FIG. 8.

Working hypothesis for the mechanism of action of glycine in PG-PS-induced arthritis in the rat. PG-PS from gram-positive bacteria plays an important role in the etiology of arthritis. It is proposed that PG-PS stimulates CD14 and TLR2, resulting in increases in intracellular calcium. This stimulates NADPH oxidase and generates superoxide, which activates NF-κB, leading to TNF-α production. Glycine (GLY) blunts PG-PS-induced increases in [Ca²⁺]_i, an effect reversed by low concentrations of strychnine or depletion of chloride. The inhibition of superoxide production and TNF-α generation by glycine is most likely due to blunting of the intracellular calcium signaling pathway. These data are consistent with the hypothesis that glycine activates a glycine receptor, leading to influx of chloride which hyperpolarizes the macrophage membrane and decreases the opening time of voltage-dependent calcium channels. In vivo treatment with glycine blocks PG-PS-induced arthritis most likely via a similar mechanism.