IL-1 alpha and IL-1 beta are structurally related polypeptides that
show approximately 25% homology at the amino acid (aa) level. Both are
synthesized as 31 kDa precursors that are subsequently cleaved into mature
proteins of approximately 17.5 kDa (6, 7). Cleavage of the IL-1 beta precursor by
Caspase-1/ICE is a key step in the inflammatory response (2, 8). Neither IL-1 alpha
nor IL-1 beta contains a typical hydrophobic signal peptide (9-11), but evidence
suggests that these factors can be secreted by non-classical pathways (12, 13).
A portion of unprocessed IL-1 alpha can be presented on the cell membrane and may
retain biological activity (14). The precursor form of IL-1 beta, unlike the IL-1 alpha
precursor, shows little or no biological activity in comparison to the
processed form (13, 15). Both unprocessed and mature forms of IL-1 beta are
exported from the cell.
IL-1 alpha and IL-1 beta exert their effects through immunoglobulin
superfamily receptors that additionally bind IL-1ra. The 80 kDa transmembrane
type I receptor (IL-1 RI) is expressed on T cells, fibroblasts, keratinocytes,
endothelial cells, synovial lining cells, chondrocytes, and hepatocytes (16,
17). The 68 kDa transmembrane type II receptor (IL-1 RII) is expressed on B cells,
neutrophils, and bone marrow cells (18). The two IL-1 receptor types show
approximately 28% homology in their extracellular domains but differ
significantly in that the type II receptor has a cytoplasmic domain of only 29
aa, whereas the type I receptor has a 213 aa cytoplasmic domain. IL-1 RII does
not appear to signal in response to IL-1 and may function as a decoy receptor
that attenuates IL-1 function (19). The IL-1 receptor accessory protein (IL-1
RAcP) associates with IL-1 RI and is required for IL-1 RI signal transduction
(20). IL-1ra is a secreted molecule that functions as a competitive inhibitor
of IL-1 (21, 22). Soluble forms of both IL-1 RI and IL-1 RII have been detected
in human plasma, synovial fluids, and the conditioned media of several human
cell lines (23, 24). In addition, IL-1 binding proteins that resemble soluble
IL-1 RII are encoded by vaccinia and cowpox viruses (25).
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