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Studies were also performed in a mouse myeloid cell line to demonstrate
the effects of cAMP on differentiation. Increasing cAMP levels using either
8-Br-cAMP or PGE
1
can induce macrophage differentiation in M1 myeloid cells,
which were engineered to express the M-CSF receptor (Wilson et al.
2005
).
Increased cAMP can potentiate M-CSF-induced differentiation in cells containing
the receptor through ERK activation, as differentiation was halted with the addition
of a MEK inhibitor. These cells also retain the ability to inhibit M-CSF stimulated
macrophage proliferation through phosphorylation of the M-CSF receptor. It has
also been shown that cAMP can modulate M-CSF-induced MAPK activation of
ERK, JNK, and p38 in a time-dependent manner, thereby inhibiting macrophage
development (Zhu et al.
2008
).
6 Conclusions
PDEs are a class of enzymes with a number of isoforms distributed throughout all
tissues and cell types in the body. PDE5 inhibition has emerged as a proven method
to treat erectile dysfunction and pulmonary hypertension. The ability to selectively
inhibit a PDE in order to modulate cellular function is an exciting prospect for
many future therapies. However, the administration of these inhibitors may carry
unintended consequences when they affect the differentiation or activation of cells
also containing the targeted PDE. For example, chronic administration of a PDE
inhibitor would presumably increase the cyclic nucleotide levels in all cell types
containing the targeted PDE. Observations of these increased levels are difficult to
confirm in vivo and in vitro work utilizing monocyte or bone marrow-derived cells
has been widely used as a surrogate for in vivo differentiation conditions.
Elevated cyclic nucleotide levels can have profound effects on the final pheno-
type of the cell when present during differentiation or maturation. Dendritic cell
differentiation can be arrested in the presence of increased cAMP or cGMP at an
intermediate stage between monocyte and dendritic cell. The capabilities of these
dendritic cells are also altered, skewing its T-cell activation capacity toward a Th2
type response, largely due to the lack of IL-12 produced. Macrophage differentia-
tion does not seem to be halted by elevated cyclic nucleotides, but a number of
characteristics are altered. cAMP normally has anti-inflammatory actions on
macrophages, but recent work has uncovered the role of cAMP in increasing
chemokine and cytokine expression.
The alteration of hematopoietic differentiation by cyclic nucleotides and PDE
inhibitors is also important regarding clinical efforts to generate therapeutic cell
types from monocytes ex vivo. Generation of specific cell types from pluripotent
and multipotent cells ex vivo for therapeutic usage holds great promise. For
example, numerous efforts have been undertaken to develop DC or macrophage
populations ex vivo that target specific antigens for fighting cancer (Paczesny et al.
2003
), to treat chest wound infections after open heart surgery (Orenstein et al.
2005
), to treat other refractory wounds (Zuloff-Shani et al.
2004
), as a treatment for
