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cells stimulated with schistosome antigen (Ag) Human liver contains an uncommonly high number
are significantly associated with the presence of of NKT cells that participate in the early regulation
hepatosplenomegaly. [75,76] As hepatosplenic disease of Thl/Th2 cell differentiation through the release
is a long-term complication of schistosomiasis and of IFN-γ and IL-4. Moritoki et al. [81] and Solari et al.
[82]
is considered to be indicative of severe hepatic and found an increased number of Vα24 positive cells
periportal fibrosis, it is conceivable that the immune and transcripts coding for this invariant Vα24 chain
mechanisms responsible for this lesion occur much in the liver of PAIH patients, pointing to a probable
earlier during infection and precede the downstream involvement of these regulatory cells as mediators of
development of hepatosplenomegaly. In addition the hepatocellular injury in PAIH.
[75]
Schistosoma japonicum significantly activates collagen
deposition and hepatic stellate cell in the liver, Cytokines and hepatic fibrosis, cirrhosis and cellular
however, fibrosis was accompanied by increased carcinoma
IFN-α, IFN-β, IFN-γ, IL-12, TNF-α, and IL-10 mRNA Chronic hepatic injury is associated with both
expression as well as decreased the expression of liver cirrhosis and liver cancer. [71] Several cytokines
IL-4, IL-5 mRNA, natural killer group 2 member D and ROS, produced in the injured liver by resident
(NKG2D) mRNA and tumor necrosis factor related macrophages and infiltrating leukocytes during
apoptosis-inducing ligand (TRAIL). [77] inflammatory conditions, cause transformation of the
quiescent HSCs into the activated phenotype, which
Cytokines and autoimmune hepatitis is responsible for fibrosis, cirrhosis and cancer. [71,83]
Autoimmune hepatitis (AIH) is an inflammatory liver
disorder, characterized by female preponderance, The perisinusoidal retinoid- storing quiescent HSCs
hypergammaglobulinaemia and interface hepatitis physiologically regulate liver architecture and blood
on histology. AIH is associated with impairment of flow by producing components of extracellular
regulatory T-cells, a lymphocyte subset key in matrix and contractility respectively. During hepatic
[78]
maintaining immune-tolerance to autoantigens. [79] injury, HSCs transform into retinoid-free proliferating
myofibroblast-like cells (activated HSCs, aHSCs),
Limited data are available for the participation of which express α-smooth muscle actin (α-SMA).
cytokines in the development of AIH. In a previous aHSCs are highly fibrogenic and contractile, and
study, Chernavsky et al. [80] analyzed the expression of play major role in causing architectural damage and

cytokines in liver biopsies from pediatric autoimmune portal hypertension. [83]
hepatitis (PAIH) patients in comparison with liver
control samples obtained from cadaveric liver A phenomenon of aHSCs rapid apoptosis was
donors. While the expression of IFN-γ and IL-12p40 observed among the proliferating cells during
[84]
was not detectable in control livers, it was clearly CCl -induced active fibrosis. During inflammatory
4
unregulated, and showed an increased expression liver injury, ROS are produced by resident
[80]
of IL-18, IL-4 and the 1L-12 β2 chain receptor in PAIH macrophages and infiltrating blood cells, particularly
[85]
patients. The unexpected increase of mRNA for IL-4, neutrophils. ROS-induced increased expressions of
a typical Th2 cytokine, was found in conjunction with α-SMA, collagen I and collagen III in rat and human
[86]
a severe histological inflammation in AIH. The up HSCs indicate their role in HSC activation and
regulation of IL-4 in PAIH but not in another disease fibrosis. While investigating the actions of ROS on
clearly suggests a more complex immunopathologic aHSCs it is noted that superoxide (SO) reduced their
mechanism. viability revealing that SO causes apoptosis of aHSCs
that involves mitochondrial release of cytochrome-C,
Th2 cytokines activate B cells and induce their activation of caspase-3 and increased expression
[87]
differentiation into antibody-producing cells. Liver- of Bax. During inflammation, the activated
infiltrat ing autoreactive B cells, in addition to their inflammatory cells produce fibrogenic cytokines
role in producing autoantibodies, also play a critical and growth factors that activate HSCs. The role
[88]
role in the development of fibrosis. The mechanism of cytokine gene polymorphism in the progression
of suppressing fibrosis by B-cell depletion is of liver fibrosis or development of cirrhosis in
independent of antibodies or T cells, raising the patients with hepatic diseases has been investigated
possibility that cytokines, produced or induced by extensively. Yee et al. indicated that TNF2 (-238A)
[89]
autoimmune B cell, are responsible for fibrosis in and TNF3 (-308A) alleles are frequently found in
autoimmune diseases targeting the liver. [81] patients with cirrhosis in chronic HCV infection.

138 Hepatoma Research | Volume 2 | June 1, 2016