Biomedical Engineering Reference
In-Depth Information
deficient B cells exhibit defects in NF-
B activation in response to engagement of
TLR9, which signals via MyD88 [61,102]. Interestingly, TAK1-deficient B cells or
IRAK4-deficient macrophages have diminished NF-
κ
B activation when stimulated
with LPS or poly I:C-signaling, which depend either partially (LPS) or completely
(poly I:C) on Toll/IL resistance domain containing protein inducing interferon beta
(TRIF) [61,95]. However,
there is one important difference between MyD88- and
TRIF-dependent NF-
κ
B activation: TRAF6 is only essential for MyD88-signaling
— at least in bone marrow derived macrophages [103,104].
So far, no data conclusively implicate other known TRAF proteins in TIR-
mediated NF-
κ
B activation. Although TRAF3, which also contains a RING-finger
motif is recruited into MyD88- and TRIF-dependent signaling complexes, experi-
ments performed with TRAF3 knockout macrophages show that it is not involved
in IKK-activation [104]. Instead, TRAF3 is required for recruitment of the IKK-
related kinase TBK1/NAK (and probably IKKi/IKK
κ
) into the TIR signaling com-
plex, thereby controlling the TLR-mediated type I interferon and IL-10 response
[104]. Notably, the C-terminus of TRIF has been found to bind RIP1 via a so-called
RHIM domain and RIP1-deficient fibroblasts exhibit reduced NF-
ε
B activation when
incubated with poly I:C [105,106]. However, at least in fibroblasts, TRIF-dependent
activation of NF-
κ
[107],
which may also explain the involvement of RIP1. It is clear that more detailed
experimental data from primary gene deficient cells will be required to resolve these
questions. Taken together, although the last few years have witnessed a substantial
increase in our understanding of microbial recognition by innate immune receptors
of the TLR family and what molecules are involved in TIR-mediated signaling, little
information has been gathered about the molecular details of the mechanism of IKK
activation beyond what has been learned from studies of TNFR signaling.
κ
B was found to require autocrine production of TNF
α
3.4.3
A
CTIVATION
OF
THE
NF-
κ
B P
ATHWAY
BY
T C
ELL
AND
B C
ELL
R
ECEPTORS
During recent years, our understanding of T cell receptor (TCR) and B cell receptor
(BCR) dependent cell activation has progressed remarkably through the identifica-
tion of several novel molecules that play critical roles in NF-
B activation [108]. In
contrast to the receptors mentioned above, TCR and BCR are directly associated
with cytoplasmic protein kinases and initiate cell activation through a sequence of
tyrosine-phosphorylation events. This cascade ultimately leads to activation and
recruitment of protein kinase C isozymes (PKC
κ
for BCR) to
the membrane in the vicinity of the activated antigen receptors. IKK activation
requires several molecules, that is, caspase recruitment domain (CARD)-membrane
associated guanylate kinase (CARMA1)/CARD11, BCL10, and mucosal associated
lymphoid tissue 1 (MALT1), whose roles in NF-
θ
for TCR and PKC
β
κ
B activation have been substanti-
ated by gene
disruption and even forward genetics experiments [108] (
Figure 3.4
).
Based on the use of mutant cells as well as transient transfection experiments it
appears that CARMA1, which is constitutively localized at the cell membrane, is
required for recruitment of BCL10 and MALT1 to the membrane in response to
receptor activation [109,110]. Interestingly, a recent paper showed that TCR-
