3 research outputs found
Nuclear localization of TRK-A in liver cells
The liver represents a site of expression of
neurotrophins and their receptors. We have characterized
the expression and intracellular localization of the nerve
growth factor (NGF) receptor, Trk-A, in liver cells in
vivo and in vitro. In both normal and fibrotic liver tissue,
Trk-A immunostaining was present in different cell
types, including parenchymal cells and cells of the
inflammatory infiltrate. In hepatocytes and activated
stellate cells (HSC), Trk-A showed a predominant
nuclear localization, both in the presence and absence of
injury. In cultured HSC, Trk-A was found to be
functional, because exposure of the cells to recombinant
NGF resulted in stimulation of cell migration and
activation of intracellular signaling pathways, including
Ras-ERK and PI3K/Akt. Remarkably, in cultured HSC,
Trk-A staining was found constitutively in the nucleus.
In these cells, Trk-A could be stained only by antibodies
directed against the intracellular domain but not by those
recognizing the extracellular portion of Trk-A
suggesting that the intracellular portion of the receptor is
the major determinant of nuclear Trk-A staining. In contrast to HSC, freshly isolated hepatocytes did not
show any nuclear localization of the intracellular portion
of Trk-A. In pheocromocytoma cells, nuclear staining
for Trk-A was not present in conditions of serum
deprivation, but could be induced by exposure to NGF or
to a mixture of soluble mediators. We conclude that
nuclear localization of the intracellular domain of Trk-A
is observed constitutively in liver cells such as HSC,
while in other cell types it could be induced in response
to soluble factors
Resistin as an Intrahepatic Cytokine : Overexpression during Chronic Injury and Induction of Proinflammatory Actions in Hepatic Stellate Cells
Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-ÎșB. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-ÎșB activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca(2+)/NF-ÎșB-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis