Biology Reference
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up to as much as 50% of the total cell population (Giordano et al.
2003
). The
authors speculate that cyclic nucleotide signaling may be a part of the intracellular
mechanisms used to modulate expansion of this subpopulation in pathological
conditions.
DCs generated in the presence of physiological concentrations of PGE
2
, and
therefore elevated cAMP, demonstrated Th-cell stimulation abilities comparable to
the control DCs differentiated in the absence of PGE
2
. However, the ability of
PGE
2
-DCs to produce IL-12 was markedly reduced when stimulated with IL-12-
inducing agents such as soluble CD40L, and even in the presence of the normally
potent IL-12 inducing agent, IFN-
g
(Kalinski et al.
1997
). When the concentration
of PGE
2
was increased to 100 nM, the cells' IL-12 producing ability was
completely abolished. Conversely, production of the anti-inflammatory cytokine
IL-10 was markedly increased with PGE
2
pretreatment, but decreased with IFN-
g
cotreatment. This profile was maintained over 48 h after the removal of PGE
2
, and
the ability of these DCs to produce other Th cell-polarizing cytokines was also
altered. PGE
2
-DCs retained higher IL-4 and IL-5 producing capacity and produced
70% less IFN-
g
than control DCs. The ability of PGE
2
-DCs to promote Th2-type
differentiation of na¨ve T cells was largely due to the absence of IL-12, which
would normally drive the cell to a Th1 phenotype, not due to the presence of an
additional secreted factor. Similar results were observed by another group when a
PDE4 inhibitor was administered during differentiation of monocytes to dendritic
cells, prior to final maturation (Heystek et al.
2003
).
In a pathological situation, cyclic nucleotide levels will be elevated not only
during differentiation of monocytes, but also during maturation into the final
macrophage or dendritic cell. The effects of PGE
2
on DC maturation were found
to act as a cofactor and synergize with TNF-
a
and IL-1
b
to induce final maturation
of immature DCs (Kalinski et al.
1998
). The adenylyl cyclase agonist, forskolin,
mimicked the effects of PGE
2
, indicating that final maturation can be influenced
directly by cAMP levels. After final DC maturation, PGE
2
and IL-10 were no
longer able to affect the phenotype of the DC, indicating that shaping of the mature
DC phenotype occurs while the immature DC is a tissue resident and capable of
taking up antigen. Therefore, the levels of IL-12 production and mature DC
phenotype are predetermined at the stage of immature DC in peripheral tissues.
The stability of the phenotype for up to 2 days after exposure to PGE
2
implies that
the DC phenotype will be retained upon its arrival in the draining lymph node,
allowing it to contribute to the development of Th2-biased responses without
picking up irrelevant signals as it migrates to the lymph node.
This effect on maturation is not isolated only to cAMP, similar effects have been
observed with elevated intracellular levels of cGMP. In one set of studies, mature
DCs were derived from CD14+ human monocytes and matured/activated with LPS
(Morita et al.
2003
). When these cells were pretreated with the guanylyl cyclase
agonist ANP, the LPS-induced expression of IL-12 and TNF-
a
was decreased and
IL-10 expression was augmented similar to what was observed for cAMP (Morita
et al.
2003
). This phenotype is also able to polarize CD4+ T cells toward promoting
Th2 responses through interactions in the absence of IL-12 production.
