forms a complex with IL-18RAcP to initiate downstream signalling.

• IL1 receptor-related protein-2 (IL-1Rrp2) is the receptor for the agonists IL-1F6, IL-1F8, and IL-1F9, which also uses IL-1RAcP as a second chain. Thus, IL-1RAcP appears to be promiscuous since, in addition to IL-1RI and IL-1Rrp2, it also associates with ST2, which has recently been shown to bind IL-33.

• IL-1R2 and SIGIRR are two inhibitory receptors, the former lacks the Toll/IL-1 receptor (TIR)- domain whereas the latter contains a single Ig domain for the extracellular segment.

• The only members that still remain without any identified function in this subfamily are IL-1RAPL and TIGIRR.

• The adaptor molecules are: the Myeloid differentiation factor 88 (MyD88) and the MyD88-adaptor-like (MAL, also known as TIRAP).

• TIRAP is the TIR domain-containing adaptor protein inducing interferon-alpha.

• MyD88 has a modular structure consisting of an N-terminal death domain (DD) separated by a short linker region from the C-terminal TIR domain.

• The IL-1 receptors and TLRs (Toll-like Receptors) share a common TIR motif in their cytoplasmic domain. While IL-1 receptors respond to traditional IL-1 family ligands, the TLRs elicit inflammatory responses via the recognition of pathogen-associated molecular patterns (PAMPs) such as bacterial proteins, nucleic acids, and cell wall components.

• The TIR domain is responsible for the propagation of the signal within the cell through interaction with a complex signalling cascade. The presence of an intracellular TIR domain is the hallmark of TLR/IL-1R super family consisting of IL-1R subfamily and the TIR-domain-containing adaptor proteins.

• The IL-1 Ligands & IL-1R/TLR Family plays critical roles in inflammation and host defence. These molecules play important roles in both innate and adaptive immunity.

• MyD88 is an important signalling adaptor for both TLR and IL-1R family members. Resident skin cells utilize IL-1R/MyD88 signalling to promote neutrophil recruitment.

• A novel IL-1RI co-receptor, TILRR, links with the signalling receptor complex and enhances recruitment of the MyD88 adapter, controls induction of the Ras GTPase, and amplifies activation of NF-kappaB and inflammatory genes.

• One of the other adaptors involved are TRIF–related adaptor molecule (TRAM) where TRIF is TIR-domain-containing adapter-inducing interferon-β. TRAM contains a TIR domain in the C-terminal region and functions exclusively in the TLR4 pathway. TRAM interacts with TIR-domain-containing adapter-inducing interferon-β (TRIF) and the sterile alpha- and armadillo-motif containing protein (SARM). These adaptors bridge the TLR/IL-1R receptors to the intracellular molecules that transduce their signals into a biological response and play a central role in innate immunity.

• SARM contains a TIR domain at C-terminus, two “sterile a” motif (SAM) protein-protein interactions domains, and an Armadillo repeat motif (ARM).It functions as an inhibitor of TRIF-dependent TLR signalling.

• Another adaptor like toll-interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP) is required to act as a bridge for MyD88 in TLR2 and TLR4 signalling, while TRIF is used in TLR3 signalling and, in association with TRAM, in TLR4 signalling.

• Based on the type of adaptor molecules involved, the TLR/IL-1R-induced pathways can be sub-grouped in two classes: MyD88-dependent and MyD88-independent responses.

• In the MyD88-dependent pathway, MyD88 associates with IL-1R-associated kinases like IRAK4, IRAK1 and/or IRAK2. IRAK4 in turn phosphorylates IRAK1 and IRAK2 and promotes their association with TNF receptor associated factor-6 (TRAF6), which serves as a platform to recruit the TGF-beta activated kinase-1 (TAK1).

• Once activated, TAK1 activates the IKK complex, composed of IKK alpha, IKK beta , and NEMO (IKK gamma), which catalyzes phosphorylation and subsequent degradation of IkappaB rendering NF-kappaB free to translocate from the cytosol to the nucleus and activate NF-kappaB-dependent genes.

• TLR/IL-1R receptors associate with MyD88 through homotypic interactions between their respective TIR domains. This interaction then allows MyD88 to recruit members of the interleukin-1 receptor-associated kinase (IRAK) family (IRAK1, IRAK2, and IRAK4) through homotypic interactions between their respective Death Domains (DDs).

• The MyD88-dependent TLR/IL-1R signalling plays a vital role early in life, but becomes less important for survival during ageing. This is likely consequent to activation and/or maturation of TLR-independent innate immunity. Moreover, these findings seem to suggest that innate immunity is more important upon the very first encounter with a pathogen. Once adaptive immunity is generated, however, resistance to infection becomes quite efficient even in the absence of crucial functional components of TLR signalling.

• Once activated by their respective ligands, IL-1R, IL-18R, and TLRs engage with one or more adaptor proteins. These adaptors, namely, MyD88, MAL/TIRAP, TRIF, and TRAM are recruited, in various combinations, to the cytoplasmic domains of the receptors through homophilic interactions between Toll/IL-1 receptor (TIR) domains present in each receptor and each adaptor.

• TLR, IL-1R and TNF-R signalling to NF-kappaB converge on a common IkappaB kinase complex that phosphorylates the NF-kappaB inhibitory protein IkappaB.

• An aberrant activation of TLR/IL-1R signalling can promote the onset of inflammatory and autoimmune diseases. The development of therapeutic strategies for the control of their function have potential to cure inflammatory and immune disorders such as sepsis syndrome, asthma, atherosclerosis, Alzheimer’s disease, rheumatoid arthritis (RA).

• Pharmaceutical modulation of TLR/IL-1R signalling pathways by inhibitors, such as decoy peptides and synthetic mimetics that interfere with protein-protein interactions between signalling molecules of the TLR/IL-1R super family, might yield clinical benefits in the treatment of inflammatory and autoimmune diseases.

• The TIR domain of TLR/IL-1R proteins is a putatively suitable target. In particular, the BB-loop region may be regarded as a critical functional interface of TIR domain for its critical role in proper signalling. BB-Loop Decoy Peptides are short amino acid sequences of a protein that are expected to mimic its interaction surface and to prevent interaction of the prototype proteins with their partners.

• For e.g. A TIRAP decoy peptide consisting of the 14 amino acid-long sequence in the BB-loop (LQLRDAAPGGAIVS), fused to the Drosophila antennapedia homeodomain to facilitate the intracellular delivery, specifically blocked TLR4-induced activation of NF-kappaB without affecting the TIRAP-independent TLR9 response. In vivo administration of TIRAP inhibitory peptide counteracted the lung inflammatory response in healthy C57BL/6 mice.

• BB-loop heptapeptides derived from MyD88 and IL-18R inhibited homomeric interaction of MyD88 TIR domain or full-length MyD88 in vitro e.g. cell permeable derivative of the MyD88 BB-loop decoy heptapeptide (RDVLPGT).

• Toshchakov and colleagues performed systematic investigations of decoy cell permeable peptides containing TIR domain BB-loop sequences derived from the adaptor proteins MyD88, TIRAP, TRAM, and TRIF as well as the receptors TLR1, 2, 4, and 6. These decoy peptides were all able to inhibit, with varying activity, the TLR signalling pathways.

• Bartfai and colleagues, by focusing on TIR-domain interactions between IL-1RI and MyD88, synthesized a low-molecular-weight molecule mimetic, hydrocinnamoyl-L-valyl pyrrolidine.

• One of the most effective compounds, termed ST2825, inhibited homomeric interaction of MyD88 TIR domains. This effect was specific for TIR domains and did not affect interaction of MyD88 DD.

Although much emphasis has been placed on the development of NF-kappaB inhibitors, generic inhibition of NF-kappaB may lead to undesired side effects. Hence, a challenging objective is to develop drugs like above that block its effects in specific pathways, while leaving its physiological functions in other contexts largely intact. A promising research is going on in this line ...So watch out for this space...