Page 145 - Read Online

production and lipid peroxidation. Elevation of the Cytokines and hepatic HCV infection

inflammatory markers above normal levels is an In HCV infection, the production of abnormal cytokine
independent predictor of several chronic diseases, levels appears to contribute in the progression of
including coronary heart disease, stroke, diabetes, the disease, viral persistence, and affects response
atherosclerosis and insulin resistance. [41] to therapy. Cytokine genes polymorphisms located
within the coding/regulatory regions have been
Cytokines and hepatic cholestasis shown to affect the overall expression and secretion
Cholestasis is defined as a decrease in canalicular bile of cytokines. [6]
flow that results in accumulation of bile in hepatocytes
and canaliculi. [42] Hepatocellular cholestasis may be The pathogenesis of liver cell damage in HCV infection
due to functional or structural alterations in the may be related to several immunologic mechanisms
[49]
biliary tree. The clinical consequences of prolonged and the subsequent T-cell responses. Patients with
cholestasis are due to the failure of bile acids to chronic HCV infection, viral persistence which is a
reach the duodenum with subsequent malabsorption characteristic feature of chronic hepatitis C may be
of fat and fat-soluble vitamins A, D, E and K as well as due to selective immune responses deficiencies and
the accumulation of biliary constituents such as bile the production of inappropriate cytokine patterns. [50]
acids, bilirubin and cholesterol in the liver. Bile acids
retention causes liver cell damage and pruritus. [43] The involvement of macrophage derived cytokines
such as TNF-α and IL1β in the production of
[51]
TNF-α plays a critical role in epithelial cell injury as inflammation has been described. TNF-α acts
well as in immune-mediated cholangiocyte injury. [44] as important mediator in liver injury and generally
Systemic levels of TNF-α are increased following biliary associated with several known cirrhosis-related
obstruction in experimental cholestasis produced complications. Moreover, TNF-α is positively related
[52]
by ethinylestradiol in rats. [45] Furthermore, TNF-α (in with the extent of liver necrosis.
combination with other inflammatory cytokines) inhibits Adhesion molecules are necessary for leucocytes
cholangiocyte secretory function in vitro. [44] to adhere tightly to endothelial cells and have
been reported to be cytokine-induced. Intercellular
In cholestatic diseases, the intrahepatic bile acids adhesionmolecule-1 (ICAM-1) is one of the principal
induce hepatocellular apoptosis by stimulating Fas adhesion molecules expressed on sinusoidal and
(a surface receptor that mediates apoptosis upon venular endothelial cells and involved in firm adhesion
oligomerization by its ligands) translocation from and trans endothelial cell migration. [53] Consequently,
the cytoplasm to the plasma membrane where self- The predominant features of HCV-C are more related
aggregation occurs to trigger apoptosis. Apoptosis with those that allow viral evasion of the immune
[46]
is known to be the mechanism leading to progressive defenses, especially although not exclusively,
inflammation and destruction of bile ducts. Also, inhibition of interferons secretion, natural killer cells
[47]
bile acids can induce hepatic inflammatory response activation and T cell-mediated cytotoxicity. [54]
via the activation of hepatic macrophages that
[46]
follows the activation of the transcription factor Several researchers have suggested that an adequate
NF-kB, since NF-kB activation has been shown to T-helper 1 (Th1) response [i.e. high interferon (IFN)-γ
have a key role in the inflammatory process. It is secretion by peripheral blood mononuclear cells]
[48]
well known that NF-kB is activated by a wide range may be associated with a protective antiviral immune
of agents and cytokines including TNF-α and IL-1α response, while insufficient systemic Th1 cytokine
[55]
secreted from the injured hepatic macrophages. [48] secretion may be associated with increased viral load
and disease progression. Indeed, serum samples
[56]
Proinflammatory cytokines were reported to stimulate from HCV patients contain significantly lower level of
the billiary epithelium to generate nitric oxide (NO), soluble IFN-γ compared with controls. [57] In this sense,
via nitric oxide synthase induction. NO causes ductular it has been reported that the IL-18 and IFN-γ mRNA
cholestasis by a reactive nitrogen oxide species expression in the liver were significantly correlated
mediated inhibition of adenyle cyclase and cAMP- with each other and both upregulated in chronic HCV
dependent HCO - and Cl- secretory mechanisms. patients. It was suggested that inheritance of IL-
[58]
3
This pathogenetic sequence may contribute to ductal 28B CT and TT, transforming growth factor (TGF)-β1
cholestasis in inflammatory cholangiopathie. [44] CT and TT and TNF-α AG and AA genotypes which
136 Hepatoma Research | Volume 2 | June 1, 2016