Inhibition of interleukin-1 responsiveness by type II receptor gene transfer: a surface "receptor" with anti-interleukin-1 function.
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 NFkappaB activation, cytokine gene expression and production. Blocking monoclonal antibodies against RII restored the capacity of RII-transfected cells to respond to IL-1 beta. 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-2. Cells transfected with 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 antiinflammatory signals, whose only known function is to capture and block IL-1.
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Istituto Ricerche Farmacologiche Mario Negri, Milano, Italy.
Sironi
M
M
Muzio
M
M
Matteucci
C
C
Introna
M
M
Orlando
S
S
Penton-Rol
G
G
Dower
S K
SK
Sims
J E
JE
Colotta
F
F
Mantovani
A
A
D001483:Base Sequence; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II; D015398:Signal Transduction; D014162:Transfection
D007375:Interleukin-1; D016328:NF-kappa B; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II