Interferon-γ inhibits liver regeneration by stimulating major histocompatibility complex class II antigen expression by regenerating liver

Abstract

The effects of interferon-gamma and interleukin-2 on liver regeneration after 70% hepatectomy in rats was studied immunohistologically, with special attention paid to major histocompatibility complex class II antigen expression. Liver regeneration 2 days after partial hepatectomy as assessed on the basis of bromodeoxyuridine labeling index revealed that regeneration was inhibited significantly in rats given a single dose of interleukin-2 or interferon-gamma compared with rats that underwent only partial hepatectomy. Simultaneous administration of interleukin-2 and interferon-gamma inhibited liver regeneration more markedly than administration of either drug. In rats subjected to partial hepatectomy, Kupffer cells around the portal vein expressed slightly more major histocompatibility complex class II antigen than did sham-operated controls. In the group given interferon-gamma, major histocompatibility complex class II antigen expression was markedly increased. Major histocompatibility complex class II antigen expression was greatest in most Kupffer cells of rats given both interleukin-2 and interferon-gamma. These results suggest that interferon-gamma activates (proliferating) Kupffer cells, in turn leading to suppression of liver regeneration. These major histocompatibility complex class II antigen-positive Kupffer cells act as antigen-presenting cells and present hepatocyte as antigen, the so-called abnormal self, to helper and cytotoxic T cells. Both types of T cells, in turn, may suppress hepatocyte proliferation. The various cytokines induced by the activated Kupffer cells and helper T cells seem to form a network with interferon-gamma to regulate liver regeneration.

TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk

“…B,C; Supporting Fig. B,C), further confirming that TIGIT might normally prevent overproduction of NK cell‐derived IFN‐γ, which directly mediate cell cycle arrest in hepatocytes, to improve liver regeneration.…”

“…The role of IFN-c in regulating liver regeneration has been extensively investigated. 5,29 Instead of inducing apoptosis, 39 IFN-c was reported to cause cell cycle arrest of hepatocytes through the generation of NO. 29 Specific cellular populations, which are reported to be critical for IFN-c production during liver regeneration, varied depending on the animal model used, although they mainly belong to the innate immune system.…”

“…The role of IFN‐γ in regulating liver regeneration has been extensively investigated . Instead of inducing apoptosis, IFN‐γ was reported to cause cell cycle arrest of hepatocytes through the generation of NO .…”

“…An intrinsic need to compensate for the loss of the hepatic tissue and its function, as well as multiple growth factors and cytokines, such as hepatocyte growth factor (HGF), interleukin (IL)‐6, and tumor necrosis factor alpha (TNF‐α), have been characterized as important factors that initiate and drive the process until the physiological function of the liver is fully regained. Other factors including interferon‐gamma (IFN‐γ) and IL‐10, on the other hand, were reported to be negative regulators of the process. In recent years, the role of various cellular populations of the innate immune system in liver regeneration have drawn attention, posing an extrinsic immune “checkpoint” for the regenerative hyperplasia process in the liver.…”

Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: Interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro

“…Hopefully, this study will spark more interest in the role of the immune system in the modulation liver growth, repair and development, under both pathological and physiological conditions (59)(60)(61). A deeper understanding of microenvironmental interactions promoting ductular proliferation, which results in portal expansion and fibrosis, may result in improved therapy for chronic liver diseases before the onset of cirrhosis.…”