Biology Reference
In-Depth Information
DCs can mature upon exposure to LPS and acquire a distinct set of surface
markers that are regulated by cyclic nucleotides. Cyclic nucleotide treatment inhib-
ited the increase in DC-LAMP and CD83 normally brought on with LPS stimulation.
DC-LAMP is a lysosome-associated membrane glycoprotein that belongs to
DC-specific apparatus for antigen processing. Different antigen-presenting
cells have distinct endocytic routes used for processing antigen, with specific
markers characterizing each step. CD68 or macrosialin is another lysosomal
marker expressed on both macrophages and DCs and is inversely regulated from
DC-LAMP; as DC-LAMP appears in these compartments, CD68 levels are reduced.
Curiously, while DC-LAMP expression was reduced in the presence of cyclic
nucleotides, CD68 remained unaffected. Therefore, it seems that an increase in
cyclic nucleotide levels during differentiation could impair the ability of DCs to
process antigen, but does not inhibit antigen-processing machinery shared with other
cells of the myeloid lineage.
DCs differentiated in the absence of PGE
2
, but matured in its presence, also
acquire an increased ability to migrate toward the lymph nodes via CCR7 and
exhibit improved ability to activate CD4 T cells suggesting the involvement of
PGE
2
in facilitating CCR7 signaling (Luft et al.
2002
; Scandella et al.
2002
).
However, when DCs are differentiated in the presence of cyclic nucleotide analogs,
the induction of CCR7 by LPS is reduced (Giordano et al.
2003
). CCR7 confers the
ability onto dendritic cells to migrate toward CCL19, which is a vital step in leading
DCs to lymph nodes and downstream T-cell activation. Despite a potential reduc-
tion in CCR7 levels, these DCs do still acquire strong antigen-presenting capabil-
ities, as they are able to activate CD4 T cells in allogenic mixed leukocyte reactions,
a measure of their function as DCs. This is likely due to the upregulation of the
costimulatory molecule CD86 and the antigen-presenting molecules MHCII DQ
and DR (Giordano et al.
2003
). This effect of cyclic nucleotides seems to be
dependent on the timing of exposure to cAMP-inducing agents during differentia-
tion or maturation, as somewhat disparate results are obtained depending on the
methodology used for differentiation, maturation, and cyclic nucleotide elevation.
Interestingly, dendritic cell maturation in serum-free conditions, but in the
presence of a cytokine cocktail, leads to a DC capable of a nonbiased Th2 response
(Morelli and Thomson
2003
; Scandella et al.
2002
). While this is in contrast with
previous in vitro data using fetal calf serum-containing media, it is likely that in
the context of an inflammatory response in vivo the effect of PGE
2
is to permit the
generation of DCs that are capable of secreting the full range of cytokines, not just
Th2 cytokines.
Stimulation of adenosine receptors and subsequent elevation of cAMP during
monocyte to DC differentiation results in a distinct cell population characterized by
changes in expression of cell surface markers common to both DCs and monocyte/
macrophages, but remaining morphologically similar to DCs (Hask´ et al.
2009
).
Using knockout animals and pharmacologic inhibition of adenosine receptors, it
was discovered that the G
a
s-coupled A
2B
adenosine receptor was the mediator of
the phenotypic observations. Adenosine-differentiated DCs express high levels
of angiogenic (VEGF), proinflammatory (IL-8, COX-2, IL-6), immune suppressive
