Biology Reference
In-Depth Information
properties of PDE4 inhibition can be of significant clinical benefit, and PDE4
inhibitors are currently being developed to treat COPD, asthma, and other inflam-
matory conditions (Houslay et al.
2005
). Recently, two large phase III clinical trials
using the PDE4-specific inhibitor roflumilast (Daxas) as treatment of COPD were
reported (Calverley et al.
2009
; Fabbri et al.
2009
), showing significant improve-
ment in lung function. However, side effects such as nausea, diarrhea, weight loss,
and headache were also reported. Roflumilast was approved in the European
Commission in July 2010 for treatment of severe COPD associated with chronic
bronchitis in adult patients but has still not obtained FDA approval.
1.4 The Functional Role of PDE7 in T Cells
The PDE7 gene family comprises two genes, PDE7A and PDE7B, and PDE7A
transcripts have been shown to be widely expressed in immune cells (Bloom and
Beavo
1996
; Gardner et al.
2000
; Hetman et al.
2000
). More specifically, expres-
sion of PDE7A1 is restricted mainly to T cells and brain, and PDE7A3 is expressed
in activated CD4
+
T cells (Bloom and Beavo
1996
; Glavas et al.
2001
; Smith et al.
2003
). Whereas resting T cells mainly express PDE3 and PDE4, TCR/CD28
costimulated cells upregulate their PDE7 levels (Li et al.
1999
). The functional
role of PDE7 in T cells has, however, been controversial. PDE7A1 was reported to
be required to obtain proper IL-2 production and proliferation in TCR/CD28
costimulated T cells in a study using targeted antisense oligonucleotides (Li et al.
1999
). However, T cells from PDE7A-deficient mice did not reveal any deficiencies
in T-cell function (Yang et al.
2003
). The expression profiles of PDE7A transcripts
indicate that PDE7-selective inhibitors could have a broad application as immuno-
suppressants, and recently, PDE7 inhibitors have become available (Guo et al.
2009
; Kadoshima-Yamaoka et al.
2009
). One PDE7A inhibitor increased the effect
of rolipram in T cells without having a similar effect itself (Smith et al.
2004
).
A recent study used the PDE7 inhibitor ASB16165 to examine the functional role
of PDE7 in generation and function of cytotoxic T lymphocytes (CTL), and it
was suggested that PDE7 and not PDE4 plays the major role in induction and
function of CTL in mice (Kadoshima-Yamaoka et al.
2009
). Development of dual
PDE4-PDE7 inhibitors is another strategy that could result in drugs blocking
T-cell components of a disease by inhibiting PDE7 in addition to possessing anti-
inflammatory properties (Giembycz
2005
; Yamamoto et al.
2007
). However, more
work is required before the exact role of PDE7 in controlling immune responses can
be teased out and PDE7 inhibitors positioned therapeutically.
2 Concluding Remarks
PDEs play a key role in compartmentalization of cAMP signaling. Scaffolding and
spatiotemporal control of receptors, cyclases, and PKA by AKAPs in addition to
generation of local pools of cAMP within the cell by the action of PDEs give rise to
