Interleukin-1 (IL-1) plays an important role in the pathogenesis of several inflammatory disorders. Two proteins displaying IL-1 activity have been described, interleukin-1-alpha (IL-1.alpha.) and interleukin-1-beta (IL-1.beta.).
Although the two proteins are products of distinct genes, they share 27-33% amino acid identity, and are known to interact with the same receptor and have similar biological activity. Each protein is proteolytically cleaved from its approximately 31 kDa precursor to its more active 17 kDa form. IL-1.alpha. precursor (preIL-1.alpha.) displays bioactivity, although less than that of its mature form. In contrast, IL-1.beta. precursor (preIL-1.beta.) displays no biological activity until processed to its mature form. Although both IL-1 molecules are secreted proteins, both lack signal peptides. The mechanism(s) of secretion have not been fully defined.
Only certain cell types process preIL-1.beta. and secrete IL-1.beta.. Monocytes and macrophages are the most efficient and prolific producers and secretors of IL-1.beta. known. Of the two IL-1 proteins synthesized and secreted following activation of monocytes and macrophages, IL-1.beta. is the more abundant.
The cellular processing of preIL-1.beta. to IL-1.beta. is mediated by the enzyme, IL-1.beta. Converting Enzyme (IL-1CE or ICE). ICE is expressed in vivo as a 45 kDa precursor molecule which is proteolytically processed in vivo into fragments of 20 and 10 kDa, that together comprise the active form of ICE.
The study of IL-1.beta. and the role it plays in the pathogenesis of several inflamatory disorders has been hampered by an insufficient amount of ICE. In vivo, monocytes and macrophages contain only small quantities of IL-1.beta. and ICE. Both ICE and IL-1.beta. are present in low quantities in cells, which limits the amount of material available for study and characterization. It has been reported that active ICE could not be produced by mixing the major protein subunits together, after separate expression in E. coli, or by coexpressing the subunits in Escherichia coli. Miller et al, "Purification and Characterization of Active Human Interleukin-1.beta.-converting Enzyme from THP.1Monocyte Cells", J. Biol. Chem. 268, pp 18062-18069 (1993). The present invention directly contradicts the teaching of Miller et al.
Substances that interact with ICE and alter the production of IL-1.beta. are of interest as therapeutics to modulate the inflammatory response.