Cytokines and the liver in health and disease. Effects on liver metabolism and fibrogenesis.

The liver is the largest organ in the body providing a large number of essential functions for the organism. It is the center for the metabolism of nutrients and drugs, and plays a key role in the unspecific immune system by harbouring Kupfer cells, the majority of all macrophages. The liver is the main site for the synthesis of many different metabolites and releases most of the plasma proteins. All these functions of the liver must be coordinated and regulated in response to metabolic changes and minor or major injuries. This is accomplished by metabolites, the autonomous nerve system, the endocrine system and by cytokines, which form a complex network of mediator molecules. Cytokines modulate liver metabolism in many ways. Synthesis of acute phase proteins is regulated by cytokines such as IL-1, IL-6, IL-11, leukemia inhibitory factor, TNF, transforming growth factor beta, epidermal growth factor, and ciliary derived neurotropic factor, which interact synergistically with corticosteroids and insulin. Hepatic lipid metabolism and hepatic carbohydrate metabolism are also regulated by cytokines and by classical hormones. Cytokines play an important role in the pathogenesis of liver diseases and liver fibrosis, which is the common morphological reaction after chronic injury of the liver. An uncontrolled production of extracellular matrix and its impaired degradation destroy the architecture of the liver and its function. Fat-storing cells (Ito cells, lipocytes, perisinusoidal cells) are the major source of extracellular matrix in the liver. They are activated to proliferate or to produce extracellular matrix compounds by cytokines like transforming growth factor beta, and platelet derived growth factor (PDGF). Interferon gamma and alpha inhibit this activation. Modulation of fibrogenesis by these cytokines may be helpful for future treatment of liver fibrosis.