The Sushi domain of soluble IL-15 receptor alpha is essential for binding IL-15 and inhibiting inflammatory and allogenic responses in vitro and in vivo

Wei Xq, M Orchardson, J A Gracie, B P Leung, Gao Bm, H Guan, W Niedbala, G K Paterson, I B McInnes, F Y Liew

Research output: Contribution to journalArticlepeer-review

Abstract

IL-15 is a pleiotropic cytokine that plays important roles in both innate and adaptive immunity. It is associated with a range of immunopathology, including rheumatoid arthritis and allograft rejection. IL-15 functions through the trimeric IL-15R complex, which consists of a high affinity binding alpha-chain and the common IL-2R beta- and gamma-chains. Characterization of IL-15/IL-15R interactions may facilitate the development of improved IL-15 antagonists for therapeutic interventions. We previously constructed soluble murine IL-15Ralpha (sIL-15Ralpha) by deleting the cytoplasmic and transmembrane domains. To localize the functional domain of IL-15Ralpha, we have now constructed various truncated versions of sIL-15Ralpha. The shortest region retaining IL-15 binding activity is a 65-aa sequence spanning the Sushi domain of IL-15Ralpha. Sushi domains, common motifs in protein-protein interactions, contain four cysteines forming two disulfide bonds in a 1-3 and 2-4 pattern. Amino acid substitution of the first or fourth cysteine in sIL-15Ralpha completely abolished its IL-15 binding activity. This also abrogated the ability of sIL-15Ralpha to neutralize IL-15-induced proinflammatory cytokine production and anti-apoptotic response in vitro. Furthermore, the mutant sIL-15Ralpha lost its ability to inhibit carrageenan-induced local inflammation and allogenic cell-induced T cell proliferation and cytokine production in vivo. Thus, the Sushi domain is critical for the functional activity of sIL-15Ralpha.

Original languageEnglish
Pages (from-to)277-82
Number of pages6
JournalJournal of Immunology
Volume167
Issue number1
DOIs
Publication statusPublished - 1 Jul 2001

Keywords

  • Acute Disease
  • Amino Acid Motifs/genetics
  • Animals
  • Apoptosis/genetics
  • Carrageenan/administration & dosage
  • Disulfides/metabolism
  • Edema/immunology
  • Female
  • Injections, Subcutaneous
  • Interleukin-15/antagonists & inhibitors
  • Isoantigens/administration & dosage
  • Lymphocyte Activation/genetics
  • Mice
  • Mutagenesis, Site-Directed
  • Necrosis
  • Protein Binding/genetics
  • Protein Structure, Tertiary/genetics
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2/genetics
  • Solubility
  • Spleen/cytology
  • T-Lymphocytes/cytology

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