Inhibition of interleukin-1 responsiveness by type II receptor gene transfer: A surface "Receptor" with anti-interleukin-1 function

Fabio Re, Marina Sironi, Marta Muzio, Cristian Matteucci, Martino Introna, Simone Orlando, Giselle Penton-Rol, Steven K. Dower, John E. Sims, Francesco Colotta, Alberto Mantovani

Research output: Contribution to journalArticlepeer-review

Abstract

The hypothesis that the type II receptor (RII) acts as a decoy for interleukin-1 (IL-1) was tested by gene transfer in cells expressing only the type I receptor (8387 fibroblasts). RII-transfected cells showed defective responsiveness to IL-1 in terms of NFkB activation, cytokine gene expression and production. Blocking monoclonal antibodies against RII restored the capacity of RII-transfected cells to respond to IL-1β. Hence defective IL-1 responsiveness of RII-transfected cells requires surface expression of the molecule. RII-transfected cells showed normal responsiveness to TNF, which shares functional properties and elements in the signal transduction pathway with IL-1. Cells transfected with a deletion mutant of RII missing 26 of 29 amino acids of the cytoplasmic portion of the molecule showed impaired responsiveness to IL-1. Cells transfected with the full-length or the cytoplasmic deletion mutant of RII released copious amounts of RII in the supernatant. However, transfected cells showed defective responsiveness to brief exposure to IL-1, in the absence of measurable released RII. These results indicate that impairment of the responsiveness to IL-1 following RII gene transfer was dependent upon surface expression of the molecule, specific for IL-1 and unaffected by truncation of the cytoplasmic portion. Thus, the type II "receptor" is a decoy surface molecule, regulated by anti-inflammatory signals, whose only known function is to capture and block IL-1.

Original languageEnglish
Pages (from-to)1841-1850
Number of pages10
JournalJournal of Experimental Medicine
Volume183
Issue number4
Publication statusPublished - Apr 1 1996

ASJC Scopus subject areas

  • Immunology

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