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 id entified and cloned. Secreted IL-1ra (sIL-1ra or IL-1ra1) contains a classi cal leader peptide giving a released mature protein. Two intracellular isof orms, icIL-1ra type I (IL-1ra2) and icIL-1ra type II (IL-1ra3), have no lea der sequence, thus predicting that these proteins remain intracellular. In an effort to define its biological role, we structurally and functionally c haracterized IL-1ra3. Endogenous immunoreactive IL-1ra3 was detected in a v ariety of inflammatory cells and tissues. We used a gene transfer strategy to explore the possible intracellular functions of IL-1ra3 land IL-1ra2) an d the cell-associated agonist IL-1 alpha. The intracellular IL-1ra3 isoform , as well as IL-1ra2, does not block the action of exogenous and endogenous IL-l under these conditions. Intact IL-1ra3 was released from the cells ki lled by NK effecters. The intracellular isoforms may represent a reservoir of IL-1ra, released upon cell death, whose function is to limit the pro-inf lammatory action of cell debris.