In Vitro Anti-inflammatory Effects of the Phenylbutyric Acid Metabolite Phenylacetyl Glutamine

Sodium 4-phenylbutyrate (PBA), which exerts a wide range of anti-inflammatory effects, is rapidly cleared from the body (approximately 98%) by urinary excretion by 24 h after oral treatment in humans. PBA was almost entirely excreted to urine as phenylacetyl glutamine (PAGIn). However, no data describe the potential anti-inflammatory effects of PAGIn. The purpose of this study was to evaluate the anti-inflammatory effects of PAGIn on mouse spleen cells and peritoneal cavity cells, and explore the potential mechanism underlying this effect. PAGIn was added to mouse spleen cell cultures stimulated by concanavalin A, or mouse peritoneal cavity cell cultures stimulated by lipopolysaccharide. After 72 h of culture, levels of inflammatory cytokines in culture supernatants were measured using a sandwich enzyme-linked immunosorbent assay system, and levels of inflammatory proteins were assessed by Western blotting. PAGIn significantly inhibited inflammatory cytokine (interferon-gamma, interleukin-6, and tumor necrosis factor-alpha) production, decrease of cell number in the spleen cell, and suppressed the expression of inflammatory proteins (nuclear factor kappa B, and inducible nitric oxide synthase). These results suggest that PAGIn possesses anti-inflammatory activity via inhibition of T cell activation and Toll-like receptor 4 signaling. This study of the anti-inflammatory mechanism of PAGIn provides useful information about its potential for therapeutic applications.