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Potential role of phosphodiesterase 7 in human T cell function: comparative effects of two phosphodiesterase
1Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd, Saitama, Japan. a-nakata@tanabe.co.jp
Abstract:
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 microM) and PDE7A with low potency (IC50 = 1.7 microM) 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 microM), RP 73401, which did not effectively suppress PDE7A (IC50 > 10 microM), inhibited the Df- and anti-CD3 MoAb-stimulated responses only weakly, even at 10 microM. 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.
Insights
Phosphodiesterase 7 (PDE7) plays a critical role in human T cell function. Selective PDE7 inhibitors show potential for treating immunological and inflammatory disorders.
Area of Science:
- Immunology
- Pharmacology
Background:
- The function of phosphodiesterase (PDE) 7 in T cells is not fully understood due to the lack of selective inhibitors.
- Assessing PDE7's role requires specific inhibitors to evaluate its impact on T cell activity.
Purpose of the Study:
- To elucidate the role of PDE7 in human T cell function.
- To determine the effects of PDE inhibitors on PDE7A activity, cytokine synthesis, proliferation, and CD25 expression in human peripheral blood mononuclear cells (PBMC).
Main Methods:
- Utilized recombinant human PDE7A in cyclic AMP-hydrolysis assays.
- Stimulated PBMC from Dermatophagoides farinae (Df)-sensitive donors with Df extract or anti-CD3 monoclonal antibody (MoAb).
- Assessed cytokine production, proliferation, CD25 expression, and mRNA synthesis in response to PDE inhibitors T-2585 and RP 73401.
Main Results:
- The PDE inhibitor T-2585, which inhibits both PDE4 and PDE7A, suppressed T cell responses (cytokine synthesis, proliferation, CD25 expression) in a dose-dependent manner correlating with PDE7A inhibition.
- The selective PDE4 inhibitor RP 73401 showed minimal impact on T cell responses, even at high concentrations, indicating a limited role for PDE4 in these specific responses.
- T-2585 demonstrated inhibition of cytokine synthesis, proliferation, and CD25 expression at concentrations where it suppressed PDE7A activity.
Conclusions:
- PDE7 appears to be crucial in regulating human T cell function.
- Selective PDE7 inhibitors represent a potential therapeutic strategy for immunological and inflammatory disorders.