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proteins can also be altered. The immediate downstream mediators for cAMP are
PKA, Epac, and nucleotide-gated ion channels. The levels of these mediators can
also change over the course of monocyte to macrophage differentiation and matu-
ration. Task
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n's group identified a number of signaling molecules downstream of
cAMP in monocytes and macrophages. Monocytes contained the regulatory PKA
subunits RI-
a
, RII-
a
and the catalytic C subunit, with high levels of RI-
a
and lower
levels of RII-
a
(Bryn et al.
2006
). Monocytes differentiated in the presence of
human AB serum and M-CSF produce macrophages that exhibit a threefold
increase in Epac1 mRNA levels. Presumably, this would translate into an increased
role for Epac and its downstream signaling through Rap1 and the MAP kinase
pathways in macrophage function. Strangely, these investigators found that Epac
activation had a minimal effect on mature macrophage functions for most condi-
tions tested, such as inhibition of TNF-
a
or IL-12 secretion. The majority of
macrophage functions remained PKA-dependent and therefore unaffected by treat-
ment with the Epac-specific activator, 8-CPT-2
0
-O-Me-cAMP. In one functional
assay for phagocytic capability, however, FcR-mediated phagocytosis was reduced
equally by both PKA and Epac-specific activators in mature macrophages, while in
undifferentiated monocytes, there was no effect of the Epac-specific cAMP analog
alone. Although this study was not exhaustive, it definitively showed a minimal
involvement of Epac in the regulation of monocyte/macrophage inflammatory
function and a major role for PKA.
2.3.3 M-CSF
When monocytes are instead differentiated using M-CSF and fetal calf serum,
a distinct set of characteristics are acquired (Geissmann et al.
2010
). These cells
have moderate levels of a number of PDEs involved in degradation of both cGMP
and cAMP and changes in guanylyl cyclase activity. M-CSF-derived macrophages
retain modest PDE4, PDE3, and PDE1 levels. For the cGMP PDEs, PDE2 activity
increases slightly with M-CSF differentiation, and PDE5 activity decreases to
undetectable levels (Bender and Beavo
2004
; Bender et al.
2004
). In addition to
the regulation of the cyclic nucleotide-degrading PDEs, these investigators also
observed changes in the levels of the cGMP-producing guanylyl cyclases, likely
affecting the availability of cGMP in the cells. The levels of GC-A were undetect-
able in monocytes, with slightly increased levels in M-CSF macrophages, while
soluble GC mRNA levels were dramatically downregulated upon differentiation to
a macrophage.
The physiological implications of these changes are not immediately clear.
Expression of particular PDEs or cyclases is often linked with specific signal
transduction pathways through localization with a specific receptor, anchoring
protein or kinase. For example, if PDE5 is tightly linked with other members of
the cGMP pathway, the loss of PDE5 with M-CSF differentiation may be coupled
to a loss in sGC and a decrease in responsiveness to NO (Bender et al.
2004
).
Similar correlations could also occur with cAMP signaling pathways, leading to
