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The expanding interleukin-1 family and its receptors

Do alternative IL-1 receptor/signaling pathways exist in the brain?

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Abstract

Interleukin-1 (IL-1) has been implicated in neuroimmune responses and has pleiotropic actions in the brain. Compelling evidence has shown that IL-1 is a major mediator of inflammation and the progression of cell death in response to brain injury and cerebral ischemia. Its expression is strongly increased in these pathological conditions, and central administration of exogenous IL-1 significantly exacerbates ischemic brain damage. In contrast, inhibiting IL-1 actions (by intracerebroventricular [icv] injection of IL-1ra, neutralizing antibody to IL-1 or caspase-1 inhibitor) significantly reduces ischemic brain damage. IL-1 acts by binding to the IL-1 type-1 receptor (IL-1RI), which is to date, the only known functional receptor for IL-1. However, our recent investigations suggest that IL-1 can act independently of IL-1RI, raising the possibility that additional, as yet undiscovered, receptor(s) for IL-1 exist in the brain. The recent characterization of putative, new IL-1 ligands and new IL-1 receptor-related molecules leads to the hypothesis that there might be alternative IL-1 signaling pathway(s) in the central nervous system (CNS).

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References

  1. Rothwell N. J. and Luheshi G. N. (2000) Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci. 23, 618–625.

    Article  PubMed  CAS  Google Scholar 

  2. Allan S. M. and Rothwell N. J. (2001) Cytokines and acute neurodegeneration. Nat. Rev. Neurosci. 2, 734–744.

    Article  PubMed  CAS  Google Scholar 

  3. Fisher M. and Garcia J. H. (1996) Evolving stroke and the ischemic penumbra. Neurology 47, 884–888.

    PubMed  CAS  Google Scholar 

  4. Touzani O., Roussel S., and MacKenzie E. T. (2001) The ischaemic penumbra. Curr. Opin. Neurol. 14, 83–88.

    Article  PubMed  CAS  Google Scholar 

  5. Saito K., Suyama K., Nishida K., Sei Y., and Basile A. S. (1996) Early increases in TNF-alpha, IL-6 and IL-1 beta levels following transient cerebral ischemia in gerbil brain. Neurosci. Lett. 206, 149–152.

    Article  PubMed  CAS  Google Scholar 

  6. Touzani O., Boutin H., Chuquet J., and Rothwell N. (1999) Potential mechanisms of interleukin-1 involvement in cerebral ischaemia. J. Neuroimmunol. 100, 203–215.

    Article  PubMed  CAS  Google Scholar 

  7. Schmidt J. A. (1984) Purification and partial biochemical characterization of normal human interleukin 1. J. Exp. Med. 160, 772–787.

    Article  PubMed  CAS  Google Scholar 

  8. Dinarello C. A. (1996) Biologic basis for interleukin-1 in disease. Blood 87, 2095–2147.

    PubMed  CAS  Google Scholar 

  9. Sims J. E., Gayle M. A., Slack J. L., et al. (1993) Interleukin 1 signaling occurs exclusively via the type I receptor. Proc. Natl. Acad. Sci. USA 90, 6155–6159.

    Article  PubMed  CAS  Google Scholar 

  10. Wesche H., Korherr C., Kracht M., Falk W., Resch K., and Martin M. U. (1997) The interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases). J. Biol. Chem. 272, 7727–7731.

    Article  PubMed  CAS  Google Scholar 

  11. Lemaitre B., Nicolas E., Michaut L., Reichhart J. M., and Hoffmann J. A. (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983.

    Article  PubMed  CAS  Google Scholar 

  12. Eldon E., Kooyer S., D’Evelyn D., Duman M., Lawinger P., Botas J., and Bellen H. (1994) The Drosophila 18 wheeler is required for morphogenesis and has striking similarities to Toll. Development 120, 885–899.

    PubMed  CAS  Google Scholar 

  13. O’Neill L. A. (2000) The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci. STKE. 2000, RE1.

  14. McMahan C. J., Slack J. L., Mosley B., et al. (1991) A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO J. 10, 2821–2832.

    PubMed  CAS  Google Scholar 

  15. Malinowsky D., Lundkvist J., Laye S., and Bartfai T. (1998) Interleukin-1 receptor accessory protein interacts with the type II interleukin-1 receptor. FEBS Lett. 429, 299–302.

    Article  PubMed  CAS  Google Scholar 

  16. Liu C., Hart R. P., Liu X. J., Clevenger W., Maki R. A., and De Souza E. B. (1996) Cloning and characterization of an alternatively processed human type II interleukin-1 receptor mRNA. J. Biol. Chem. 271, 20,965–20,972.

    CAS  Google Scholar 

  17. Jensen L. E., Muzio M., Mantovani A., and Whitehead A. S. (2000) IL-1 signaling cascade in liver cells and the involvement of a soluble form of the IL-1 receptor accessory protein. J. Immunol. 164, 5277–5286.

    PubMed  CAS  Google Scholar 

  18. Wesche H., Henzel W. J., Shillinglaw W., Li S., and Cao Z. (1997) MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7, 837–847.

    Article  PubMed  CAS  Google Scholar 

  19. Cao Z., Henzel W. J., and Gao X. (1996) IRAK: a kinase associated with the interleukin-1 receptor. Science 271, 1128–1131.

    Article  PubMed  CAS  Google Scholar 

  20. Muzio M., Ni J., Feng P., and Dixit V. M. (1997) IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278, 1612–1615.

    Article  PubMed  CAS  Google Scholar 

  21. Cao Z., Xiong J., Takeuchi M., Kurama T., and Goeddel D. V. (1996) TRAF6 is a signal transducer for interleukin-1. Nature 383, 443–446.

    Article  PubMed  CAS  Google Scholar 

  22. O’Neill L. A. and Greene C. (1998) Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J. Leukoc. Biol. 63, 650–657.

    PubMed  CAS  Google Scholar 

  23. Breder C. D., Dinarello C. A., and Saper C. B. (1988) Interleukin-1 immunoreactive innervation of the human hypothalamus. Science 240, 321–324.

    Article  PubMed  CAS  Google Scholar 

  24. Lue F. A., Bail M., Jephthah-Ochola J., Carayanniotis K., Gorczynski R., and Moldofsky H. (1988) Sleep and cerebrospinal fluid interleukin-1-like activity in the cat. Int. J. Neurosci. 42, 179–183.

    Article  PubMed  CAS  Google Scholar 

  25. Ban E., Milon G., Prudhomme N., Fillion G., and Haour F. (1991) Receptors for interleukin-1 (alpha and beta) in mouse brain: mapping and neuronal localization in hippocampus. Neuroscience 43, 21–30.

    Article  PubMed  CAS  Google Scholar 

  26. French R. A., VanHoy R. W., Chizzonite R., et al. (1999) Expression and localization of p80 and p68 interleukin-1 receptor proteins in the brain of adult mice. J. Neuroimmunol. 93, 194–202.

    Article  PubMed  CAS  Google Scholar 

  27. Liu C., Chalmers D., Maki R., and De Souza E. B. (1996) Rat homolog of mouse interleukin-1 receptor accessory protein: cloning, localization and modulation studies. J. Neuroimmunol. 66, 41–48.

    Article  PubMed  CAS  Google Scholar 

  28. Tomozawa Y., Inoue T., and Satoh M. (1995) Expression of type I interleukin-1 receptor mRNA and its regulation in cultured astrocytes. Neurosci. Lett. 195, 57–60.

    Article  PubMed  CAS  Google Scholar 

  29. Zetterstrom M., Lundkvist J., Malinowsky D., Eriksson G., and Bartfai T. (1998) Interleukin-1-mediated febrile responses in mice and interleukin-1 beta activation of NFkappaB in mouse primary astrocytes, involves the interleukin-1 receptor accessory protein. Eur. Cytokine Netw. 9, 131–138.

    PubMed  CAS  Google Scholar 

  30. Pousset F., Cremona S., Dantzer R., Kelley K. W., and Parnet P. (2001) Dexamethasone upregulates type II IL-1 receptor in mouse primary activated astrocytes. J. Neurochem. 76, 901–909.

    Article  PubMed  CAS  Google Scholar 

  31. Brogi A., Strazza M., Melli M., and Costantino-Ceccarini E. (1997) Induction of intracellular ceramide by interleukin-1 beta in oligodendrocytes. J. Cell Biochem. 66, 532–541.

    Article  PubMed  CAS  Google Scholar 

  32. Blasi F., Riccio M., Brogi A., Strazza M., et al. (1999) Constitutive expression of interleukin-1beta (IL-1beta) in rat oligodendrocytes. Biol. Chem. 380, 259–264.

    Article  PubMed  CAS  Google Scholar 

  33. Buttini M., Sauter A., and Boddeke H. W. (1994) Induction of interleukin-1 beta mRNA after focal cerebral ischaemia in the rat. Brain Res. Mol. Brain Res. 23, 126–134.

    Article  PubMed  CAS  Google Scholar 

  34. Hillhouse E. W., Kida S., and Iannotti F. (1998) Middle cerebral artery occlusion in the rat causes a biphasic production of immunoreactive interleukin-1beta in the cerebral cortex. Neurosci. Lett. 249, 177–179.

    Article  PubMed  CAS  Google Scholar 

  35. Giulian D., Baker T. J., Shih L. C., and Lachman L. B. (1986) Interleukin 1 of the central nervous system is produced by ameboid microglia. J. Exp. Med. 164, 594–604.

    Article  PubMed  CAS  Google Scholar 

  36. Davies C. A., Loddick S. A., Toulmond S., Stroemer R. P., Hunt J., and Rothwell N. J. (1999) The progression and topographic distribution of interleukin-1beta expression after permanent middle cerebral artery occlusion in the rat. J. Cereb. Blood Flow Metab. 19, 87–98.

    Article  PubMed  CAS  Google Scholar 

  37. Pearson V. L., Rothwell N. J., and Toulmond S. (1999) Excitotoxic brain damage in the rat induces interleukin-1beta protein in microglia and astrocytes: correlation with the progression of cell death. Glia 25, 311–323.

    Article  PubMed  CAS  Google Scholar 

  38. Sairanen T. R., Lindsberg P. J., Brenner M., and Siren A. L. (1997) Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level. J. Cereb. Blood Flow Metab. 17, 1107–1120.

    Article  PubMed  CAS  Google Scholar 

  39. Wang X., Barone F. C., Aiyar N. V., and Feuerstein G. Z. (1997) Interleukin-1 receptor and receptor antagonist gene expression after focal stroke in rats. Stroke 28, 155–161.

    PubMed  CAS  Google Scholar 

  40. Touzani O., Boutin H., LeFeuvre R., Parker L., Miller A., Luheshi G., and Rothwell N. (2002) Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type I receptor. J. Neurosci. 22, 38–43.

    PubMed  CAS  Google Scholar 

  41. Loddick S. A., MacKenzie A., and Rothwell N. J. (1996) An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat. Neuroreport 7, 1465–1468.

    Article  PubMed  CAS  Google Scholar 

  42. Relton J. K. and Rothwell N. J. (1992) Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res. Bull. 29, 243–246.

    Article  PubMed  CAS  Google Scholar 

  43. Yamasaki Y., Matsuura N., Shozuhara H., Onodera H., Itoyama Y., and Kogure K. (1995) Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats. Stroke 26, 676–680.

    PubMed  CAS  Google Scholar 

  44. Schielke G. P., Yang G. Y., Shivers B. D., and Betz A. L. (1998) Reduced ischemic brain injury in interleukin-1 beta converting enzyme-deficient mice. J. Cereb. Blood Flow Metab. 18, 180–185.

    Article  PubMed  CAS  Google Scholar 

  45. Friedlander R. M., Gagliardini V., Hara H., et al. (1997) Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J. Exp. Med. 185, 933–940.

    Article  PubMed  CAS  Google Scholar 

  46. Boutin H., Lefeuvre R. A., Horai R., Asano M., Iwakura Y., and Rothwell N. J. (2001) Role of IL-1alpha and IL-1beta in ischemic brain damage. J. Neurosci. 21, 5528–5534.

    PubMed  CAS  Google Scholar 

  47. Ushio S., Namba M., Okura T., et al. (1996) Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J. Immunol. 156, 4274–4279.

    PubMed  CAS  Google Scholar 

  48. Parnet P., Garka K. E., Bonnert T. P., Dower S. K., and Sims J. E. (1996) IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1R AcP. J. Biol. Chem. 271, 3967–3970.

    Article  PubMed  CAS  Google Scholar 

  49. Torigoe K., Ushio S., Okura T., et al. (1997) Purification and characterization of the human interleukin-18 receptor. J. Biol. Chem. 272, 25,737–25,742.

    Article  CAS  Google Scholar 

  50. Born T. L., Thomassen E., Bird T. A., and Sims J. E. (1998) Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling. J. Biol. Chem. 273, 29,445–29,450.

    Article  CAS  Google Scholar 

  51. Mulero J. J., Pace A. M., Nelken S. T., Loeb D. B., Correa T. R., Drmanac R., and Ford J. E. (1999) IL1HY1: A novel interleukin-1 receptor antagonist gene. Biochem. Biophys. Res. Commun. 263, 702–706.

    Article  PubMed  CAS  Google Scholar 

  52. Smith D. E., Renshaw B. R., Ketchem R. R., Kubin M., Garka K. E., and Sims J. E. (2000) Four new members expand the interleukin-1 superfamily. J. Biol. Chem. 275, 1169–1175.

    Article  PubMed  CAS  Google Scholar 

  53. Busfield S. J., Comrack C. A., Yu G., Chickering T. W., Smutko J. S., Zhou H., Leiby K. R., Holmgren L. M., Gearing D. P., and Pan Y. (2000) Identification and gene organization of three novel members of the IL-1 family on human chromosome 2. Genomics 66, 213–216.

    Article  PubMed  CAS  Google Scholar 

  54. Kumar S., McDonnell P. C., Lehr R., et al. (2000) Identification and initial characterization of four novel members of the interleukin-1 family. J. Biol. Chem. 275, 10,308–10,314.

    CAS  Google Scholar 

  55. Pan G., Risser P., Mao W., et al. (2001) IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine 13, 1–7.

    Article  PubMed  CAS  Google Scholar 

  56. Lin H., Ho A. S., Haley-Vicente D., et al. (2001) Cloning and characterization of IL-1HY2, a novel interleukin-1 family member. J. Biol. Chem. 276, 20,597–20,602.

    CAS  Google Scholar 

  57. Dunn E., Sims J. E., Nicklin M. J., and O’Neill L. A. (2001) Annotating genes with potential roles in the immune system: six new members of the IL-1 family. Trends Immunol. 22, 533–536.

    Article  PubMed  CAS  Google Scholar 

  58. Mitcham J. L., Parnet P., Bonnert T. P., et al. (1996) T1/ST2 signaling establishes it as a member of an expanding interleukin-1 receptor family. J. Biol. Chem. 271, 5777–5783.

    Article  PubMed  CAS  Google Scholar 

  59. Lovenberg T. W., Crowe P. D., Liu C., et al. (1996) Cloning of a cDNA encoding a novel interleukin-1 receptor related protein (IL 1R-rp2). J. Neuroimmunol. 70, 113–122.

    Article  PubMed  CAS  Google Scholar 

  60. Born T. L., Smith D. E., Garka K. E., Renshaw B. R., Bertles J. S., and Sims J. E. (2000) Identification and characterization of two members of a novel class of the interleukin-1 receptor (IL-1R) family. Delineation of a new class of IL-1R-related proteins based on signaling. J. Biol. Chem. 275, 29,946–29,954.

    Article  CAS  Google Scholar 

  61. Sana T. R., Debets R., Timans J. C., Bazan J. F., and Kastelein R. A. (2000) Computational identification, cloning, and characterization of IL-1R9, a novel interleukin-1 receptor-like gene encoded over an unusually large interval of human chromosome Xq22.2-q22.3. Genomics 69, 252–262.

    Article  PubMed  CAS  Google Scholar 

  62. Carrie A., Jun L., Bienvenu T., et al. (1999) A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nat. Genet. 23, 25–31.

    PubMed  CAS  Google Scholar 

  63. Thomassen E., Renshaw B. R., and Sims J. E. (1999) Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine 11, 389–399.

    Article  PubMed  CAS  Google Scholar 

  64. Debets R., Timans J. C., Homey B., et al. (2001) Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. J. Immunol. 167, 1440–1446.

    PubMed  CAS  Google Scholar 

  65. Kumar S., Hanning C. R., Brigham-Burke M. R., et al. (2002) Interleukin-1F7b (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7b binds to the IL-18 receptor but does not induce IFN-gamma production. Cytokine 18, 61–71.

    Article  PubMed  CAS  Google Scholar 

  66. Bufler P., Azam T., Gamboni-Robertson F., Reznikov L. L., Kumar S., Dinarello C. A., and Kim S. H. (2002) A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity. Proc. Natl. Acad. Sci. USA 99, 13,723–13,728.

    Article  CAS  Google Scholar 

  67. Wheeler R. D., Culhane A. C., Hall M. D., Pickering-Brown S., Rothwell N. J., and Luheshi G. N. (2000) Detection of the interleukin 18 family in rat brain by RT-PCR. Brain Res. Mol. Brain Res. 77, 290–293.

    Article  PubMed  CAS  Google Scholar 

  68. Jander S., Schroeter M., and Stoll G. (2002) Interleukin-18 expression after focal ischemia of the rat brain: association with the late-stage inflammatory response. J. Cereb. Blood Flow Metab. 22, 62–70.

    Article  PubMed  CAS  Google Scholar 

  69. Jander S. and Stoll G. (1998) Differential induction of interleukin-12, interleukin-18, and interleukin-1beta converting enzyme mRNA in experimental autoimmune encephalomyelitis of the Lewis rat. J. Neuroimmunol. 91, 93–99.

    Article  PubMed  CAS  Google Scholar 

  70. Gatti S., Beck J., Fantuzzi G., Bartfai T., and Dinarello C. A. (2002) Effect of interleukin-18 on mouse core body temperature. Am. J. Physiol Regul. Integr. Comp. Physiol. 282, R702-R709.

    PubMed  CAS  Google Scholar 

  71. Conti B., Park L. C., Calingasan N. Y., Kim Y., Kim H., Bae Y., Gibson G. E., and Joh T. H. (1999) Cultures of astrocytes and microglia express interleukin 18. Brain Res. Mol. Brain Res. 67, 46–52.

    Article  PubMed  CAS  Google Scholar 

  72. Loddick S. A., Liu C., Takao T., Hashimoto K., and De Souza E. B. (1998) Interleukin-1 receptors: cloning studies and role in central nervous system disorders. Brain Res. Brain Res. Rev. 26, 306–319.

    Article  PubMed  CAS  Google Scholar 

  73. Glaccum M. B., Stocking K. L., Charrier K., et al. (1997) Phenotypic and functional characterization of mice that lack the type I receptor for IL-1. J. Immunol. 159, 3364–3371.

    PubMed  CAS  Google Scholar 

  74. Labow M., Shuster D., Zetterstrom M., et al. (1997) Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice. J. Immunol. 159, 2452–2461.

    PubMed  CAS  Google Scholar 

  75. Luheshi G., Hopkins S. J., Lefeuvre R. A., Dascombe M. J., Ghiara P., and Rothwell N. J. (1993) Importance of brain IL-1 type II receptors in fever and thermogenesis in the rat. Am. J. Physiol. 265, E585-E591.

    PubMed  CAS  Google Scholar 

  76. Parker L. C., Luheshi G. N., Rothwell N. J., and Pinteaux E. (2002) IL-1beta signalling in glial cells in wildtype and IL-1RI deficient mice. Br. J. Pharmacol. 136, 312–320.

    Article  PubMed  CAS  Google Scholar 

  77. Kumar S., Tzimas M. N., Griswold D. E., and Young P. R. (1997) Expression of ST2, an interleukin-1 receptor homologue, is induced by proinflammatory stimuli. Biochem. Biophys. Res. Commun. 235, 474–478.

    Article  PubMed  CAS  Google Scholar 

  78. Berglöf E., Andre R., Renshow B. R., et al. (2003) IL-1Rrp2 expression and IL-1F9 (IL-1H1) actions in brain cells. J. Immunol. 139, 36–43.

    Google Scholar 

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Authors and Affiliations

  1. School of Biological Sciences, University of Manchester, Oxford Road, M13 9PT, Manchester, UK

    Herve Boutin, Nancy J. Rothwell & Emmanuel Pinteaux

  2. Syngenta, Central Toxicology Laboratory, Alderley Park, SK10 4TJ, Macclesfield, UK

    Ian Kimber

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  1. Herve Boutin
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Boutin, H., Kimber, I., Rothwell, N.J. et al. The expanding interleukin-1 family and its receptors. Mol Neurobiol 27, 239–248 (2003). https://doi.org/10.1385/MN:27:3:239

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