Potential role of phosphodiesterase 7 in human T cell function: comparative effects of two phosphodiesterase inhibitors

Abstract

SUMMARY Even though the existence of phosphodiesterase (PDE) 7 in T cells has been proved, the lack of a selective PDE7 inhibitor has confounded an accurate assessment of PDE7 function in such cells. In order to elucidate the role of PDE7 in human T cell function, the effects of two PDE inhibitors on PDE7A activity, cytokine synthesis, proliferation and CD25 expression of human peripheral blood mononuclear cells (PBMC) were determined. Recombinant human PDE7A was obtained and subjected to cyclic AMP‐hydrolysis assay. PBMC of Dermatophagoides farinae mite extract (Df)‐sensitive donors were stimulated with the relevant antigen or an anti‐CD3 monoclonal antibody (MoAb). PBMC produced IL‐5 and proliferated in response to stimulation with Df, while stimulation with anti‐CD3 MoAb induced CD25 expression and messenger RNA (mRNA) synthesis of IL‐2, IL‐4 and IL‐5 in peripheral T cells. A PDE inhibitor, T‐2585, which suppressed PDE4 isoenzyme with high potency (IC50 = 0·00013 μM) and PDE7A with low potency (IC50 = 1·7 μM) inhibited cytokine synthesis, proliferation and CD25 expression in the dose range at which the drug suppressed PDE7A activity. A potent selective inhibitor of PDE4 (IC50 = 0·00031 μM), RP 73401, which did not effectively suppress PDE7A (IC50 > 10 μM), inhibited the Df‐ and anti‐CD3 MoAb‐stimulated responses only weakly, even at 10 μM. PDE7 may play a critical role in the regulation of human T cell function, and thereby selective PDE7 inhibitors have the potential to be used to treat immunological and inflammatory disorders.

Functional characterization of the human phosphodiesterase 7A1 promoter

“…These observations might be relevant in the context of T-cell activation, which involves PKC signalling, and requires induction of hPDE7A [12]. Moreover, the use of selective inhibitors has revealed the general contribution of hPDE7 to the regulation of T-cell functions [32]. hPDE7A1 and hPDE7A3 might share a common promoter hPDE7A isoforms are differentially expressed in some tissues.…”

“…Genomic DNA (30 µg) was digested with BamHI, BamHI + HpaII or BamHI + MspI. Digested DNAs were then analysed by electrophoresis on 0.8 % agarose/ Tris/borate/ EDTA gels, transferred to nylon and hybridized with a randomly labelled 32 P probe spanning nucleotides − 1425 to − 290 of the hPDE7A 5 -flanking region.…”

Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use

“…PDE7 antisense oligonucleotides inhibited proliferation and IL-2 production in a PKA-dependent manner (Li et al, 1999). With PDE4/PDE7 dual inhibitors, it was also reported that PDE7 may play a role in Tlymphocyte activation (Nakata et al, 2002). However, in another study the PDE7 selective inhibitor BRL 50481 had only a small effect on CD8 ϩ lymphocyte cell proliferation and only in the context of concomitant PDE4 inhibition (Smith et al, 2004).…”

“…The functions of the enzyme remain largely to be determined. However, PDE7 mRNA and protein are expressed in a wide variety of immune cells (Smith et al, 2003), and evidence suggests that PDE7 may play a role in T-lymphocyte activation (Li et al, 1999;Glavas et al, 2001;Nakata et al, 2002;Smith et al, 2004). Given the high value of pharmacological targets that are involved in inflammation, a great deal of effort has been expended in developing PDE7 selective inhibitors.…”

Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia

“…Both PDE7 inhibitors, used at concentrations below the IC 50 for inhibition of other PDEs, selectively induced apoptosis of CLL cells (Fig. 3A) (16)(17)(18).…”