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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA045143-01A1
Application #
3188145
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1988-06-01
Project End
1991-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
Schools of Arts and Sciences
DUNS #
City
University Park
State
PA
Country
United States
Zip Code
16802
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Gaffney, E V (1991) Characterization of inhibitory activities secreted by THP-1 leukemia cells and regulation by interferon-gamma. Growth Regul 1:85-94
Gaffney, E V; Stoner, C R; Lingenfelter, S E et al. (1990) Secretion of interleukin-1 beta by a leukemia cell line in response to lipopolysaccharide and mezerein. J Biol Response Mod 9:205-11
Gaffney, E V; Stoner, C R; Lingenfelter, S E et al. (1989) Demonstration of IL-1 alpha, and IL-1 beta secretion by the monocytic leukemia cell line, THP-1. J Immunol Methods 122:211-8
Gaffney, E V; Loucks, T L; Kendall, M E (1988) Quantitation of IL-1 secretion from individual cells. Biotechniques 6:862-6
Gaffney, E V; Koch, G; Tsai, S C et al. (1988) Correlation between human cell growth response to interleukin 1 and receptor binding. Cancer Res 48:5455-9