Biomedical Engineering Reference
In-Depth Information
effort to characterize the role of NF-
κ
B in the development of primary lymphoid
tissues, one NF-
B family member has a clear role in thymic development — RelB.
RelB is responsible for much of the constitutive NF-
κ
B activity observed in various
tissues, in addition to being the primary mediator of gene expression resulting from
activation of the alternative pathway. Deletion of
relB
results in decreased basal
NF-
κ
B activity in the thymus and spleen as well as severe deficits in adaptive
immunity [1]. Furthermore, there is a specific defect in thymic medullary epithelial
cells and a loss of functional thymic dendritic cells in mice lacking
relB
[2]. Deletion
of p52 and p50 results in thymic atrophy, perhaps also due to a decrease in RelB-
dependent signaling via RelB:p52 containing complexes. Although the role of RelB
in the thymus is not known definitively, there is one promising RelB target. In the
thymus RelB regulates the expression of autoimmue regulator (AIRE), a transcription
factor that has a role in organizing medullary thymic stroma [3], and there is some
evidence that suggests RelB does so in response to LT
κ
R knockouts
share phenotypic similarities with AIRE knockouts, in terms of autoimmune tissue
infiltration, and have decreased upregulation of AIRE in the thymic medullary epi-
thelial cells [4]. Given that lymphotoxin knockouts do not have thymic medullary
defects [5], it is likely that RelB acts both upstream and downstream of LT
β
R signaling. LT
β
R
signaling and that AIRE expression requires stimuli in addition to that mediated by
LT
β
R stimulation is
but one of the important functions carried out by RelB in thymic organogenesis.
Bone marrow is the central repository for all hematopoietic lineages, is the site
of the initial stages of hematopoietic development and differentiation, and has a role
in lymphocyte homeostasis and function. A subset of NF-
β
R. Consequently, regulation of AIRE expression following LT
β
B pathway knockouts
display phenotypes in bone that are worth discussing here, as they are not discussed
tion of bone and develop from monocytes, a process mediated primarily by activation
of receptor activator of NF-
κ
B (RANK, also known as TNFR super family member
11A) by RANKL (also known as TRANCE, ODF, OPGL and TNFSF11) expressed
on stromal cells [7]. RANKL is also important in the activation of mature osteoclasts
in normal bone remodeling, as well as inflammation-induced bone destruction.
RANK mediates NF-
κ
B activation through TRAF6, and TRAF6-deficient animals
show a similar defect in osteoclastogenesis to that observed in RANK knockouts
[7,8,9,10,11]. The NF-
κ
B p50 and p52 dKO, which interferes with classical and
alternative pathways, leads to a loss of osteoclasts and consequent osteopetrosis, a
disease in which bones are overly dense [12,13].
While these data clearly show the importance of NF-
κ
B in osteoclastogenesis,
the relative contribution of the alternative and classical pathways is somewhat
unclear. NIK deficient mice have normal bone development, but display defects in
late stages of osteoclastogenesis when analyzed
in vitro
[14,15]. IKK
κ
deficient
embryos have decreased multinucleate osteoclast formation
in vivo
, although when
IKK
α
(AA) no osteo-
petrosis is observed in adult mice [16,17]. The same study that failed to observe
defects in IKK
α
knockouts are complemented
in vivo
with defective IKK
α
(AA) mice reported defects in the formation of multinucleated
giant cells, the final stage of osteoclastogenesis, in IKK
α
/TNFR1 dKO mice. This
suggests that the classical pathway is more important for osteoclastogenesis
in vivo
.
β
