The
oral administration of
proline, one of the non-
essential amino acids, has been shown to effectively protect the liver from D-
galactosamine (GalN)-induced liver injury and to improve the survival rate. The aim of this study was to investigate the mechanism of this protective action of
proline. We paid particular attention to the effect of
proline on inflammatory activation, regenerative response, and the associated signal transduction in the liver. Male Fischer rats received
intraperitoneal injections of GalN (1.4 g/kg) with or without the
oral administration of
proline (2 g/kg) 1 h before GalN treatment. Liver pathology, plasma indices of
inflammation, and the level of proliferative marker in the liver were monitored. The hepatic activation of
interleukin-6 (IL-6)/signal transducer and activator of transcription (STAT)-3 pathway, which is downstream of
tumor necrosis factor (TNF)-α/nuclear factor-κB, was also studied. GalN induced massive inflammatory expansion in the liver, leading to a high death rate (60 %) more than 72 h after the treatment.
Proline administration significantly suppressed inflammatory infiltration in the live after 48 h, which was accompanied by depletion of plasma TNF-α,
glutamic oxaloacetic transaminase, and
glutamic pyruvic transaminase. The
mRNA expression of
histone H3, a marker of proliferation, was significantly upregulated in the liver of
proline-treated animals. Furthermore, IL-6/STAT-3 pathway, an anti-inflammatory and regenerative signaling pathway, was strongly activated prior to these observations, with the upregulated expression of downstream genes. These results suggest that the tissue-protective mechanism of
proline involves the early activation of IL-6/STAT-3 pathway in the liver, with subsequent activation of the regenerative response and suppression of massive inflammatory activation.