Disease relevance of PDE4B

• These findings suggested that PDE4, PDE4B and/or 4D regulate cell growth through cAMP targets in the HMG malignant melanoma cell line [1].
• The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT-dependent apoptosis in diffuse large B-cell lymphoma [2].
• Infection of rPASMC with an adenovirus specifying a dominant negative cAMP response element binding protein (CREB) mutant inhibited the GSNO-induced increase of PDE4B gene expression [3].
• Recombinant baculoviruses were constructed to express cDNAs encoding two distinct subtypes of human cAMP-specific phosphodiesterase (hPDE4A and hPDE4B) [4].

High impact information on PDE4B

• LPS stimulation of mouse peripheral leukocytes induced PDE4B mRNA accumulation and increased PDE4 activity [5].
• These findings demonstrate that PDE4B gene activation by LPS constitutes a feedback regulation essential for an efficient immune response [5].
• Hence, DLBCLs that express high PDE4B levels may be resistant to cAMP-induced apoptosis, contributing to their less favorable outcome [2].
• Herein, we confirmed the risk-related expression of PDE4B in an independent series of primary DLBCLs and defined the enzyme's role in modulating cAMP-induced apoptosis in parental DLBCL cell lines or those reconstituted with wild-type or mutant PDE4B [2].
• Phosphodiesterase 4B (PDE4B) inactivates the second messenger cyclic adenosine 3',5' monophosphate (cAMP) and abrogates its inhibitory effects in B lymphocytes [2].

Biological context of PDE4B

• For PDE4B, the catalytic domain is sufficient for interactions with the inhibitors studied: IBMX, trequinsin, rolipram, TVX 2706, RP 73401 and RS-25344 [6].
• The amount of message for PDE4A and PDE4B appeared to increase upon up-regulation, whereas mRNA for PDE4D was not detected in treated cells [7].
• 4. In both sets of experiments, mean IC50 values were significantly correlated with compound potency against the catalytic activity of recombinant human PDE4A or PDE4B when analysed by either linear regression of log IC50 values or by Spearman's rank-order correlation [8].
• Our results reveal that selectivity of PDE4B activation can be achieved by differential receptor association and phosphorylation of the alternatively spliced forms of this PDE [9].
• Very recently, we found in monocytes that PDE4B gene expression is selectively induced by lipopolysaccharide (LPS) and that the induction is inhibited by interleukin (IL)-10 and IL-4 [10].

Anatomical context of PDE4B

• In CD4 and CD8 lymphocytes PDE4A, PDE4B and PDE4D were detected, with no significant differences observed between healthy and asthmatic groups [11].
• 5. These results suggest that PDE4A and/or PDE4B may play the major role in regulating these two inflammatory cell functions but do not rule out PDE4D as an important mediator of other activities in mononuclear leukocytes and other immune and inflammatory cells [8].
• DMSO-treated HL60 cells: a model of neutrophil-like cells mainly expressing PDE4B subtype [12].
• In peripheral blood T cells, two previously reported PDE4B isoforms could be detected: one was 75-80 kDa (PDE4B1) and the other was 65-67 kDa (PDE4B2) [9].
• In the present study, we demonstrate, for the first time, that lipopolysaccharide (LPS) significantly and selectively stimulated PDE4B mRNA production in human monocytes [13].

Associations of PDE4B with chemical compounds

• RESULTS: Rolipram increased levels of PDE4B and, to a variable extent, PDE4D [14].
• The kinetics of phosphorylation of TCR-associated PDE4B2 correlated with changes in cAMP levels, suggesting that tyrosine phosphorylation of the TCR-associated PDE4B isoform upon engagement of this receptor may be an important regulatory step in PDE4B function [9].
• Interestingly, unlike LPS induction, the dibutyryl-cAMP induction of PDE4B mRNA expression was not inhibited by IL-10 [13].
• The GSNO-induced increase in PDE4B mRNA levels was blocked by actinomycin D but augmented by cycloheximide [3].
• Cyclic AMP phosphodiesterases in the zebra finch: distribution, cloning and characterization of a PDE4B homolog [15].

Regulatory relationships of PDE4B

• In this study, we show that the PDE4B gene is constitutively expressed in neutrophils and that this expression remains unaffected by LPS or IL-10 [10].

Other interactions of PDE4B

• Using semi-quantitative RT-PCR, we detected a 50-70% decrease in the mRNA of PDE4A and PDE4B subtypes following Dex treatment [16].
• PDE4A and PDE4B mRNAs also are markedly abundant, whereas lower expression is observed for PDE4C mRNAs [17].
• To identify amino acid residues involved in PDE3-selective inhibitor binding, we selected eight presumed interacting residues in the substrate-binding pocket of PDE3A using a model created on basis of homology to the PDE4B crystal structure [18].
• A model of PDE3B was constructed based on the X-ray crystal structure of PDE4B [19].
• All of the 4 expressed isoforms of PDE (PDE1C, PDE2, PDE 4A, and PDE4B) were increased in mRNA expression; the levels of PKA RIalpha, RIbeta, and RIIbeta were increased moderately, however, those of RIIalpha and Calpha were increased remarkably [20].

Analytical, diagnostic and therapeutic context of PDE4B

• Western blots showed increases in the amount of protein for both PDE4A and PDE4B after treatment [7].
• Molecular cloning and transient expression in COS7 cells of a novel human PDE4B cAMP-specific phosphodiesterase, HSPDE4B3 [21].
• Identification of overlapping but distinct cAMP and cGMP interaction sites with cyclic nucleotide phosphodiesterase 3A by site-directed mutagenesis and molecular modeling based on crystalline PDE4B [22].

References