Role of JNK in Liver Endogenous Immunity and Non-parenchymal
Cells
JNK-mediated hepatocyte necrosis releases DAMP which interacts with
pattern recognition receptors (such as toll-like receptors) on
inflammatory cells, leading to release of pro-inflammatory cytokines
(such as TNFαand INF-γ) thus promoting inflammatory responses. In
addition, a previous study reports that phosphorylation of JNK was
significantly inhibited after silencing TLR4 in the RAW264.7 immune cell
line [140]. Therefore, TLR4 can activate JNK signaling pathway to
induce an inflammatory response and infiltration of macrophages thus
promoting APAP-induced liver injury [140]. Also, it has been
reported that TLR3 can act on JNK to be injury-provoking in the model of
APAP-induced liver injury [141]. Hematoxylin-eosin (HE) staining
shows significant infiltration of inflammatory cells in areas with liver
injury [142]. Therefore, the endogenous immune system, including
liver macrophages, is induced during APAP hepatotoxicity, causing
aseptic inflammation [143]. Moreover, previous studies report an
increase in release of inflammatory factors such as TNF-α, IL-1β and
IL-6 and immune cells such as neutrophils, macrophages, NK cells and NKT
cells are recruited. These factors may exacerbate liver damage through
the effect of NKT cells and effectors such as INF-γ[97].
Additionally, neutrophil-mediated damage, secondary to hepatocyte
necrosis, may promote APAP-induced liver injury [144].
Mannan-binding Lectin (MBL), a molecule in the innate immune system that
is mainly produced by the liver, promotes JNK activation and
up-regulates nuclear expression of Specificity Protein 1 (SP1) to
aggravate liver damage [145]. Previous studies report that JNK
regulates secretion of IL-2, proliferation of CD8+ T cells and
differentiation of CD4+ T cells into helper T cells [146].
Furthermore, knockout of TNF or TNFR1 protects liver cells against
APAP-induced damage. These findings show that JNK regulates immune cells
or the immune factor TNF or FasL-induced injury of liver cells during
APAP-induced liver injury. However, these immune or inflammatory cells,
including NK cells and NKT, can also play protective roles
[147-149]. Furthermore, mice devoid of the interferon Fas or Fas
ligand did not show APAP-induced liver damage whereas those that lacked
interleukin-10 and interleukin-6 were protected against liver damage
[150].
Therefore, in vivo studies provide reliable findings compared
with in vitro experiments on the role of the endogenous immune
system in APAP-induced liver injury (regardless of whether it aggravates
damage or offers protection). In addition, should be carried out to
explore the specific role of JNK in regulation of immune cells in
APAP-induced liver injury.
A previous study reports that JNK1 is highly induced and a significant
increase in levels of p-JNK is observed in mice with specific knockout
of JNK1 and JNK2 in their hepatocytes. In addition, the levels of
infiltration in the liver explains the phenomenon of JNK activation
after APAP administration [109]. Notably, a previous study using a
hepatocellular carcinoma model reported that the effect of JNK in
promoting development of liver cancer mainly involves non-parenchymal
cells and not hepatocytes [151]. Furthermore, sinusoidal endothelial
cells are more sensitive compared with hepatocytes to APAP-induced liver
injury [152]. Therefore, studies on the role of JNK in APAP-induced
liver injury should also focus on the effects on non-parenchymal cells.