Dietary glycine prevents peptidoglycan polysaccharide-induced reactive arthritis in the rat: Role for glycine-gated chloride channel

Peptidoglycan polysaccharide (PG-PS) is a primary structural component of b acterial cell walls and causes rheumatoid-like arthritis in rats. Recently, glycine has been shown to be a potential immunomodulator; therefore, the p urpose of this study was to determine if glycine would be protective in a P G-PS model of arthritis in vivo. In rats injected with PG-PS intra-articula rly, ankle swelling increased 21% in 24 to 48 h and recovered in about 2 we eks. Three days prior to reactivation with PG-PS given intravenously (i.v.) , rats were divided into two groups and fed a glycine-containing or nitroge n-balanced control diet. After Lv. PG-PS treatment joint swelling increased 2.1 +/- 0.3 mm in controls but only 1.0 +/- 0.2 nun in rats fed glycine. I nfiltration of inflammatory cells, edema, and synovial hyperplasia in the j oint were significantly attenuated by dietary glycine. Tumor necrosis facto r alpha (TNF-alpha) mRNA was detected in ankle homogenates from rats fed th e control diet but not in ankles from rats fed glycine. Moreover, intracell ular calcium was increased significantly in splenic macrophages treated wit h PG-PS; however, glycine blunted the increase about 50%. The inhibitory ef fect of glycine was reversed by low concentrations of strychnine or chlorid e-free buffer, and it increased radiolabeled chloride influx nearly fourfol d, an effect also inhibited by strychnine. In isolated splenic macrophages, glycine blunted translocation of the p65 subunit of NF-kappaB into the nuc leus, superoxide generation, and TNF-alpha production caused by PG-PS. Furt her, mRNA for the beta subunit of the glycine receptor was detected in sple nic macrophages. This work supports the hypothesis that glycine prevents re active arthritis by blunting cytokine release from macrophages by increasin g chloride influx via a glycine-gated chloride channel.