The results from numerous studies indicate that interleukin 1 (IL 1), a low molecular weight protein produced by stimulated macrophages and perhaps several other cell types, can markedly affect the maturation, functional activation, and proliferation of a broad range of cell types that share a common involvement in immune or inflammatory responses. In view of the proposed role of IL 1 in immunity and inflammation, it is important to understand the pathway(s) and regulation of IL 1 synthesis, release, and extracellular processing, as well as its mechanism of action at the molecular level. Thus the major goals of this proposal are: To elucidate the sequence of events that occur between the synthesis of the 33,000 molecular weight (m.w.) IL 1 precursor in stimulated human and murine monocytes/macrophages and the appearance of low m.w. IL 1 (17-19,000) in the extracellular environment; to define the amino acid sequence(s) in the IL 1 precursor that serves to target this protein for secretion; to determine the amino acid sequences in the IL 1 precursor that serve as primary sites for extracellular processing; and to elucidate the mechanism by which calcium enhances the secretion of IL 1 as well as its extracellular processing. In the work outlined in this proposal, we will depend on the use of recombinant forms of precursor and low molecular weight human and murine IL 1, highly specific anti-IL 1 antibodies, and IL 1 cDNA probes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025836-02
Application #
3139509
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1988-03-01
Project End
1993-02-28
Budget Start
1989-03-01
Budget End
1990-02-28
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Kavita, U; Mizel, S B (1995) Differential sensitivity of interleukin-1 alpha and -beta precursor proteins to cleavage by calpain, a calcium-dependent protease. J Biol Chem 270:27758-65
Siders, W M; Mizel, S B (1995) Interleukin-1 beta secretion. A possible multistep process that is regulated in a cell type-specific manner. J Biol Chem 270:16258-64
Siders, W M; Klimovitz, J C; Mizel, S B (1993) Characterization of the structural requirements and cell type specificity of IL-1 alpha and IL-1 beta secretion. J Biol Chem 268:22170-4
Lord, P C; Wilmoth, L M; Mizel, S B et al. (1991) Expression of interleukin-1 alpha and beta genes by human blood polymorphonuclear leukocytes. J Clin Invest 87:1312-21
Carruth, L M; Demczuk, S; Mizel, S B (1991) Involvement of a calpain-like protease in the processing of the murine interleukin 1 alpha precursor. J Biol Chem 266:12162-7
Suttles, J; Giri, J G; Mizel, S B (1990) IL-1 secretion by macrophages. Enhancement of IL-1 secretion and processing by calcium ionophores. J Immunol 144:175-82
Suttles, J; Carruth, L M; Mizel, S B (1990) Detection of IL-1 alpha and IL-1 beta in the supernatants of paraformaldehyde-treated human monocytes. Evidence against a membrane form of IL-1. J Immunol 144:170-4
Mizel, S B (1989) The interleukins. FASEB J 3:2379-88
Minnich-Carruth, L L; Suttles, J; Mizel, S B (1989) Evidence against the existence of a membrane form of murine IL-1 alpha. J Immunol 142:526-30
Shirakawa, F; Mizel, S B (1989) In vitro activation and nuclear translocation of NF-kappa B catalyzed by cyclic AMP-dependent protein kinase and protein kinase C. Mol Cell Biol 9:2424-30

Showing the most recent 10 out of 11 publications