Structure-function relationship of interleukin-1 giving new insights for its therapeutic potential

Abstract

The pleiotropic activities of IL-1 have fostered a series of studies on the structure-function relationship in these proteins. In fact, the attempt to dissociate different biological functions of IL-1 should simplify its therapeutic use. About human IL-1β, which has been more extensively studied in this respect, enzymatic cleavage of the precursor protein to generate the mature polypeptide appears necessary for its full biological activity. The almost complete integrity of the mature IL-1gb protein is also required for its ability to bind to the receptor and trigger cellular functions. However, by the use of monoclonal antibodies and recombinant or synthetic peptides, it has been possible to map some IL-1gb regions important for different activities. Both N-terminal and C-terminal fragments are important for receptor binding. A domain around amino acids 187-204 is apparently involved in the hyperalgesic effects of IL-1β. Finally, the fragment in position 163–171 appears to be responsible for a restricted series of the IL-1β activities, mainly directed to the immune system, although irrelevant for inflammation-related effects and unable of binding to the IL-1 R. It is thus possible, within the sequence of a cytokine, to isolate selectively active domains. This will give us new tools for new therapeutic approaches. Thus, IL-1 might be the prototype of a new generation of cytokines developed with the goal of stimulating specific biological activities without activating the cascade effects which are typical for many cytokines.