st in the development and course of
diseases of various organs and systems, including the digestive system.
Cytokines - endogenous bioactive mediators - representing
vast heterogeneous group of low molecular weight proteins, polypeptides.
Cytokines consist of one - two, rarelymorepolpeptidnyh (homo-and heterologous)
chains (monomers, dimmers, trimmers) with a molecular weight of 8 to 90 kD in
mostly 15-35 kDa encoded by their own genes. Cytokines produced by activated
cells, mainly lymphocytes, monocytes and tissue macrophages
in response to an external, extracellular stimulus. In addition to these
cells in the synthesis of cytokines may be involved fibroblasts, endothelial,
epithelial and other cells. Depending on the type producing cells
(leukocytes, monocytes), cytokines, referred to as interleukins (IL), monokini, etc.
[Tsaregorodtseva TM, Serova TI, 2003].
They regulate intercellular and inter-system interactions, determine
cell survival, stimulation or inhibition of their growth, differentiation,
functional activity and apoptosis. They ensure the consistency of
immune, endocrine and nervous systems in normal conditions and in response to
pathological effects.
now identifiedmorethan 100 cytokines, and their number continues to grow
. Cytokines provide a signal transmission, exchange of information between
cells within one organ, the relationship between the organs and systems, as in
physiological conditions and action of various pathogenic factors -
infectious organisms, mechanical, thermal, and chemical injuries. In
healthy cytokines is minimal, they are detected only in trace amounts
. In pathological states of the total number and content of individual
cytokines increases dramatically. Inducers of increased synthesis of cytokines are
infectious organisms (viasses, bacteria), products of their activity,
toxins, metabolites, and altered, modified cells
own body, some proteins of plant origin, edible, medicinal
allergens and other
Cytokines are active in very low concentrations. Their biological effect on cells,
realized through interaction with specific receptors localized on
cell cytoplasmic membrane. Formation and secretion of cytokines
is short and strictly regulated.
All cytokines on the stasctural characteristics and biological effects are divided into several independent groups
. Grouping of cytokines on the mechanism of action of cytokines
to divide into the following groups:
proinflammatory to ensure the mobilization of the inflammatory response;
anti restricting the development of inflammation;
regulators of cellular and humoral immunity - natural or
specific) having its own effector functions
(antiviral, cytotoxic).
We are interested in the correlation interaction between the pro-inflammatory cytokines
- gamma-interferon (g-IFN), interleukin 2 (IL2), and anti-inflammatory interleukin 10
(IL10) in seasm of patients
metabolic syndrome (MS) with a manifestation of gallstone disease (GSD). So
as we found out that in some cases, MS and CL is accompanied by infection
various hepatotropic viass with subsequent development of steatohepatitis,
chronic hepatitis, liver cirrhosis and hepatocellular carcinoma,
tsiokinovogo due to impaired balance. That cytokine imbalance,
in our opinion, play a key role in the genesis of the formation
chronic liver disease.
As is known, the spectra of the biological activity of cytokines is largely
overlap: the same process can stimulated in a cell formorethan one cytokine
. In many cases, the actions of cytokines observed synergism.
Cytokines - antigennespetsificheskie factors. Therefore, the specific diagnosis
infectious, autoimmune and allergic diseases by determining the levels of cytokines
impossible. But the determination of their concentration in the blood gives
information on the functional activity of different types of immune cells
; the severity of the inflammatory process and its transition to a system level and
the prognosis of the disease.
From cross-sectional studies found, that only a small group of patients
has risk factors for nonalcoholic fatty liver encountered in
metabolic syndrome, including the manifestation of gallstone disease, and that
subsequently develops from simple fatty liver (steatosis) to inflammation (steatohepatitis),
fibrosis and, ultimately, liver cirrhosis and hepatocellular carcinoma [Day
CP, 2005]. Need a clear understanding of the mechanisms that lead to
progression of the disease to develop strategies to prevent
diseases. Data from several studies published during
the last 2 years - mainly in the field of insulin resistance -
begun to shed light on the relationship between hepatic steatosis - still regarded as a purely
"metabolic" disease, steatohepatitis and insulin resistance related
with obesity and type 2 diabetes.
Recent genetic studies in an experiment on rats have shown that
liver steatosis is associated with a state of chronic liver inflammation [Arkan
MC et al., 2005; Cai D. et al., 2005]. Both of these models are characterized by increased activity of nuclear
indicator B (NF-B) and co-activator flow
IKK-NF-B - specific rate of transcription of the sequence, which
functioning as a pro-inflammatory "master key" during inflammation,
governing the allocation of a wide variety of inflammatory mediators.
Accordingly, the increased activity of nuclear factor (NF-B) in the liver of obese mice
high fat diet is associated with increased hepatic
release of inflammatory cytokines, including TNF, IL-6, IL-2 and IL-1 and activation of Kupffer cells
.
hepatocyte allocates specific nuclear factor NF-B, which lowers elevated
release of inflammatory genes and activation of Kupffer cells in response to receiving
fatty foods. As a result, may recover a specific allocation
hepatocyte co-activator (IKK-HFD). In the experiment, the obese mice were found
hepatic and systemic insulin resistance, which can be suppressed
allocated hepatocyte nuclei factor NF-B, which contains known cytokines
TNF, Il-6 and Il-1 [Samuel VT et al., 2004; Ueki K. Et al., 2004].
study Day CP [2005] clearly shows that obesity is associated with
liver steatosis caused by increased release of inflammatory cytokines
hepatocytes, which activate nuklearny factor NF-B, Kupffer cells
, and increase insulin resistance. Dedicated inflammatory cytokines
hepatocytes activates Kupffer cells and probably play a major role in shaping
steatohepatitis from steatosis.
Cytokines are able to determine all the classic histological features
non-alcoholic steatohepatitis (NASH), including necrosis / apoptosis of hepatocytes,
neutrophil chemotaxis, IL-8 by activating stellate cells and liver cells
Mallory. It was shown elevated cytokine in the liver of patients with NASH in
compared with control patients [Crespo J. et al., 2001]. Last
reports that apoptosis is an important way of cell death in NASH due to the influence
tumor-necrosis factor (TNF), can play a role in the interim
liver damage, as well as engender apoptosis in hepatocytes under oxidative
tension found in the liver of patients with NASH. Obesity also contributes to
proinflammatory cytokine release and the formation of
inflammation in the liver [Li Z. 2005].
Hyperlipidemia and hyperinsulinemia, hypoxia and viral infection may disaspt
homeostasis endoplasmic reticulum and activate a set of indicators
transcription and kinases [Ron D., 2002]. It coordinates the open protein response (UPR),
which slows protein synthesis and increases protein degradation. Nevertheless,
if this response inadequate, a number of proteins are activated and cause
endoplasmic reticulum, which can lead to insulin resistance (through
IRE1, JNK1), apoptosis (via caspase-12 in mouse cells and caspase- 4
human cells), inflammation (via NF-B) and mitochondrial dysfunction [Hidvegi
T. et al., 2005]. It is now believed that this is the answer
plays an indirect role in the formation of NASH, like alcohol, which causes liver damage
.
Addition to hepatocytes, synthesizing cytokines postulated
at least two other mechanisms that play a role in the activation of Kupffer cells in NASH and,
thus contributing to the pathogenesis of liver damage by cellular
inflammation. First, the clearance of oxidative deposits play a major role in the life
Kupffer cells by regulating the number of receptors. The combination of steatosis and
oxidative stress observed in NASH can lead to activation of Kupffer cells
. Secondly, consider that endotoxemia in portal blood,
coming from the intestine, subsequently might contribute to the Kupffer cells
with NASH. Excessive bacterial growth in the small intestine has been described in obese and
patients with diabetes and hyperinsulinemia due to lower
contractile ability of the intestine. The study showed that due to the inhibition of protein
hepatocyte NF-kB - enough to block
increased allocation of pro-inflammatory genes and activate the macrophages in the obese mouse model
with steatosis, and, nevertheless, testifies against his
participate in the activation of Kupffer cells [Day CP, 2005].
Finally, the recent confirmation of our assumption that the adipose tissue in
liver in obesity is characterized by infiltration of macrophages, and causes
chronic inflammation, is a source of cytokines, and thanks to her
endocrine role, contributes to the transformation of steatosis steatohepatitis.
exact mechanism of activation of macrophages, adipose tissue is not yet known, but
cytokines, isolated from the metabolic changes of adipocytes, macrophages,
adsorb oxidized lipids and systemic endotoxemia may play an important role in uncovering
pathogenesis of hepatic inflammation. At present, the selection
classical pro-inflammatory cytokines by adipose tissue macrophages
seems the most likely factor that plays a role in the formation of insulin resistance,
due to obesity through paracrine properties of adipocytes and muscle cells [Arkan
MC et al., 2005]. On the other hand, this seems unlikely to explain
significant endocrine effects in the liver, generating strong intrapechenochnye
sources of cytokines. However, elevated circulating levels of cytokines,
allocated adipocytes (adipokines), and leptin, discovered in obesity may
play a key role in the progression of steatosis to NASH [Day CP, 2005].
As noted above, cytokines play a cascial role in the immune response. They
participate in the development of the inflammatory process and play an important role in
liver injury by activating cytotoxic effector mechanisms. According to several authors
, HCV infection leads to the stimulation of cytokine production of Th1-type
interferon-gamma and IL-2. Elevated levels of proinflammatory cytokines
IL-1beta and TNF-alpha are installed in chronic hepatitis C. According to another
data, HCV and HBV infection increased seasm concentrations of IL-4 and IL-6,
simultaneously reducing the level of IL-2 .
To clarify the influence of some cytokines in liver tissue of patients we have studied the concentration of proinflammatory
g - interferon, interleukin (IL) 2 and
anti-IL-10 in 20 patients with metabolic syndrome
manifestation of gallstone disease II-1 and HCV infection (Table 1).

Table 1. Concentrations of