PDE4B Is a Homeostatic Regulator of Cyclic AMP in Dendritic Cells

Amy M Chinn; Cristina Salmerón; Jihyung Lee; Krishna Sriram; Eyal Raz; Paul A Insel

doi:10.3389/fphar.2022.833832

PDE4B Is a Homeostatic Regulator of Cyclic AMP in Dendritic Cells

Front Pharmacol. 2022 Mar 21:13:833832. doi: 10.3389/fphar.2022.833832. eCollection 2022.

Authors

Amy M Chinn¹, Cristina Salmerón¹, Jihyung Lee², Krishna Sriram¹, Eyal Raz², Paul A Insel^{1

2}

Affiliations

¹ Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States.
² Department of Medicine, University of California, San Diego, La Jolla, CA, United States.

Abstract

Chronic decreases in the second messenger cyclic AMP (cAMP) occur in numerous settings, but how cells compensate for such decreases is unknown. We have used a unique system-murine dendritic cells (DCs) with a DC-selective depletion of the heterotrimeric GTP binding protein Gα_s-to address this issue. These mice spontaneously develop Th2-allergic asthma and their DCs have persistently lower cAMP levels. We found that phosphodiesterase 4B (PDE4B) is the primary phosphodiesterase expressed in DCs and that its expression is preferentially decreased in Gα_s-depleted DCs. PDE4B expression is dynamic, falling and rising in a protein kinase A-dependent manner with decreased and increased cAMP concentrations, respectively. Treatment of DCs that drive enhanced Th2 immunity with a PDE4B inhibitor ameliorated DC-induced helper T cell response. We conclude that PDE4B is a homeostatic regulator of cellular cAMP concentrations in DCs and may be a target for treating Th2-allergic asthma and other settings with low cellular cAMP concentrations.

Keywords: PDE4B; Th2 immunity; compensation; cyclic AMP (cAMP); phosphodiesterase (PDE).

Grants and funding

R01 HL141999/HL/NHLBI NIH HHS/United States