Invited Minireview
IL-1 receptor 2 (IL-1R2) and its role in immune regulation

https://doi.org/10.1016/j.bbi.2012.11.006Get rights and content

Abstract

The cytokine IL-1 is critical to the pathogenesis of a variety of human conditions and diseases. Unlike most other cytokines, IL-1 is counterbalanced by two endogenous inhibitors. The functional significance of IL-1 receptor antagonist (IL-1RA) is well documented due to the clinical utilization of the recombinant human IL-1RA analog, anakinra. In contrast, much less is known about the type 2 IL-1 receptor (IL-1R2), which acts as a decoy receptor for IL-1. While IL-1R2 is structurally similar to the type 1 IL-1 receptor (IL-1R1) responsible for IL-1 signal transduction, its truncated cytoplasmic domain and lack of Toll-IL-1 receptor (TIR) region renders IL-1R2 incapable of transmembrane signaling. IL-1R2 competes with IL-1R1 for ligands and for the IL-1R1 co-receptor, IL-1 receptor accessory protein (IL-1RAP). Additionally, IL-1R2 exists in both a membrane bound and soluble form (sIL-1R2) that has biological properties similar to both a decoy receptor and a binding protein. Thus far, IL-1R2 has been implicated in arthritis, endometriosis, organ transplantation, sepsis/sickness behavior, diabetes, atherosclerosis, autoimmune inner ear disease (AIED), Alzheimer’s disease and ulcerative colitis. In this review, we will detail the functional properties of IL-1R2 and examine its role in human disease.

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)

  • A. Garlind et al.

    Soluble interleukin-1 receptor type II levels are elevated in cerebrospinal fluid in Alzheimer’s disease patients

    Brain Res.

    (1999)
  • R. Gazvani et al.

    New considerations for the pathogenesis of endometriosis

    Int. J. Gynaecol. Obstet.

    (2002)
  • S.A. Greenfeder et al.

    Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex

    J. Biol. Chem.

    (1995)
  • A. Heguy et al.

    A chimeric type II/type I interleukin-1 receptor can mediate interleukin-1 induction of gene expression in T cells

    J. Biol. Chem.

    (1993)
  • A. Kharfi et al.

    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.

    (2002)
  • K. Khoufache et al.

    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.

    (2012)
  • Z. Kondera-Anasz et al.

    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.

    (2005)
  • W.J. Lukiw et al.

    The interleukin-1 type 2 receptor gene displays immediate early gene responsiveness in glucocorticoid-stimulated human epidermal keratinocytes

    J. Biol. Chem.

    (1999)
  • D. Malinowsky et al.

    Interleukin-1 receptor accessory protein interacts with the type II interleukin-1 receptor

    FEBS Lett.

    (1998)
  • A. Mantovani et al.

    Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines

    Trends Immunol.

    (2001)
  • S. Orlando et al.

    Role of metalloproteases in the release of the IL-1 type II decoy receptor

    J. Biol. Chem.

    (1997)
  • J. Pou et al.

    Type II interleukin-1 receptor expression is reduced in monocytes/macrophages and atherosclerotic lesions

    Biochim. Biophys. Acta

    (2011)
  • C. Rachal Pugh et al.

    The immune system and memory consolidation: a role for the cytokine IL-1beta

    Neurosci. Biobehav. Rev.

    (2001)
  • P. Sambo et al.

    Reactive oxygen intermediates cause rapid release of the interleukin-1 decoy receptor from human myelomonocytic cells

    Blood

    (1996)
  • J.E. Sims et al.

    Genomic organization ot the type I and type II IL-1 receptors

    Cytokine

    (1995)
  • J.L. Slack et al.

    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.

    (2000)
  • D.E. Smith et al.

    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

    (2003)
  • M.K. Spriggs et al.

    Molecular characterization of the interleukin-1 receptor (IL-1R) on monocytes and polymorphonuclear cells

    Cytokine

    (1992)
  • Y. Taketani et al.

    Comparison of cytokine levels and embryo toxicity in peritoneal fluid in infertile women with untreated or treated endometriosis

    Am. J. Obstet. Gynecol.

    (1992)
  • E.E. Tuppo et al.

    The role of inflammation in Alzheimer’s disease

    Int. J. Biochem. Cell Biol.

    (2005)
  • M. van Deuren et al.

    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

    (1997)
  • X. Wang et al.

    Expression of interleukin-1beta, interleukin-1 receptor, and interleukin-1 receptor antagonist mRNA in rat carotid artery after balloon angioplasty

    Biochem. Biophys. Res. Commun.

    (2000)
  • P.W. Yu et al.

    Molecular characterization of the bovine type II IL-1 receptor

    Cytokine

    (1997)
  • A. Akoum et al.

    Imbalance in the expression of the activating type I and the inhibitory type II interleukin 1 receptors in endometriosis

    Hum. Reprod.

    (2007)
  • C.A. Anderson et al.

    Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

    Nat. Genet.

    (2011)
  • Arcalyst [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.;...
  • W.P. Arend et al.

    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.

    (1994)
  • N. Bessis et al.

    The type II decoy receptor of IL-1 inhibits murine collagen-induced arthritis

    Eur. J. Immunol.

    (2000)
  • S. Chun et al.

    The association between endometriosis and polymorphisms in the interleukin-1 family genes in korean women

    Am. J. Reprod. Immunol.

    (2012)
  • F. Colotta et al.

    Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4

    Science

    (1993)
  • F. Colotta et al.

    Chemoattractants induce rapid release of the interleukin 1 type II decoy receptor in human polymorphonuclear cells

    J. Exp. Med.

    (1995)
  • F. Colotta et al.

    Regulated expression and release of the IL-1 decoy receptor in human mononuclear phagocytes

    J. Immunol.

    (1996)
  • X. Cui et al.

    Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding

    J. Immunol.

    (2003)
  • R. Dantzer

    Cytokine-induced sickness behavior: mechanisms and implications

    Ann. NY Acad. Sci.

    (2001)
  • J.M. Daun et al.

    Aspirin-induced increases in soluble IL-1 receptor type II concentrations in vitro and in vivo

    J. Leukoc. Biol.

    (1999)
  • J. Dawson et al.

    Effects of soluble interleukin-1 type II receptor on rabbit antigen-induced arthritis: clinical, biochemical and histological assessment

    Rheumatology

    (1999)
  • C.A. Dinarello

    Immunological and inflammatory functions of the interleukin-1 family

    Ann. Rev. Immunol.

    (2009)
  • C.A. Dinarello

    Blocking interleukin-1beta in acute and chronic autoinflammatory diseases

    J. Intern. Med.

    (2011)
  • Cited by (168)

    • Molecular and functional characterization of chicken interleukin 1 receptor 2 (chIL-1R2)

      2023, Poultry Science
      Citation 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 7
    • Endometrial expression of members of the IL-1 family: their involvement in delayed conception of dairy cows

      2023, Theriogenology
      Citation 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].

    View all citing articles on Scopus
    1

    These authors contributed equally.

    View full text