Biomedical Engineering Reference
In-Depth Information
15
% amino acid sequence homology
and at least six cell-surface receptors have been
described. The two members of this cytokine
family that have been the most extensively
characterized are TNF and Fas ligand (FasL).
The ligands of this family are all predominantly
type II transmembrane proteins. The receptors
are all type I transmembrane proteins and are
believed to aggregate upon interaction with
their ligands. Although the extracellular side
of the receptors is conserved and composed
of cysteine repeats, the cytoplasmic domains of
the receptors are different and mediate unique
activities that lead to a multitude of biological
responses through variations in their coupled
signal transduction processes. These cytokines
have been implicated in a wide variety of
diseases, including tumorigenesis, septic shock,
viral replication, bone resorption, rheumatoid
arthritis, diabetes, and other infl ammatory
diseases [
% to
25
growth, primarily through the activation of the
nuclear factor
B) and c-Jun N-terminal
kinase (JNK) transcription factors. The dichot-
omy of cellular responses to these cytokines
resides in the receptors that are activated and
the downstream signal transduction molecules
that interact with these receptors. Signal trans-
duction is mediated through a two-part system
of docking proteins including MORT/FADD,
TRADD, RIP, and CRADD, which bind to the
death domain (DD) of the receptors, and the
adaptor proteins that have been named TRAFs.
Downstream from the coupled responses to
TNFR
κ
B (NF
κ
that mediate cell survival
are the various mitogen-activated protein
(MAP)-related kinases. Downstream from the
apoptotic activation of TNFR
1
and TNFR
2
and FAS is the
activation of specifi c proteases (caspases) [
1
19
,
121
]. There is a further bifurcation
of the apoptotic cascade, with two separate
pathways that can mediate apoptosis: an intrin-
sic (mitochondria-dependent low caspase
,
153
,
187
]. Recently, several
therapeutic regimens have been approved that
antagonize TNF-
19
,
121
,
153
,
187
)
pathway and an extrinsic (mitochondria-
independent high caspase
8
activity to treat a variety of
autoimmune diseases, including rheumatoid
arthritis and Crohn's disease [
α
]. To
understand the complex regulatory functions
within a tissue that are mediated through the
actions of the TNF cytokine family, it is neces-
sary to defi ne the ligands and to specify the
actions of specifi c receptors and the specifi c
mechanisms of intracellular transduction
within that tissue.
8
) pathway [
185
]. Pre-
liminary studies have also examined whether
these approaches can be used to impede the
loosening of orthopedic prostheses [
163
,
184
].
The TNF family members with the most
homogeneity are TNF-
37
α
, TNF-
β
(LT-
α
), and
LT-
β
. Both TNF-
α
ligands and TNF-
β
(LT-
α
)
are homotrimers, whereas LT-
β
is a heterotri-
mer of (LT-
)
2.
There are three receptors
in this family: TNFR
α
)
1
(LT-
β
2.2.1.1 TNF Cytokines as Arbitrators of the
Tissue Microenvironment by Selective
Promotion of Cell Death or Survival
The TNF family of cytokines plays a central
role in the timing of the immune response,
namely, when to terminate activation of the
innate infl ammatory response and initiate the
acquired immune response, and when to termi-
nate an innate or acquired response and initi-
ate local tissue repair and regeneration. Thus
both TNFR
1
/p
55
/death receptor
1
/
DR
receptor. Both
TNF ligands bind both TNF receptors, but LT-
β
1
, TNFR
2
(p
75
), and LT-
β
trimers only bind to the LT receptor.
FasL is a unique family member and is solely
recognized by its receptor, FAS/Apo
/TNF-
α
1
/DR
2
[
211
].
Most cells express TNF-
and its receptors, but
the expression of TNF-
α
and its receptor
appears to be restricted to T cells and natural
killer cells. TNFR
β
) is constitutively
expressed by almost all cells, but TNFR
1
(p
55
)
is strongly induced in immune and infl amma-
tory responses. FasL and Fas are also expressed
by many cells but show unique expression
during many developmental processes, includ-
ing the hypertrophy of chondrocytes [
2
(p
75
and Fas mediate activation-
induced cell death in macrophages, T cells, and
B cells [
1
]. The pathological manifes-
tations of inappropriate control of the apop-
totic processes in immune function are seen in
mice that are defi cient in TNFR
99
,
111
,
187
]
and the regulation of immune cell differentia-
tion [
72
,
174
1
, Fas, and FAS/
and related cyto-
kines either mediate programmed cell death
(apoptosis)
17
,
23
,
55
,
192
]. TNF-
α
TNFR
. These animals exhibit more severe
autoimmune disease and accelerated lym-
phoproliferation. These responses indicate that
1
or
facilitate
cell
survival
and
