The role of cytokines in liver regeneration
Science Articles / / May 14, 2016
Shapiro IY Frolov AI
Department of Hospital Therapy State Medical Academy.Mechnikov, St. Petersburg,
City Clinical Hospital №1, Tolyatti
Despite the large number of studies on the morphological aspects of liver regeneration, regeneration of the problem of regulation is still far from being resolved.This is due primarily to a lack of information about the underlying mechanisms of regeneration under physiological conditions and patoloschchesdih effects.The successes of the last decades in the field of molecular biology and basic immunology gave a powerful impetus to the study of regeneration of the regulation at the molecular level.This primarily refers to cytokines.
Cytokines (mediators, factors of cellular interaction) - the substance of protein nature, are produced by different types of cells in the body and are a kind of tongue cells communicate with each other.Stimulators of cytokine formation can be biological, chemical and physical stimuli.The action itself is not specific cytokines.Expre
cytokine system has considerable stability thanks to the interchangeability, the duplication of mediators, their diversity, the presence of synergists and antagonists, cascading nature of their education, etc .. The family of cytokines include interleukins - IL (lymphokines and monokines), interferon - IFN, colony stimulating factors and CSF, growth factors - GF, tumor necrosis factors - TNF, chemokines.
Over the past 20 years have shown that the majority of effects mediated immunoregulatory cytokines that on the one hand, the protective function is performed, and on the other - are involved in the pathogenesis of many diseases.Received numerous certificates cytokine regulation of both normal and diseased response.Action
cytokines often occurs locally, where the immune response is generated or at the point of penetration of the pathogen.Normally cytokines formed in the primary immune response, practically do not enter the blood.Only in pathology con serum content of cytokines increases.The course, severity, outcome largely depends on the involvement of cytokines.A special role in the induction of proinflammatory assigned inflammation (IL -1, IL -6, IL -8, -12 IL, IFN alpha, IFN -gamma) and antiinflammatory cytokines (IL -4, IL -10, IL -13, TGF -beta).Pro-inflammatory cytokines (IL -1, IL -6, TNF alpha) mediates many common hematologic and metabolic changes characteristic of the body's response to infection: fever, neutrophilia, gipoforremiyu, synthesis of acute-phase proteins and glucocorticoids, increased coagulation, increased vascular permeability,weight loss.However, they are effective in stimulating nonspecific defense mechanisms and specific immune responses and activate the reparative processes in the damaged tissues.
Involvement of cytokines in the regulation of regeneration mainly studied in models of partial resection of healthy hepatic tissue.Identified cytokines - TNF alpha, IL -6, HGF (hepatocyte growth factor), EGF (epidermal growth factor), IGF (insulin growth factor), participating in the regulatory mechanisms of regeneration.The role of TNF alpha and IL -6 in launching early liver regeneration mechanisms in response to her injury.Molecular studies have identified a series of immediately-early genes such as proto-oncogenes c-fos, c-myc, c-jun and jun B, which are induced within minutes after partial hepatectomy and require synthesis for activation.They activate transcription factors, existing in hepatic cells.In more recent studies have identified these factors - nuclear factor kappa B (NF - kV) and signal transducer and activator of protein transkriptatsionnogo 3 (STAT 3), which activation occurs as part of the primary reaction to hepatectomy.Inducer of NF -sq is a TNF alpha, the level of which is enhanced by the production of activated-producing cells of the cytokine - resident macrophages and endothelial cells.In turn, NF - kB induces the production of IL -6, which activates STAT 3. Study regenerative process deficient mice revealed IL -6 its key role in this process.The introduction of recombinant IL -6 to these mice completely restored STAT 3 activity and hepatocyte proliferation.These first steps trigger a cascade of events that involve the transfer of the cell cycle of hepatocyte quiescent state in Go phase G 1 and S phase (DNA synthesis), G 2 M phase (mitosis) and division of cells.It is found that a violation of the regulatory system that controls the G1 phase of the cell cycle is the basis for the development of gepatokartsinogeneza.These data, combined with observations of the animals in which liver regeneration is inhibited in the absence of endotoxins provided the basis for the hypothesis.Acute hepatic tissue loss causes high levels of endotoxin in the portal vein, which activates the endothelial cells and Kupffer cells.Neparenhimatoanye stimulated cells release TNF alpha that activates NF - kB followed by release of IL -6.IL -6, affecting the surrounding hepatocytes directly transactivate-early genes through the binding of STAT 3, followed by proliferation of hepatocytes.
However, the protective role of proinflammatory cytokines significantly reduced when the damage is already morphologically altered liver.Comparison of the liver of healthy rats and rats chronically exposed to ethanol plunge revealed the latter's vulnerability to fatal signals that are triggered by activation of the type I TNF alpha receptor.Mediated by TNF - alpha increased production of active oxygen radicals hepatocytes holds in damage.
study on the role of cytokines in damage, maintaining the activity of the inflammatory process and liver regeneration altered numerous.The greatest coverage was given to the effect of TNF alpha on the activity of the inflammatory process in the liver.It was found that the level of TNF alpha in the blood serum is positively correlated with the concentration of alanine aminotransferase.Liver biopsies of patients of chronic cal hepatitis and cirrhosis of the liver with high ALT synthesized more of TNF alpha than liver tissue with low cytolytic.In chronic viral hepatitis and cirrhosis of the liver TNF alpha.have a special role in tissue damage.It is shown that the source of this cytokine with chronic viral hepatitis are not only the infiltration of inflammatory cells and hepatocytes.
Thus ostrofaznyh increased production of cytokines (IL -1, IL -6, TNF alpha) is necessary only for a short period to initiate cell growth.Lack of control of the process leads to the stage of acute phase response to the stimulation of production of amyloid peptides, protein synthesis inhibition of hepatocytes, inhibition of gluconeogenesis, disruption of mitochondrial respiration and induction of hepatocellular apoptosis.Moreover, a persistent increase in pro-inflammatory cytokines can lead to the progression of liver cirrhosis and current converting stellate cells into the collagen-producing cells.
mechanism that reduces the activity of liver regeneration progression cirrhotic process with the increase of hepatic failure, has not been determined.Since the proliferation of hepatocytes, the activity of which is determined by the index of the cell nucleus antigen proliferation (PCNA), is an essential component of the regenerative response to injury, a number of studies devoted to the study of this index, its relationship with other components that determine the course of hepatic cirrhosis.Of interest is the sequence of PCNA index decrease, depending on the pathophysiological and pathological nature of liver disease.The proportion of hepatocytes positive for PCNA, decreases in the following order: acute viral hepatitis, chronic viral hepatitis, liver cirrhosis.Thus, increasing of liver fibrosis can be associated with low levels of hepatocyte proliferation.
Reduced proliferative activity of hepatocytes in liver cirrhosis has nothing to do with liver growth factors.The absence of communication hepatocyte growth factor (HGF) regeneration of liver after hepatectomy about hepatocarcinoma etc. and metastases in the liver, its level is not significantly different in patients with cirrhosis and healthy individuals.Moreover, HGF levels were higher in patients with liver cirrhosis decompensated patients unlike in compensated cirrhosis stage.
TGF - alpha (transforming growth factor - from Alfa), a potent mitogen of hepatocytes, determined in all patients with cirrhosis of the liver in 60% of patients with chronic hepatitis and only 33% of healthy individuals.These data indicate that hepatic growth factors increases with deterioration of liver function.However, PCNA index detected negative correlation with the level of TGF -beta1, primary cytokine responsible for fibrogenesis.It is suggested that the increase in the level of TGF -beta1, as well as a decrease in hepatic function may reflect fibrogenesis activity, increasing fibrosis.
A direct correlation PCNA index of serum albumin, reflecting belkovosinteticheskuyu liver function.Quantitative ranges PCNA index, allowing a forecast position to evaluate for cirrhosis.Patients with an index value was above 4.4%, had a higher probability of survival.PCNA index equal to 4.4% or lower, significantly reduces the probability of survival.
literature These data suggest that the cirrhotic process of acute phase cytokines (or pro-inflammatory cytokines) mainly act as damaging factors that support inflammation and fibrogenesis.It is of interest to establish levels of TNF alpha and IL -6, determining the course of liver cirrhosis, and their relationship with biochemical indicators reflecting belkovosinteticheskuyu function and activity of the inflammatory process, the identification of the role of anti-inflammatory cytokine IL -10.These studies appear relevant in connection with the creation of recombinant cytokines and development of methods of cytokine and anti-cytokine therapy.