Native and recombinant forms of human interleukin-1 (IL-1) possess both growth inhibiting and growth enhancing properties depending on the type of target cell. The importance of this dual- role is unclear, but bifunctional regulatory activities have been observed for other biological response modifiers. This proposal outlines three approaches to elucidate the mechanisms underlying the growth modulating activities expressed by human IL-1. First, a series of experiments are described which will elucidate the kinetics of growth inhibition of stimulation with established cell lines and primary cultures of malignant cells. These studies address cell type sensitivity measured by growth and clonogenic assays, cell cycle phase sensitivity and the temporal sequence of changes in macromolecular synthesis second; receptor affinities and internalization of receptor-ligand complexes are studied with the aim of correlating growth response and the mechanisms of IL- 1 alpha or beta membrane interaction in malignant cells. Third, HPLC purified tryptic digest fragments and synthetic peptides representing portions of the mature form of rIL-1 beta will be used to identify epitopes responsible for biological activity. These fragments are used in conjunction with a series of monoclonal and polyclonal antibodies in ELISA, thymocyte and growth assays. These studies should lead to a better understanding of the importance of the direct antitumor effects of IL-1 and provide additional knowledge on the interaction of this monokine with both immune and non-immune cells.
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