Review in Depth
Overview Eduard F. Stange
Peptide growth factors in the intestine Axel U. Dignass and Andreas Sturm
Defensins – innate immunity at the epithelial frontier Klaus Fellermann and Eduard F. Stange
Cytokines in the liver Giuliano Ramadori and Thomas Armbrust
Apoptosis in liver disease Marcus Schuchmann and Peter R. Galle
The role of the liver in the production of thrombopoietin compared with erythropoietin Wolfgang Jelkmann
Eduard F. Stange
The world of gastrointestinal and hepatic peptides is developing rapidly, and it has been the focus of many researchers interested in cell growth, differentiation, defence and death. The multitude of intestinal growth factors and their interrelationships via receptor sharing or mutual modulation are of particular importance in maintaining normal mucosal cellular homeostasis, during adaptive processes following resective small bowel surgery, and in cancer formation. Another interesting field of growing importance is that of defensins, the endogenous antibiotic barrier common to most, if not all, of the surface tissues exposed to bacteria. In this respect, their potential role in inflammatory bowel disease is particularly exciting. In parallel to the enormous gain in basic knowledge about the role of cytokines in these intestinal diseases, the field of hepatic cytokines appears to be of comparable relevance to pathophysiology. These cytokines , along with a wide range of other triggering factors, modulate apoptosis, the cellular suicide machinery. Recently, the potential of interfering with these mechanisms has opened up a novel approach to severe disease states, such as fulminant hepatic failure. Finally, the liver has an important function in regulating thrombocyte production by synthesizing thrombopoietin. This peptide may be of relevance when thrombopenia develops in end-stage liver disease. Thus, many of the peptides discussed in this Review in Depth are not only of interest to the basic scientist but appear on the horizon of the physician looking for new avenues to treatment. It is always a better understanding of pathophysiology that leads to the most rational treatment evolution.
Peptide growth factors in the intestine
The intestinal peptide growth factors may be categorized into the transforming growth factor alpha (TGF-α)/epidermal growth factor (EGF), the transforming growth factor beta (TGF-β), insulin-like growth factor (IGF), fibroblast growth factor (FGF), colony-stimulating factor (CSF), trefoil factor (TFF), and the hepatocyte growth factor (HGF) family. Dignass and Sturm present a concise overview of the complexity of this enormous variety of related peptides with a multitude of modulatory factors affecting a vast number of target cells. For example, TGF-α exerts trophic effects on various cellular components of the mucosa, including blood vessels, but also affects polyamine synthesis and electrolyte and nutrient transport. The trophic effects may be exerted from the lumen after binding to the brush border, and may be utilized for maintaining mucosal integrity by addition of these peptides to nutrient solutions in several clinical situations.
Defensins – innate immunity at the epithelial frontier
The intestinal barrier was formerly believed to be maintained mainly by the physical integrity of the epithelial lining and overlaying mucus. However, it was difficult to believe that the massive load of microbes in the colon could be restricted to the lumen by physical means only: hence the importance of the discovery that more than 100 peptides with antibiotic activity help maintain mucosal integrity by killing bacteria and other pathogens, such as Giardia, probably directly at the epithelium. The conservation of these peptides during evolution is remarkable. As detailed in the review by Fellermann and Stange, the most important group is the defensin family, cationic antimicrobial peptides with at least eight different members found in humans. In addition to their killing potential, defensins are chemotactic and, similarly to the growth factors mentioned above, may stimulate cell proliferation. Although the clinical importance of these peptides remains to be clarified, a role in infectious and inflammatory bowel diseases is quite conceivable.
Cytokines in the liver
As noted in the overview by Ramadori and Armbrust, cytokines comprise a group of peptides released from certain cells to influence other cells via binding to highly specific surface cell receptors. Following binding, a series of complicated intracellular signalling cascade are triggered, affecting primarily host defence but also an array of other functions. In the liver, most of the cytokines appear to be synthesized by non-parenchymal cells, especially the Kupffer cells. Hepatocytes are a prime target for cytokine action in different situations. Thus, the important function of these small molecules in liver regeneration, fibrosis and liver metastasis is discussed in some detail.
Apoptosis and regulatory peptides in liver disease
Apoptosis is the ability of individual cells to commit suicide along a programmed series of events following an appropriate trigger. In the present context, apoptosis was focused in a review by Schuchmann and Galle because it is one of the major events governed by regulatory peptides in the liver. As they state, apoptosis is modulated by extremely complex pro- and anti-apoptotic signals that modify tissue homeostasis and integrity in clinically relevant situations, such as fulminant hepatic failure or hepatic carcinoma. Caspases form the core of the apoptotic machinery. They are stimulated by the binding of various ligands to the cell death receptors of the TNF receptor family. Thus, the cytokines link to the apoptotic process, which is related not only to tissue shaping but also to the ultimate fate of the patient.
The role of the liver in the production of thrombopoietin and erythropoietin
As an organism matures, the role of the kidneys becomes superior to the liver with respect to the production of erythropoietin. In contrast, the megakaryocytic growth factor thrombopoietin is produced predominantly in the liver, even in adults, and its hepatic production is apparently rather stable. There is a simple feedback by the binding of this factor to circulating platelets, i.e. during thrombopenia more of this factor is available in the free form for action in the bone marrow. It was only recently that the importance of this factor for thrombopenia in liver failure was elucidated. It is another example of the major importance of these minor peptides not only in physiology but also in gastrointestinal and hepatic disease.