Nonparenchymal cells from regenerating rat liver generate interleukin-1alpha and -1beta: a mechanism of negative regulation of hepatocyte proliferation.

Following experimental partial hepatectomy of 70% in the rat, there is a semisynchronized surge of hepatocyte proliferation that ceases after 48 to 72 hours. Little is known about the determinants governing the termination of the proliferative phase, although transforming growth factor (TGF) beta has been implicated as an important inhibitor of hepatocyte replication in this model. We previously reported an additional non-TGF-beta inhibitor in medium conditioned by nonparenchymal cells isolated from regenerating liver (CM-NPC-Reg) between 24 and 48 hours after partial hepatectomy, but it was not found in medium conditioned by nonparenchymal cells from unoperated control liver. CM-NPC-Reg suppressed replicative DNA synthesis of primary rat hepatocytes in response to hepatocyte growth factor (HGF), epidermal growth factor (EGF), or TGF-alpha as assessed by 3H-thymidine incorporation. We now present evidence that interleukin (IL)-1 is the major inhibitor of hepatocyte DNA synthesis present in CM-NPC-Reg. IL-1 receptor antagonist abrogated the inhibition, as did antibodies to rat IL-1alpha and -beta; a combination of both antibodies was required, implicating both IL-1alpha and IL-1beta as active constituents in CM-NPC-Reg. To investigate in vivo changes in IL-1 expression, we assessed expression of IL-1alpha messenger RNA (mRNA) in whole rat liver following partial hepatectomy; mRNA was down-regulated at 10 hours in the pre-replicative phase of liver regeneration and up-regulated at 24 hours and 48 hours when proliferation is waning. Rat hepatocytes isolated from liver 24 hours after partial hepatectomy showed increased sensitivity to the inhibitory action of IL-1. Exogenous IL-1beta, administered parenterally to a group of rats at 0 and 12 hours after partial hepatectomy significantly reduced the incorporation of the thymidine analogue, bromodeoxyuridine (BrdU), into hepatocytes at 18 hours. These data indicate that nonparenchymal cells isolated from regenerating rat liver elaborate IL-1, and support the hypothesis that IL-1 plays a role suppressing hepatocyte proliferation and terminating the surge of DNA synthesis induced after partial hepatectomy.