Biomedical Engineering Reference
In-Depth Information
ditions [20]. As TNF
is thought to play an important role in DC development, it
is not surprising that p65-/p50-deficient cells are susceptible to apoptosis induced
by this stimulus [21]. Thus, it appears that DC development broadly requires classical
NF-
α
κ
B complexes, while CD8
α
-
DC development is selectively dependent on the
alternative RelB-containing NF-
κ
B species.
6.3.2
S
URVIVAL
OF
C
ELLS
OF
THE
I
NNATE
I
MMUNE
S
YSTEM
Hematopoietic cells of the innate immune system have a finite lifespan in the
periphery. NF-
B plays a crucial role in protection of cells from apoptosis, and this
role is particularly crucial during exposure to proinflammatory stimuli. Therefore,
it is predicted that the cells of the innate immune system, which must function in
the presence of these same stimuli, will require NF-
κ
B to survive. Indeed, a large
body of evidence, both genetic and otherwise, validates the hypothesis that NF-
κ
B
protects innate immune cells from the induction of apoptosis by proinflammatory
cytokines. However, during the resolution phase of the inflammatory response, it is
beneficial to rid the host of activated cells that would otherwise needlessly prolong
the inflammatory process. As discussed in detail in
Chapter 8
, it has recently become
apparent that NF-
κ
B is also critical in mediating this process. Independent of inflam-
matory processes, however, ongoing maintenance of leukocyte homeostasis requires
careful orchestration of cell survival and death.
Survival of DCs, which exhibit variable turnover rates depending on subtype,
tends to be quite brief following activation. However, once stimulated, DC survival
can be prolonged through CD40 signaling induced by interactions with T cells. DCs
deficient in both p50 and c-Rel have decreased survival despite CD40 stimulation
[20]. The importance of CD40-mediated NF-
κ
B activation in the survival of activated
DCs has been confirmed in human cells using expression of inhibitory I
κ
κ
B
α
[22].
Therefore, NF-
B functions to prolong the survival of DCs that are destined to
undergo AICD. Whether NF-
κ
κ
B acts as a prosurvival factor in DC homeostasis,
however, is not known.
The role of neutrophils in the inflammatory response is discussed in detail in
Chapter 8. Nevertheless, it is relevant to mention here that NF-
B functions in
regulating the survival of circulating neutrophils. Under normal circumstances, neu-
trophils undergo daily turnover and have been shown to rapidly apoptose
in vitro
.
Despite their limited lifespan, there is evidence that NF-
κ
κ
B does enhance the survival
of mature neutrophils. Inhibition of NF-
B in neutrophils results in accelerated
apoptosis as well as sensitization to pro-apoptotic stimuli, including TNF
κ
. It is
interesting to note that neutrophils appear to lack p52 and RelB [23], which are
crucial in the maintenance of long-lived lymphocytes. However, neutrophils are
capable of activating NF-
α
B in response to many proinflammatory stimuli [24], and
protection from apoptosis is likely to be important during the inflammatory response.
Indeed, many TLR ligands increase neutrophil survival
in vitro,
and based on phar-
macological inhibition, this effect is likely due to NF-
κ
κ
B mediated expression of
antiapoptotic genes [25]. Thus, NF-
B promotes survival, differentiation, and pro-
liferation during the development and homeostasis of leukocytes and other cellular
components of the innate immune system.
κ
