PDE8 Regulates Rapid Teff Cell Adhesion and Proliferation Independent of ICER

Abstract

BackgroundAbolishing the inhibitory signal of intracellular cAMP by phosphodiesterases (PDEs) is a prerequisite for effector T (Teff) cell function. While PDE4 plays a prominent role, its control of cAMP levels in Teff cells is not exclusive. T cell activation has been shown to induce PDE8, a PDE isoform with 40- to 100-fold greater affinity for cAMP than PDE4. Thus, we postulated that PDE8 is an important regulator of Teff cell functions.Methodology/Principal FindingsWe found that Teff cells express PDE8 in vivo. Inhibition of PDE8 by the PDE inhibitor dipyridamole (DP) activates cAMP signaling and suppresses two major integrins involved in Teff cell adhesion. Accordingly, DP as well as the novel PDE8-selective inhibitor PF-4957325-00 suppress firm attachment of Teff cells to endothelial cells. Analysis of downstream signaling shows that DP suppresses proliferation and cytokine expression of Teff cells from Crem −/− mice lacking the inducible cAMP early repressor (ICER). Importantly, endothelial cells also express PDE8. DP treatment decreases vascular adhesion molecule and chemokine expression, while upregulating the tight junction molecule claudin-5. In vivo, DP reduces CXCL12 gene expression as determined by in situ probing of the mouse microvasculature by cell-selective laser-capture microdissection.Conclusion/SignificanceCollectively, our data identify PDE8 as a novel target for suppression of Teff cell functions, including adhesion to endothelial cells.

Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP-signaling modules in T cells

“…This site has been previously reported to regulate ARHGEF2 activity (40). Moreover, ARHGEF2-dependent RhoA activity also has been shown to regulate the uropod of migrating T cells (71), in accordance with the report by Vang et al (88) that PDE8 inhibition caused a decrease in T-cell motility. In the current study, the combination of PDEs 1, 7, and 8 showed the largest increase in ARHGEF2 phosphorylation.…”

PDE3 and PDE4 Isozyme-Selective Inhibitors Are Both Required for Synergistic Activation of Brown Adipose Tissue

“…Rolipram (Enzo Life Sciences, New York, NY) is a selective PDE4 inhibitor that does not distinguish between PDE4 isoforms. PF-04957325 (Pfizer, New York, NY) is a selective PDE8 inhibitor that will inhibit PDE8A and PDE8B with similar affinities and was a gift from the manufacturer (structure published in Vang et al, 2010). IBMX (Sigma-Aldrich) is a nonselective PDE inhibitor.…”

Proteomic analysis of exhaled breath condensate for diagnosis of pathologies of the respiratory system

“…In this study the EBC proteomic composition of the 79 donors, including patients with different pathologies of the respiratory system has been investigated. Cytoskeletal keratins type II (1, 2, 3, 4, 5, 6) and cytoskeletal keratins the type I (9,10,14,15,16) were invariant for all samples. Analyzing the frequency of occurrence of proteins in different groups of examined patients, several categories of protein have been recognized: found in all pathologies (Dermcidin, Alpha-1-microglobulin, SHROOM3), found in several pathologies (CSTA, LCN1, JUP, PIP, TXN), and specific for a single pathology (PRDX1, Annexin A1/A2).…”

“…Во всех группах с различной частотой встречаемости присутствовали цитоскелетные кератины II типа (1, 2, 3, 4, 5, 6) и цитоскелетные кератины I типа (9,10,14,15,16). Примерно с одинаковой частотой во всех рассматриваемых группах доноров были идентифицированы такие белки, как иммуноглобулин альфа, кинниноген, сывороточный альбумин, цинк-альфа2-гликопротеин, лизоцим.…”

“…В рамках данного исследования проанализирован протеомный состав КВВ 53 доноров, включая пациентов с различными заболеваниями дыхательной системы. Инвариантными для всех проб являлись цитоскелетные кератины II типа (1, 2, 3, 4, 5, 6) и цитоскелетные кератины I типа (9,10,14,15,16). Анализируя частоту встречаемости белков в разных группах можно выделить несколько категорий белков: обнаруженные у всех (дермцидин, альфа-1-микроглобулина, SHROOM3), в двух группах одновременно (CSTA, LCN1, JUP, PIP, TXN) и специфичные для одной группы (PRDX1, Аннексин А1/A2).…”