Biology Reference
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The activity and type of cyclase present is another factor that can affect cyclic
nucleotide levels in any cell. CD14+ monocytes were found to have high levels of
soluble guanylyl cyclase, which was decreased slightly upon differentiation to
a macrophage with GM-CSF (Bender et al.
2004
). The levels of GC-A were
undetectable in monocytes, with greatly increased levels in macrophages. These
changes could affect the cells' ability to respond to a number of cGMP-increasing
factors including nitric oxide and atrial natriuretic peptide (ANP).
More recently, the effects of chronic elevated cyclic nucleotide levels on the
function and final phenotype of monocytes differentiating to alveolar-type macro-
phages were investigated (Hertz et al.
2009b
). Human CD14+ monocytes were
differentiated in the presence of GM-CSF for 6 days in combination with cAMP-
increasing agents, such as the adenylyl cyclase agonist forskolin, the EP receptor
agonist PGE
2
, and selective PDE inhibitors to assess the effects of elevated cAMP
levels on the final phenotype of the macrophage. Initially, monocytes were treated
with a high dose of forskolin in culture for 6 days. A microarray analysis was
performed on RNA extracted from the resulting macrophages and, unexpectedly,
a number of proinflammatory genes were upregulated, especially chemokines
binding to the CXCR2 and CCR2 classes of receptors. Expression of the cytokines
IL-10 and IL-6, as well as a number of genes involved in wound-healing, were also
increased upon differentiation in the presence of cAMP (see Fig.
2a
). A phenotypic
analysis of these forskolin-treated cells showed that differentiation was not halted
as was seen previously with GM-CSF + IL-4-induced dendritic cell differentiation
(Giordano et al.
2003
), but the expression of a number of surface markers was
altered. Notably, the downregulation of CD14, the coreceptor for LPS, and CD163,
a scavenger receptor, was prevented with forskolin treatment.
Fig. 2 Effects of cAMP on monocytic differentiation to macrophages and dendritic cells. Mono-
cytes isolated from human blood can be differentiated in the presence of cytokines GM-CSF or
GM-CSF plus IL-4 to give rise to macrophages and dendritic cells, respectively. When differ-
entiated in the presence of elevated cyclic nucleotides, the final phenotypes of these cells are
altered. Differences in cytokine and chemokine production are observed as well as changes in
surface marker expression levels
