The long-term goal of the principal investigator's studies is to elucidate the mechanisms of action of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF) and interleukin-1 (IL-1). The major aim of the present application is to elucidate the role of the TNF/IL-1-inducible TSG-6 protein in inflammation, especially in inflammatory and degenerative joint diseases. Earlier studies from the principal investigator's laboratory demonstrated that high levels of TSG-6 protein are present in the synovial fluids of patients with rheumatoid arthritis and some other forms of arthritis. The TSG-6 protein was shown to have the following activities: (a) TSG-6 binds to hyaluronan, a major component of the extracellular matrix, (b) TSG-6 forms a stable complex with components of the serine protease inhibitor, inter-alpha-inhibitor (I-alpha-I), (c) TSG-6 potentiates the plasmin-inhibitory activity of I-alpha-I, and (d) recombinant TSG-6 protein exerts a potent antiinflammatory action in a mouse model. The first specific aim is to clarify the mechanism of the antiinflammatory action of TSG-6. These studies should reveal whether the antiinflammatory action of TSG-6 is causally related to any of its other demonstrated activities, thereby either confirming or refuting the principal investigator's hypothesis that inhibition of plasmin activity via interaction with I-alpha-I is central to the antiinflammatory action of TSG-6. Cell culture models of inflammation will be devised in which the effects of wild-type and mutant TSG-6 proteins can be evaluated. The second major aim is to determine the role of endogenously produced TSG-6 protein in the intact organism. It will be determined whether targeted deletion of the tsg6 gene or overexpression of human TSG-6 protein in transgenic mice leads to phenotypic alterations and whether it affects susceptibility toward the induction of acute or chronic (collagen-induced arthritis) inflammatory responses. Transgenic mice and tsg6 knockout mice will also be used to determine if TSG-6 plays a role in other disease models involving TNF or IL-1 actions: the lethal action of bacterial lipopolysaccharide and susceptibility to intracellular bacterial infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044351-04
Application #
6171866
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
1997-08-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2002-06-30
Support Year
4
Fiscal Year
2000
Total Cost
$247,114
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Wisniewski, Hans-Georg; Snitkin, Evan S; Mindrescu, Catalin et al. (2005) TSG-6 protein binding to glycosaminoglycans: formation of stable complexes with hyaluronan and binding to chondroitin sulfates. J Biol Chem 280:14476-84
Wisniewski, Hans-Georg; Vilcek, Jan (2004) Cytokine-induced gene expression at the crossroads of innate immunity, inflammation and fertility: TSG-6 and PTX3/TSG-14. Cytokine Growth Factor Rev 15:129-46
Mindrescu, C; Dias, A A M; Olszewski, R J et al. (2002) Reduced susceptibility to collagen-induced arthritis in DBA/1J mice expressing the TSG-6 transgene. Arthritis Rheum 46:2453-64
Mindrescu, C; Thorbecke, G J; Klein, M J et al. (2000) Amelioration of collagen-induced arthritis in DBA/1J mice by recombinant TSG-6, a tumor necrosis factor/interleukin-1-inducible protein. Arthritis Rheum 43:2668-77