Interleukin-1 receptor antagonist (IL-1ra) exists in two forms which are produced through alternate start sites and internal splicing of a single gene. Secretory IL-1ra (sIL-1ra) has a leader sequence, is secreted, is a significant product of monocytes, and probably functions as an antagonist of extracellular IL-1. Intracellular IL-1ra (icIL-1ra) lacks a leader sequence, probably remains predominantly intracellular, is a significant product of epithelial cells, and may function as an antagonist of intracellular IL-1. The hypothesis to be examined in these studies is that monocyte/macrophage cells produce both sIL-1ra and icIL-1ra. It is further hypothesized production of both forms of IL-1ra by these cells is regulated separately.
Four specific aims will be pursued: 1) to accurately quantitate sIL-1ra and icIL-1ra mRNA utilizing quantitative PCR techniques, 2)to accurately quantitate sIL-1ra and icIL-1ra protein concentrations utilizing a sensitive and specific ELISA, 3) to examine the differential regulation of sIL-1ra and icIL-1ra mRNA and protein production in different cell types, and 4) to examine the potential biologic role of icIL-1ra. The results of these studies should clarify the possible in vivo relevance of sIL-1ra and icIL-1ra in rheumatoid arthritis and in other chronic inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR001883-04
Application #
2077393
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1992-09-15
Project End
1997-07-31
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Malyak, M; Guthridge, J M; Hance, K R et al. (1998) Characterization of a low molecular weight isoform of IL-1 receptor antagonist. J Immunol 161:1997-2003
Malyak, M; Smith Jr, M F; Abel, A A et al. (1998) The differential production of three forms of IL-1 receptor antagonist by human neutrophils and monocytes. J Immunol 161:2004-10