Biology Reference
In-Depth Information
PDE inhibitors have been investigated as anti-inflammatory agents, anti-hyperten-
sives, anti-depressants and as a therapy for muscular dystrophies. Of the most
relevance to monocyte function and development are a number of clinical studies
that have been conducted with PDE4 inhibitors as anti-inflammatory agents. While
promising as in vitro agents and in preclinical studies, so far the PDE4 inhibitors
have met with limited success as anti-inflammatory therapeutics in the clinic. Until
recently, little has been known about how cyclic nucleotides and PDE inhibition
can affect monocytic differentiation. Since drugs that selectively inhibit PDEs will
increase cyclic nucleotide levels in targeted cells at all stages of differentiation,
they are likely to affect the final phenotype of the differentiating cell as well as the
differentiation process itself. PDE profiles can also change over the lifetime of the
cell or during the progression of a disease state, thereby affecting its response to
endogenous cyclic nucleotide-increasing agonists or to PDE inhibitor therapy
(Bender et al.
2004
; Essayan
2001
; Gantner et al.
1997b
). Indeed, in the presence
of such agonists as histamine, adenosine, and prostaglandins, it is possible for
macrophages to acquire a role as so-called regulatory macrophages (Mosser and
Edwards
2008
), while DCs are altered in their ability to activate the adaptive
immune response (Morelli and Thomson
2003
).
PDE profiling is a first step in analyzing the contribution of PDEs to cellular
signaling pathways. In monocytes and monocyte-derived cells, PDE4 is generally
considered a major PDE controlling many important inflammatory functions (Conti
et al.
2003
; Houslay et al.
2005
; Spina
2008
). However, it is important to note that
PDE activity measurements can vary depending on substrate concentrations and
methods used to analyze activity. PDEs also function in discrete compartments
within the cell to limit the spread of the second messengers cAMP and cGMP
(Bornfeldt
2006
; Fischmeister et al.
2006
; Houslay
2010
). Therefore, a PDE whose
total activity level is low could still contribute significantly to cellular function by
controlling an important microdomain within the cell.
This chapter explores the role of altered cyclic nucleotide levels and inhibition
of PDEs in monocytic differentiation and maturation into macrophages, dendritic
cells, and osteoclasts, as well as the effect on the phenotype of the final differ-
entiated cell.
2 Macrophage Differentiation
2.1 HL-60
Over 20 years ago, the HL-60 cell line was isolated from the peripheral blood of a
patient with acute promyelocytic leukemia (Harris and Ralph
1985
). HL-60 cells
can be induced to differentiate to macrophage-like cells by a number of agents,
including those that elicit a sustained elevation of intracellular cAMP or cGMP
(Bang et al.
1994
; Boss
1989
; Nonaka et al.
1992
).
