The type II IL-1 receptor interacts with the IL-1 receptor accessory protein: a novel mechanism of regulation of IL-1 responsiveness.

IL-1 binds to two types of receptors on the cell membrane, of which only type I (IL-1RI) transduces signals in concert with the coreceptor IL-1 receptor accessory protein (IL-1RAcP) while type II (IL-1RII) allegedly functions solely as ligand sink and decoy receptor without participating in IL-1 signaling. To investigate the regulatory role of IL-1RII on IL-1 responsiveness, a chimeric receptor encompassing the extracellular and transmembrane portions of IL-1RII and the cytoplasmic signal-transducing domain of IL-1RI was transfected into two murine EL-4-derived sublines that do or do not express IL-1RAcP, respectively. The chimeric receptor was able to transduce the IL-1 signal and induce IL-2 production only in the cell line which expressed IL-1RAcP, suggesting effective interaction between the extracellular domains of IL-1RII and IL-1RAcP in the presence of IL-1. The physical association of ligated IL-1RII with IL-1RAcP was proven by crosslinking experiments with radio-iodinated IL-1 and subsequent immunoprecipitations in normal human B cells and in EL-4 D6/76 cells transiently cotransfected with IL-1RII and IL-1RAcP, respectively. Based on these findings, it is proposed that upon IL-1 binding IL-1RII can recruit IL-1RAcP into a nonfunctional trimeric complex and thus modulate IL-1 signaling by subtracting the coreceptor molecule from the signaling IL-1RI. In this novel mechanism of coreceptor competition, the ratio between IL-1RII and IL-1RI becomes the central factor in determining the IL-1 responsiveness of a cell and the availability of IL-1RAcP becomes limiting for effective IL-1 signaling.

[1]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[2]  J. Lowenthal,et al.  Interleukin 1-dependent induction of both interleukin 2 secretion and interleukin 2 receptor expression by thymoma cells. , 1986, Journal of immunology.

[3]  C. March,et al.  cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. , 1988, Science.

[4]  W. Falk,et al.  Internalization of interleukin 1 (IL 1) correlates with IL 1‐induced IL 2 receptor expression and IL 2 secretion of EL4 thymoma cells , 1989, European journal of immunology.

[5]  H. Land,et al.  Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. , 1990, Nucleic acids research.

[6]  K. Huebner,et al.  A novel IL‐1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. , 1991, The EMBO journal.

[7]  A. Heguy,et al.  Amino acids conserved in interleukin-1 receptors (IL-1Rs) and the Drosophila toll protein are essential for IL-1R signal transduction. , 1992, The Journal of biological chemistry.

[8]  A. Heguy,et al.  A chimeric type II/type I interleukin-1 receptor can mediate interleukin-1 induction of gene expression in T cells. , 1993, The Journal of biological chemistry.

[9]  A. Mantovani,et al.  Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. , 1993, Science.

[10]  S. Murakami,et al.  Structure and function of the intracellular portion of the mouse interleukin 1 receptor (type I). Determining the essential region for transducing signals to activate the interleukin 8 gene. , 1993, The Journal of biological chemistry.

[11]  W. Arend.  Interleukin-1 receptor antagonist. , 1993, Advances in immunology.

[12]  M. Gayle,et al.  Interleukin 1 signaling occurs exclusively via the type I receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Dower,et al.  Interleukin-1 receptors. , 1994, European cytokine network.

[14]  G. Nabel,et al.  The cytoplasmic domain of the interleukin-1 receptor is required for nuclear factor-kappa B signal transduction. , 1994, The Journal of biological chemistry.

[15]  M. Labow,et al.  Molecular Cloning and Characterization of a Second Subunit of the Interleukin 1 Receptor Complex (*) , 1995, The Journal of Biological Chemistry.

[16]  D. Goeddel,et al.  NF-κB Activation by Interleukin-1 (IL-1) Requires an IL-1 Receptor-associated Protein Kinase Activity (*) , 1995, The Journal of Biological Chemistry.

[17]  M. Muda,et al.  Transfected type II interleukin-1 receptor impairs responsiveness of human keratinocytes to interleukin-1. , 1995, The American journal of pathology.

[18]  Z. Cao,et al.  IRAK: A Kinase Associated with the Interleukin-1 Receptor , 1996, Science.

[19]  A. Mantovani,et al.  Inhibition of interleukin-1 responsiveness by type II receptor gene transfer: a surface "receptor" with anti-interleukin-1 function , 1996, The Journal of experimental medicine.

[20]  S. Saccani,et al.  Regulated expression and release of the IL-1 decoy receptor in human mononuclear phagocytes. , 1996, Journal of immunology.

[21]  C. Dinarello,et al.  Biologic basis for interleukin-1 in disease. , 1996, Blood.

[22]  P. Feng,et al.  IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. , 1997, Science.

[23]  P. Bossù,et al.  Inhibitory activity of IL-1 receptor antagonist depends on the balance between binding capacity for IL-1 receptor type 1 and IL-1 receptor type II. , 1997, Journal of immunology.

[24]  Z. Cao,et al.  MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. , 1997, Immunity.

[25]  W. B. Berg.  Lessons for joint destruction from animal models. , 1997 .

[26]  Klaus Resch,et al.  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)* , 1997, The Journal of Biological Chemistry.

[27]  A. H. Drummond,et al.  Role of Metalloproteases in the Release of the IL-1 type II Decoy Receptor* , 1997, The Journal of Biological Chemistry.

[28]  Z. Cao,et al.  Recruitment of IRAK to the interleukin 1 receptor complex requires interleukin 1 receptor accessory protein. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[29]  W. Falk,et al.  A critical role for interleukin‐1 receptor accessory protein in interleukin‐1 signaling , 1997, European journal of immunology.

[30]  T. Bártfai,et al.  Interleukin‐1 receptor accessory protein interacts with the type II interleukin‐1 receptor , 1998, FEBS letters.