Biology Reference
In-Depth Information
liver disease and fulminant hepatic failure. TNF
is a pro-inflammatory
cytokine produced mainly by activated macrophages and in smaller
amounts by other cell types. Hepatocyte apoptosis induced through
the extrinsic pathway is initiated by the activation and signaling
through the TNF receptor family of proteins following the binding of
ligands such as TNF
α
-related apoptosis-
inducing ligand (TRAIL; also called APO-2L) or APO-3L to their
respective receptors. TNF
α
, Fas ligand (FasL), TNF
α
and FasL are considered to play major
roles in liver injury. Following the binding of TNF
α
to its receptor
TNFR1, the receptor trimerizes and together with the adaptor pro-
tein TNFR-associated death domain (TRADD) recruits the receptor
interacting protein (RIP) and TNFR associated factor (TRAF2) that
trigger downstream signaling and activation of NF
α
B.
71
TRADD
can also recruit the Fas-associated death domain (FADD) protein,
triggering a series of events leading to FADD-mediated apoptosis
(Fig. 4). Binding of FasL to Fas (or CD95) initiates signaling through
DISC (death inducing signaling complex) by recruiting FADD to the
cytoplasmic tail of Fas. The N-terminal death effector domain (DED)
of FADD recruits pro-caspase 8/10, causing its proteolytic activation
by the FADD-like IL-1
κ
converting enzyme (FLICE).
72
The death
receptor-initiated pathway diverges at this point. One pathway is inde-
pendent of mitochondria and Bcl2 and is based on the activation of
pro-caspase 3
73
(Fig. 4). The other pathway is mediated through cas-
pase 8/10-mediated cleavage of Bid, and the truncated Bid (tBid)
molecule opens mitochondrial channels causing the release of
cytochrome c.
73
An alternate pathway in which TRAF2 or the Fas-
binding protein Daxx recruits the Ask1 kinase results in activation of
the c-Jun N-terminal kinase (JNK) and suppression of the anti-apop-
totic effects of Bcl2 on mitochondria. Depending upon their ability to
activate caspase 8, caspase10 or NF
β
B, the TNF family members are
regarded as pro-apoptotic or anti-apoptotic proteins.
The HCV core protein activates NF
κ
B signaling by binding to
the death domain of TNFR1,
74,75
thereby contributing to liver dam-
age. However, expression of the HCV core protein confers resistance
to TNF-induced apoptosis. Immunohistochemical studies showed a
higher frequency of NF
κ
κ
B staining in HCV-infected livers compared
