Characterization of type II intracellular IL-1 receptor antagonist (IL-1ra3): a depot IL-1ra.
Three molecular forms of the IL-1 receptor antagonist (IL-1ra) have been identified and cloned. Secreted IL-1ra (sIL-1ra or IL-1ra1) contains a classical leader peptide giving a released mature protein. Two intracellular isoforms, icIL-1ra type I (IL-1ra2) and icIL-1ra type II (IL-1ra3), have no leader sequence, thus predicting that these proteins remain intracellular. In an effort to define its biological role, we structurally and functionally characterized IL-1ra3. Endogenous immunoreactive IL-1ra3 was detected in a variety of inflammatory cells and tissues. We used a gene transfer strategy to explore the possible intracellular functions of IL-1ra3 (and IL-1ra2) and the cell-associated agonist IL-1alpha. The intracellular IL-1ra3 isoform, as well as IL-1ra2, does not block the action of exogenous and endogenous IL-1 under these conditions. Intact IL-1ra3 was released from the cells killed by NK effectors. The intracellular isoforms may represent a reservoir of IL-1ra, released upon cell death, whose function is to limit the pro-inflammatory action of cell debris.
Muzio
M
M
Department of Immunology and Cell Biology, Mario Negri Institute, Milan, Italy.
Polentarutti
N
N
Facchetti
F
F
Peri
G
G
Doni
A
A
Sironi
M
M
Transidico
P
P
Salmona
M
M
Introna
M
M
Mantovani
A
A
D000818:Animals; D005091:Exons; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D020033:Protein Isoforms; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D020033:Protein Isoforms; D012795:Sialoglycoproteins