Biomedical Engineering Reference
In-Depth Information
differentiate properly, although this defect is independent of NF-
κ
B activity. The
IKK
α
-/-
mouse can be rescued by knocking-in or reconstituting
in vitro
with IKK
α
in which both of the activation loop serines are mutated to alanines (IKK
α
AA)
[9,10]. As an aside, it appears that IKK
in keratinocytes is also responsible for
limb bud development, as selective expression of IKK
α
α
or kinase dead IKK
α
in
basal keratinocytes rescues the morphogenetic defects of the
IKK
α
-/-
mice [11]. The
mechanism of NF-
B-independent control of keratinocyte differentiation immedi-
ately downstream of IKK
κ
is unknown. However, it is dependent on the presence
of a previously unrecognized nuclear localization signal (NLS) in IKK
α
(aa232-
240) [11], suggesting that, perhaps, this function is mediated by the proposed role
of IKK
α
α
in histone modification (
Chapter 5
). Therefore, while NF-
κ
B is critical to
epidermal proliferation, differentiation, and function, IKK
has a distinct role in
epidermal development that is independent of these pathways.
NF-
α
B has also been proposed to have an important role in the maintenance of
other epithelial tissues. In particular, NF-
κ
B is necessary for wound reconstitution
using intestinal epithelial cells
in vitro
[12], while induction of NF-
κ
B protects
epithelial cells from radiation damage
in vivo
[13]. Despite contributing to inflam-
mation, NF-
κ
κ
B is likely also important in repair of damaged lung epithelium [14].
6.3
DEVELOPMENT AND SURVIVAL OF INNATE
IMMUNE CELLS
Many hematopoietic cells are subject to relatively high levels of turnover and con-
sequently these populations are sensitive to changes in rates of apoptosis or prolif-
eration. Consistent with its role as an antiapoptotic survival factor, NF-
B serves
several key functions in the homeostasis of many hematopoetic lineages. There are
two stages in the life of a leukocyte where cell survival decisions are particularly
important — hematopoiesis and activation/maturation. Leukocyte development, like
embryonic development, is marked by an abundance of both proliferation and apo-
ptosis that shapes the resulting tissue/cell population. In addition, during activation
and maturation into effector cells, many leukocytes undergo rapid proliferation that
must also be resolved apoptosis, in this case a process termed activation induced
cell death (AICD). In many regards our understanding of the contribution of NF-
κ
B
to the development and homeostasis of these cells has lagged relative to our knowl-
edge of individual signaling events. However, as the pathways responsible for the
development of natural killer (NK) cells, dendritic cells, macrophages, and granu-
locytes become better understood, it is likely that our appreciation for the role of
NF-
κ
κ
B in their regulation will expand.
6.3.1
D
EVELOPMENT
OF
I
NNATE
I
MMUNE
C
ELLS
Hematopoietic components of the innate immune system include monocytes, mac-
rophages, dendritic cells (myeloid and lymphoid), NK cells, granulocytes (basophils,
eosinophils, and neutrophils), and mast cells (
Figure 6.1
). While many cells of the
body contribute significantly to pathogen recognition, these marrow-derived cells
mediate inflammation and activation of the adaptive immune system and are, there-
