ESTROGEN, CYTOKINES AND LIVER AGING

Loyola University Chicago, Maywood IL

Investigators

Abstract

The most consistent age-induced change in liver function is a decrease in the rate of hepatocyte regeneration This observation has important clinical implications concerning the recovery of the elderly individual from toxic injury and surgical interventions such as hepatic resection. In fact, aging delays the post-necrotic restoration of liver function for which hepatocyte proliferation is crucial and the mortality rate following hepatic resection increases incrementally with age, sixty percent of the death being due to hepatic failure. Among the cytokines that promote hepatocyte proliferation are tumor necrosis factor alpha (TNF) and interleukin 6 (IL-6). Estrogen has a favorable effect on hepatocyte proliferation. Following partial hepatectomy, in men as well as in women, an elevation of circulating estrogen and estrogen receptor levels occurs in the liver. It is known that estrogen regulate TNF and IL-6 production by monocytes and macrophages. It has been recently reported that estrogen enhances the production of IL-6 by endothelial cells and that the Kupffer cells production of TNF is under estrogen control. It can be therefore hypothesized that, in aged animals, the decrease in circulating levels of estrogen contributes to the decrease in hepatocyte regeneration. To date, the influence of endocrine-senescence on the aging of the liver has not been explored. In the present study, young (5 month old) and aged (24 month old) mice subjected to partial hepatectomy will be used to begin to characterize the effect of aging on the hepatic production of cytokine involved in hepatic proliferation and their relationship with the circulating estrogen levels. To do so, young, aged, castrated and hormonally manipulated mice will be studied. The relationship between aging, estrogen status, the hepatic production of IL-6 and TNF and hepatocyte turnover will be defined. The long-term goal of the present study is to provide the molecular basis for the treatment of elderly subject with estrogens in order to reduce the mortality due to drug-induced hepatitis and surgical procedures in such growing segment of the US population.