Transforming growth factor-β1 released from the spleen exerts a growth inhibitory effect on liver regeneration in rats

Several previous reports indicated that partial hepatectomy (PH) when combined with splenectomy enhances the regenerative capacity of the liver, most probably due to the removal of unknown inhibitory factors released from the spleen. Transforming growth factor (TGF)-beta1 is a major antiproliferative factor for the hepatocytes, and the role of splenic TGF-beta1 in liver regeneration is yet to be clarified. The splenic expression of TGF-beta1 and its secretion into the portal circulation from the spleen were evaluated in a standardized two-thirds hepatectomy model in rats. Rats in the control group underwent only the hepatectomy, while splenectomy was added in the splenectomy group. The hepatocyte proliferation rate was assessed by proliferating cell nuclear antigen (PCNA) immunostaining, and the results were compared with the TGF-beta1 kinetics in the portal blood. Significant increase in PCNA index and decrease in portal TGF-beta1 level were noticed in the splenectomy group at 48 hours after PH compared with the control group. Both TGF-beta1 protein and mRNA expression level in the spleen were strongest at 48 hours after PH and coincided with the peak of the plasma TGF-beta1 level. TGF-beta type 11 receptor (TbetaR-II) expression in the liver after PH was assessed immunohistochemically. The expression of TbetaR-II decreased at 12 hours and returned to preoperative level at 24 hours after PH in both groups. The changes of TbetaR-II expression were similar in both groups, and the significant difference was not observed at 48 hours after PH. Namely, splenectomy did not alter the expression of TbetaR-II in remnant liver at the peak of hepatocytes proliferation. In conclusion we found that TGF-beta1 was produced and secreted by the spleen during the early phase of liver regeneration and removal of the spleen enhanced proliferation of hepatocytes. Splenectomy thus may exert a salutary effect in selected patients with jeopardized regenerative capacity of the liver.