Certain forms of inflammatory arthritis involve autoreactive immunologic processes (1-3), which are accompanied by an increase in the pivotal inflammatory cytokine, TNF-alpha. Our laboratory has shown that a diet rich in glycine can prevent increases in TNFalpha in several other models of inflammatory tissue injury. Thus, it is hypothesized that glycine will prevent arthritis by decreasing TNFalpha production by macrophages. In studies of liver injury, glycine blunted the LPS-induced increased in calcium and cytokines in Kupffer cells, a phenomenon which was blocked by strychnine and was dependent on chloride, just like the glycine-gated chloride channel in the CNS. In a initial series of proposed experiments, 4 groups of Lewis female rats (10 each) will be compared in a model of arthritis using bacterial group A steptococcal peptidoglycan- polysaccharide (PG-PS) (control, glycine 5%, PG-PS and glycine + PG-PS). In the acute phase of this model, inflammation peaks in 1-2 days after the i.a. injection of PG-PS and resolves in 3 weeks. Subsequent i.v. injections of PG-PS causes 100% reactivation of chronic inflammation. Food consumption, body weight, the arthritis index and ankle thickness will be monitored at 1-3 day intervals for 6 weeks. When maximal swelling occurs, rats will be sacrificed and joint tissue will be fixed for histological evaluation. We expect dietary glycine to minimize or prevent arthritis. Second, the dose-response for glycine in PG-PS induced arthritis will be determined. Dietary glycine will be varied (0% to 5%) and the parameters described above will be evaluated. In all groups, blood samples will be collected and serum glycine levels determined. We expect glycine to be protective in experimental arthritis in the 0.5-1.0 Mm range. Third, the ability of glycine to reverse arthritis will be evaluated. To test this unique idea, glycine or control diet will be initiated at the peak of inflammation and the time course of recovery will be evaluated. Fourth, to evaluate mechanism, splenic macrophages and blood lymphocytes will be isolated at the peaks of inflammation in the 4 groups detailed above. Changes in intracellular calcium, membrane potential and key cytokines (TNFalpha, IFNgamma, IL-2, IL-4 and IL-10) will be measured as well as the response to added PG-PS. The transcription factor NFkappaB will also be determined as it is pivotal in TNFalpha production. We expect that glycine will prevent arthritis b activating a strychnine sensitive glycine-gated chloride channel in macrophages and/or T-lymphocytes making them less responsive to inflammatory agonists. Collectively, we expect these studies to demonstrate that dietary glycine will block cytokine release, reduce inflammation and prevent arthritis. This work is timely and practical and will lead to simple, dietary interventions to prevent arthritis.

Project Start
1999-07-01
Project End
2000-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
18
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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