Invited MinireviewIL-1 receptor 2 (IL-1R2) and its role in immune regulation
Highlight
► The first dedicated comprehensive review of IL-1R2 in the biomedical literature.
Introduction
The IL-1 system includes an interesting array of at least 21 distinct molecules encompassing receptors, co-receptors, ligands, and endogenous antagonists (Dinarello, 2009). IL-1α and IL-1β (collectively referred to as IL-1) serve as soluble and principally extracellular activators of the IL-1 system, whereas IL-1 receptor antagonist (IL-1RA) is a competitive inhibitor that prevents IL-1α and IL-1β from interacting with the IL-1 receptor 1 (IL-1R1). IL-1R1, in turn, associates with IL-1 receptor accessory protein (IL-1RAP) to create a transmembrane signaling complex that initiates IL-1-dependent intracellular signaling (Korherr et al., 1997). Somewhat unique to the IL-1 system is the existence of two distinct types of IL-1Rs, namely IL-1R1 and the type 2 IL-1 receptor (IL-1R2). IL-1R1, as noted above, is responsible for IL-1 signal transduction. IL-1R2 serves as an endogenous inhibitor of IL-1 signaling (Fig. 1). IL-1R2 was first characterized by McMahan et al. (1991) and is considered the prototypical decoy receptor. More recently, analogous decoy receptors have been identified for IL-18 and TNF (Mantovani et al., 2001). The purpose of these non-signaling receptors is still somewhat unclear, but functionally, they serve as important negative regulators.
The IL-1 pathway regulates inflammation, angiogenesis, hematopoiesis and cognition (Rachal Pugh et al., 2001, Shieh et al., 1991). As the first interleukin to be characterized, IL-1 was initially termed endogenous pyrogen for its ability to produce fever in animals and humans. Subsequent work demonstrated the importance of IL-1 to a variety of sickness behaviors, including anorexia, lethargy, locomotion and social exploration (Dantzer, 2001). Confirming the mechanistic importance of IL-1 to sickness were experiments demonstrating that IL-1 antagonism mitigates LPS-dependent reductions in social exploration and food-motivated behavior in mice (Bluthe et al., 1992, Kent et al., 1992, Laye et al., 2000). Overall, much of what is known about IL-1 bioaction is derived from work using IL-1 and IL-1R1 knock out (KO) mice or administered IL-1RA. Given the near absence of IL-1R2 mouse models and IL-1R2 recombinant/synthetic molecules/analogs, the functional role of IL-1R2 is often extrapolated from work with IL-1RA. IL-1R2, however, is quite unique and is likely much more than a redundancy within the system of endogenous IL-1 antagonists.
Section snippets
IL-1R2 gene
In humans, the IL-1R2 gene (IL1R2) is located on the long arm of chromosome 2 at band 2q12. In mice, IL1R2 is found in the centromere proximal position of chromosome 1 (Copeland et al., 1991). In both humans and mice, the genes for IL-1R2 and IL-1R1 are adjacent (Dale and Nicklin, 1999, Sims et al., 1995) with the IL-1R2 and IL-1R1 demonstrating similar transmembrane regions but only a 28% homology in their extracellular domains. The IL-1R2 cDNA and amino acid sequences are similar across
IL-1R2 message
IL-1R2 mRNA, in vivo, is up-regulated following middle cerebral artery occlusion, (Wang et al., 2000), acute hypoxia (Johnson et al., 2007) and LPS administration (Herman et al., 2010, Gabellec et al., 1996). In vitro, At T-20 cells treated with IL-1β or TNF-α can increase the number of IL-1R2 gene transcripts within 3 h (Bristulf and Bartfai, 1995). Depending on the stimulus, time of peak expression of IL-1R2 mRNA varies from 2 h following acute hypoxia (Johnson et al., 2007) or LPS
IL-1R2 protein
IL-1R2, in humans and non-human primates, is a protein comprised of 398 amino acids. In mice and rats, it is slightly longer at 410 and 416 amino acids, respectively. As a decoy receptor, IL-1R2 cannot signal. This is due to its lack of an intracellular TIR domain, a conserved region shared by IL-1R1 and the Toll-like receptors (TLRs) as part of the IL-1/TLR superfamily (Dunne and O’Neill, 2003, Xu et al., 2000). Interestingly, Heguy et al. constructed a functional receptor by combining the
IL-1R2 expression
IL-1R2 is natively found on neutrophils, B-cells, monocytes and macrophages (Colotta et al., 1996, McMahan et al., 1991). It can also be induced in keratinocytes and endothelial cells (Groves et al., 1995, Lukiw et al., 1999, McMahan et al., 1991). Monocytes at rest possess 1.3 × 103 receptors/cell and after 24 h of IL-13 treatment express 3.5 × 103 receptors/cell. In comparison, 12.0 × 103 sIL-1Rs/cell were elaborated into the media in the same time period (Colotta et al., 1996). IL-1R1 is expressed by
IL-1R2 function
Monoclonal antibody blocking studies show that when IL-1 is prevented from interacting with IL-1R2, IL-1 bioaction in neutrophils, lymphocytes and monocytes is not inhibited (Colotta et al., 1993, Sims et al., 1993). Blocking the IL-1/IL-1R1 interaction in neutrophils and monocytes does prevent IL-1-induced production of IL-6, IL-8 and TNF-α (Sims et al., 1993). As recently reviewed by Weber et al., the initial step in IL-1 signaling is IL-1 binding to IL-1R1 with subsequent IL-1R1
IL-1R2 in disease
IL-1-mediated inflammation contributes to the pathology of many diseases including rheumatoid arthritis, adult-onset Still’s disease, type 2 diabetes, gout, systolic heart failure and pustular psoriasis (Dinarello et al., 2012). Therefore, inhibition of IL-1 signaling is considered a major therapeutic target. Experimentally, transfection or overexpression of IL-1R2 has been used to create anti-inflammatory profiles in animal models of collagen induced arthritis (Bessis et al., 2000),
Conclusions
Since its discovery in 1991 (McMahan et al., 1991), IL-1R2 has been characterized as a decoy receptor responsible for capturing IL-1 and reducing IL-1 bioavailability. Given that it can disrupt IL-1R1/IL-1RAP heterodimerization, and that its soluble form can function like a binding protein, the biology of IL-1R2 is varied and complex. Since sIL-1R2 can interact with sIL-1RAP, it is also possible that sIL-1R2 could foster improved IL-1 bioaction because sIL-1RAP may interfere with the ability of
References (97)
- et al.
Decreased expression of the decoy interleukin-1 receptor type II in human endometriosis
Am. J. Pathol.
(2001) - et al.
Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat
Brain Res.
(1992) - et al.
Interleukin-1 beta and tumour necrosis factor-alpha stimulate the mRNA expression of interleukin-1 receptors in mouse anterior pituitary AtT-20 cells
Neurosci. Lett.
(1995) - et al.
Ectopic expression of interleukin-1 receptor type II enhances cell migration through activation of the pre-interleukin 1alpha pathway
Cytokine
(2009) - et al.
Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice
Cell
(1996) - et al.
Interleukin-13 induces expression and release of interleukin-1 decoy receptor in human polymorphonuclear cells
J. Biol. Chem.
(1994) - et al.
Chromosomal location of murine and human IL-1 receptor genes
Genomics
(1991) - et al.
Blockade of brain type II interleukin-1 receptors potentiates IL1beta-induced anorexia in mice
Neurosci. Lett.
(1998) - et al.
Interleukin-1 receptor cluster: gene organization of IL1R2, IL1R1, IL1RL2 (IL-1Rrp2), IL1RL1 (T1/ST2), and IL18R1 (IL-1Rrp) on human chromosome 2q
Genomics
(1999) - et al.
Interleukin-1 receptors type I and type II in the mouse brain: kinetics of mRNA expressions after peripheral administration of bacterial lipopolysaccharide
J. Neuroimmunol.
(1996)
Soluble interleukin-1 receptor type II levels are elevated in cerebrospinal fluid in Alzheimer’s disease patients
Brain Res.
New considerations for the pathogenesis of endometriosis
Int. J. Gynaecol. Obstet.
Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex
J. Biol. Chem.
A chimeric type II/type I interleukin-1 receptor can mediate interleukin-1 induction of gene expression in T cells
J. Biol. Chem.
Soluble interleukin-1 receptor type II blocks monocyte chemotactic protein-1 secretion by U937 cells in response to peripheral blood serum of women with endometriosis
Fertile Steril.
Soluble human IL-1 receptor type 2 inhibits ectopic endometrial tissue implantation and growth: identification of a novel potential target for endometriosis treatment
Am. J. Pathol.
Concentrations of interleukin (IL)-1alpha, IL-1 soluble receptor type II (IL-1 sRII) and IL-1 receptor antagonist (IL-1 Ra) in the peritoneal fluid and serum of infertile women with endometriosis
Eur. J. Obstet. Gynecol. Reprod. Biol.
The interleukin-1 type 2 receptor gene displays immediate early gene responsiveness in glucocorticoid-stimulated human epidermal keratinocytes
J. Biol. Chem.
Interleukin-1 receptor accessory protein interacts with the type II interleukin-1 receptor
FEBS Lett.
Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines
Trends Immunol.
Role of metalloproteases in the release of the IL-1 type II decoy receptor
J. Biol. Chem.
Type II interleukin-1 receptor expression is reduced in monocytes/macrophages and atherosclerotic lesions
Biochim. Biophys. Acta
The immune system and memory consolidation: a role for the cytokine IL-1beta
Neurosci. Biobehav. Rev.
Reactive oxygen intermediates cause rapid release of the interleukin-1 decoy receptor from human myelomonocytic cells
Blood
Genomic organization ot the type I and type II IL-1 receptors
Cytokine
Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways
J. Biol. Chem.
The soluble form of IL-1 receptor accessory protein enhances the ability of soluble type II IL-1 receptor to inhibit IL-1 action
Immunity
Molecular characterization of the interleukin-1 receptor (IL-1R) on monocytes and polymorphonuclear cells
Cytokine
Comparison of cytokine levels and embryo toxicity in peritoneal fluid in infertile women with untreated or treated endometriosis
Am. J. Obstet. Gynecol.
The role of inflammation in Alzheimer’s disease
Int. J. Biochem. Cell Biol.
The pattern of interleukin-1beta (IL-1beta) and its modulating agents IL-1 receptor antagonist and IL-1 soluble receptor type II in acute meningococcal infections
Blood
Expression of interleukin-1beta, interleukin-1 receptor, and interleukin-1 receptor antagonist mRNA in rat carotid artery after balloon angioplasty
Biochem. Biophys. Res. Commun.
Molecular characterization of the bovine type II IL-1 receptor
Cytokine
Imbalance in the expression of the activating type I and the inhibitory type II interleukin 1 receptors in endometriosis
Hum. Reprod.
Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47
Nat. Genet.
Binding of IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist by soluble IL-1 receptors and levels of soluble IL-1 receptors in synovial fluids
J. Immunol.
The type II decoy receptor of IL-1 inhibits murine collagen-induced arthritis
Eur. J. Immunol.
The association between endometriosis and polymorphisms in the interleukin-1 family genes in korean women
Am. J. Reprod. Immunol.
Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4
Science
Chemoattractants induce rapid release of the interleukin 1 type II decoy receptor in human polymorphonuclear cells
J. Exp. Med.
Regulated expression and release of the IL-1 decoy receptor in human mononuclear phagocytes
J. Immunol.
Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding
J. Immunol.
Cytokine-induced sickness behavior: mechanisms and implications
Ann. NY Acad. Sci.
Aspirin-induced increases in soluble IL-1 receptor type II concentrations in vitro and in vivo
J. Leukoc. Biol.
Effects of soluble interleukin-1 type II receptor on rabbit antigen-induced arthritis: clinical, biochemical and histological assessment
Rheumatology
Immunological and inflammatory functions of the interleukin-1 family
Ann. Rev. Immunol.
Blocking interleukin-1beta in acute and chronic autoinflammatory diseases
J. Intern. Med.
Cited by (168)
Molecular and functional characterization of chicken interleukin 1 receptor 2 (chIL-1R2)
2023, Poultry ScienceCitation Excerpt :To the best of our knowledge, this study is the first to report that chIL-1R2 mRNA is expressed in healthy tissues and tissues infected with HPAI in chickens. However, recent research has demonstrated a novel function of IL-1R2 as a positive or negative regulator of transduction signaling pathways that activate IL-6/VEGF-A, IFNγ, IL-12, and IL-17 synthesis (Szretter et al., 2007; Peters et al., 2013), which are essential proinflammatory cytokines and angiogenic factors. Overall, these results suggest that chIL-1R2 expression is specifically associated with anti-viral host response and may thus be correlated with IL-1β-mediated cellular responses.
Neuroimmunology and sleep
2023, Translational Neuroimmunology: Neuroinflammation: Volume 7Endometrial expression of members of the IL-1 family: their involvement in delayed conception of dairy cows
2023, TheriogenologyCitation Excerpt :IL-1α and IL-1β bind IL-1RI independently, triggering signal transduction, whereas IL-1Ra binds IL-1RI with similar specificity and affinity, but does not activate the receptor or trigger downstream signaling [6,20–24]. In contrast, IL-1RII binds IL-1α and IL-1β but lacks a cytosolic domain competent in signaling and acts as an endogenous inhibitor of IL-1 signaling [22]. Production of IL-1Ra by endometrial epithelial cells and macrophages is coordinated, with IL-1 being produced in response to the same stimulus [2,25].
- 1
These authors contributed equally.