IL-1 alpha and IL-1 beta are structurally related polypeptides that
show approximately 25% homology at the amino acid 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
amino acids (aa), whereas the type I receptor has a 217 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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