{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T22:12:46Z","timestamp":1790979166750,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2009,5,1]],"date-time":"2009-05-01T00:00:00Z","timestamp":1241136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Phosphodiesterase (PDE)4 inhibitors, which activate cAMP signaling by reducing cAMP catabolism, are known to induce apoptosis in B lineage chronic lymphocytic leukemia (CLL) cells but not normal human T cells. The explanation for such differential sensitivity remains unknown. In this study, we report studies contrasting the response to PDE4 inhibitor treatment in CLL cells and normal human T and B cells. Affymetrix gene chip analysis in the three cell populations following treatment with the PDE4 inhibitor rolipram identified a set of up-regulated transcripts with unusually high fold changes in the CLL samples, several of which are likely part of compensatory negative feedback loops. The high fold changes were due to low basal transcript levels in CLL cells, suggesting that cAMP-mediated signaling may be unusually tightly regulated in this cell type. Rolipram treatment augmented cAMP levels and induced ATF-1\/CREB serine 63\/133 phosphorylation in both B lineage cell types but not T cells. As treatment with the broad-spectrum PDE inhibitor 3-isobutyl-1-methylxanthine induced T cell CREB phosphorylation, we tested a series of family-specific PDE inhibitors for their ability to mimic 3-isobutyl-1-methylxanthine-induced ATF-1\/CREB phosphorylation. Whereas PDE3 inhibitors alone had no effect, the combination of PDE3 and PDE4 inhibitors induced ATF-1\/CREB serine 63\/133 phosphorylation in T cells. Consistent with this observation, PDE3B transcript and protein levels were low in CLL cells but easily detectable in T cells. Combined PDE3\/4 inhibition did not induce T cell apoptosis, suggesting that cAMP-mediated signal transduction that leads to robust ATF-1\/CREB serine 63\/133 phosphorylation is not sufficient to induce apoptosis in this lymphoid lineage.<\/jats:p>","DOI":"10.4049\/jimmunol.0804255","type":"journal-article","created":{"date-parts":[[2009,4,21]],"date-time":"2009-04-21T01:07:38Z","timestamp":1240276058000},"page":"5400-5411","source":"Crossref","is-referenced-by-count":24,"title":["Chronic Lymphocytic Leukemia and B and T Cells Differ in Their Response to Cyclic Nucleotide Phosphodiesterase Inhibitors"],"prefix":"10.1093","volume":"182","author":[{"given":"John A","family":"Meyers","sequence":"first","affiliation":[{"name":"Evans Department of Medicine, Section of Hematology and Oncology, Boston Medical Center , Boston, MA 02118"},{"name":"Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derrick W","family":"Su","sequence":"additional","affiliation":[{"name":"Evans Department of Medicine, Section of Hematology and Oncology, Boston Medical Center , Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Lerner","sequence":"additional","affiliation":[{"name":"Evans Department of Medicine, Section of Hematology and Oncology, Boston Medical Center , Boston, MA 02118"},{"name":"Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,5,1]]},"reference":[{"key":"2026012807041011600_R1","first-page":"11236","article-title":"Inhibition of calmodulin dependent phosphodiesterase induces apoptosis in human leukemic cells.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1996"},{"key":"2026012807041011600_R2","first-page":"1489","article-title":"Phosphodiesterase 4 inhibitors and inflammatory bowel disease: emerging therapies in inflammatory bowel disease.","volume-title":"Expert Opin. Investig. Drugs","year":"2007"},{"key":"2026012807041011600_R3","first-page":"21","article-title":"Cyclic nucleotide phosphodiesterases as targets for treatment of haematological malignancies.","volume-title":"Biochem J.","year":"2006"},{"key":"2026012807041011600_R4","first-page":"1585","article-title":"Small-molecule inhibitors of PDE-IV and -VII in the treatment of respiratory diseases and chronic inflammation.","volume-title":"Expert Opin. Investig. Drugs","year":"2007"},{"key":"2026012807041011600_R5","first-page":"4847","article-title":"TCR- and CD28-mediated recruitment of phosphodiesterase 4 to lipid rafts potentiates TCR signaling.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012807041011600_R6","first-page":"533","article-title":"Identification and characterization of Ca2+-calmodulin-sensitive cyclic nucleotide phosphodiesterase in a human lymphoblastoid cell line.","volume-title":"Biochem. J.","year":"1987"},{"key":"2026012807041011600_R7","first-page":"6319","article-title":"T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2001"},{"key":"2026012807041011600_R8","first-page":"848","article-title":"CD3 and CD28-dependent induction of PDE7 required for T cell activation.","volume-title":"Science","year":"1999"},{"key":"2026012807041011600_R9","first-page":"97","article-title":"Rapid regulation of PDE-2 and PDE-4 cyclic AMP phosphodiesterase activity following ligation of the T cell antigen receptor on thymocytes: analysis using the selective inhibitors erythro-9-(2-hydroxy-3-nonyl)-adenine(EHNA) and rolipram.","volume-title":"Cell. Signal.","year":"1996"},{"key":"2026012807041011600_R10","first-page":"784","article-title":"Cyclic AMP phosphodiesterases in human lymphocytes.","volume-title":"Br. J. Haematol.","year":"1997"},{"key":"2026012807041011600_R11","first-page":"221","article-title":"In vitro differentiation of human monocytes to macrophages: change of PDE profile and its relationship to suppression of TNF-\u03b1 release by PDE inhibitors.","volume-title":"Br. J. Pharmacol.","year":"1997"},{"key":"2026012807041011600_R12","first-page":"238","article-title":"Life after PDE4: overcoming adverse events with dual-specificity phosphodiesterase inhibitors.","volume-title":"Curr. Opin. Pharmacol.","year":"2005"},{"key":"2026012807041011600_R13","first-page":"2484","article-title":"Type 4 cyclic adenosine monophosphate phosphodiesterase as a therapeutic target in chronic lymphocytic leukemia.","volume-title":"Blood","year":"1998"},{"key":"2026012807041011600_R14","first-page":"4122","article-title":"PDE4 inhibitors activate a mitochondrial apoptotic pathway in chronic lymphocytic leukemia cells that is regulated by protein phosphatase 2A.","volume-title":"Blood","year":"2003"},{"key":"2026012807041011600_R15","first-page":"2661","article-title":"Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis.","volume-title":"Blood","year":"2004"},{"key":"2026012807041011600_R16","first-page":"1041","article-title":"Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions.","volume-title":"Cell","year":"2004"},{"key":"2026012807041011600_R17","first-page":"8561","article-title":"Gene expression patterns define key transcriptional events in cell-cycle regulation by cAMP and protein kinase A.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2005"},{"key":"2026012807041011600_R18","first-page":"228","article-title":"CREM: A master-switch regulating the balance between differentiation and apoptosis in male germ cells.","volume-title":"Mol. Reprod. Dev.","year":"2000"},{"key":"2026012807041011600_R19","first-page":"875","article-title":"Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor.","volume-title":"Cell","year":"1993"},{"key":"2026012807041011600_R20","first-page":"20858","article-title":"The pro-apoptotic protein Bim is a convergence point for cAMP\/protein kinase A- and glucocorticoid-promoted apoptosis of lymphoid cells.","volume-title":"J. Biol. Chem.","year":"2004"},{"key":"2026012807041011600_R21","first-page":"473","article-title":"Type 4 cAMP phosphodiesterase (PDE4) inhibitors augment glucocorticoid-mediated apoptosis in B cell chronic lymphocytic leukemia (B-CLL) in the absence of exogenous adenylyl cyclase stimulation.","volume-title":"Biochem. Pharmacol.","year":"2005"},{"key":"2026012807041011600_R22","first-page":"4920","article-title":"Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells.","volume-title":"Clin. Cancer Res.","year":"2007"},{"key":"2026012807041011600_R23","first-page":"365","article-title":"Primer3 on the WWW for general users and for biologist programmers.","volume-title":"Methods Mol. Biol.","year":"2000"},{"key":"2026012807041011600_R24","first-page":"L832","article-title":"Human airway smooth muscle expresses 7 isoforms of adenylyl cyclase: a dominant role for isoform V.","volume-title":"Am. J. Physiol.","year":"2001"},{"key":"2026012807041011600_R25","first-page":"R16","article-title":"Preferred analysis methods for Affymetrix GeneChips revealed by a wholly defined control dataset.","volume-title":"Genome Biol.","year":"2005"},{"key":"2026012807041011600_R26","first-page":"D562","article-title":"NCBI GEO: mining millions of expression profiles\u2014database and tools.","volume-title":"Nucleic Acids Res.","year":"2005"},{"key":"2026012807041011600_R27","first-page":"509","article-title":"A Bayesian framework for the analysis of microarray expression data: regularized t test and statistical inferences of gene changes.","volume-title":"Bioinformatics","year":"2001"},{"key":"2026012807041011600_R28","first-page":"59","article-title":"Improved statistical tests for differential gene expression by shrinking variance components estimates.","volume-title":"Biostatistics","year":"2005"},{"key":"2026012807041011600_R29","first-page":"500","article-title":"GenePattern 2.0.","volume-title":"Nat. Genet.","year":"2006"},{"key":"2026012807041011600_R30","first-page":"2357","article-title":"Coordinate analysis of murine immune cell surface markers and intracellular phosphoproteins by flow cytometry.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012807041011600_R31","first-page":"1291","article-title":"Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts.","volume-title":"Curr. Biol.","year":"2000"},{"key":"2026012807041011600_R32","first-page":"42438","article-title":"Fos-related antigen 2 controls protein kinase A-induced CCAAT\/enhancer-binding protein \u03b2 expression in osteoblasts.","volume-title":"J. Biol. Chem.","year":"2004"},{"key":"2026012807041011600_R33","first-page":"1101","article-title":"Genome-wide analysis of CREB target genes reveals a core promoter requirement for cAMP responsiveness.","volume-title":"Mol. Cell","year":"2003"},{"key":"2026012807041011600_R34","first-page":"5177","article-title":"The epidermal growth factor-like growth factor amphiregulin is strongly induced by the adenosine 3\u2032,5\u2032-monophosphate pathway in various cell types.","volume-title":"Endocrinology","year":"2004"},{"key":"2026012807041011600_R35","first-page":"6333","article-title":"Exchange protein activated by cyclic AMP (Epac)-mediated induction of suppressor of cytokine signaling 3 (SOCS-3) in vascular endothelial cells.","volume-title":"Mol. Cell. Biol.","year":"2006"},{"key":"2026012807041011600_R36","first-page":"7728","article-title":"Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK\/BMAL1 activity.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2002"},{"key":"2026012807041011600_R37","first-page":"2715","article-title":"Analysis of fra-2 gene expression.","volume-title":"Nucleic Acids Res.","year":"1993"},{"key":"2026012807041011600_R38","first-page":"1634","article-title":"TGF-\u03b21 and cyclic AMP promote apoptosis in resting human B lymphocytes.","volume-title":"J. Immunol.","year":"1995"},{"key":"2026012807041011600_R39","first-page":"55","article-title":"Differential expression of adenylyl cyclase subtypes in human cardiovascular system.","volume-title":"Mol. Cell. Endocrinol.","year":"2004"},{"key":"2026012807041011600_R40","first-page":"1","article-title":"PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization.","volume-title":"Biochem J.","year":"2003"},{"key":"2026012807041011600_R41","first-page":"827","article-title":"The transcriptional repressor ICER and cAMP-induced programmed cell death.","volume-title":"Oncogene","year":"1997"},{"key":"2026012807041011600_R42","first-page":"14771","article-title":"A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2005"},{"key":"2026012807041011600_R43","first-page":"935","article-title":"Cyclic nucleotide phosphodiesterases (PDE) 3 and 4 in normal, malignant, and HTLV-I transformed human lymphocytes.","volume-title":"Biochem. Pharmacol.","year":"1999"},{"key":"2026012807041011600_R44","first-page":"771","article-title":"Foxp3-dependent programme of regulatory T cell differentiation.","volume-title":"Nature","year":"2007"},{"key":"2026012807041011600_R45","first-page":"112","article-title":"Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737.","volume-title":"J. Clin. Invest.","year":"2007"},{"key":"2026012807041011600_R46","first-page":"1607","article-title":"The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C4-induced contractions in passively sensitized human airways.","volume-title":"Br. J. Pharmacol.","year":"2000"},{"key":"2026012807041011600_R47","first-page":"869","article-title":"Multiple high-affinity cAMP-phosphodiesterases in human T lymphocytes.","volume-title":"Biochem. Pharmacol.","year":"1991"},{"key":"2026012807041011600_R48","first-page":"1945","article-title":"Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD4+ and CD8+ T lymphocytes: role in regulating proliferation and the biosynthesis of interleukin-2.","volume-title":"Br. J. Pharmacol.","year":"1996"},{"key":"2026012807041011600_R49","volume-title":"Cyclic Nucleotide Phosphodiesterases in Health and Disease","year":"2007"},{"key":"2026012807041011600_R50","first-page":"589","article-title":"Inhibition of PDE3B augments PDE4-inhibitor-induced apoptosis in leukemic cells from a subset of patients with chronic lymphocytic leukemia.","volume-title":"Clin. Cancer Res.","year":"2002"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/9\/5400\/62687299\/8902.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/9\/5400\/62687299\/8902.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:04:33Z","timestamp":1769601873000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/182\/9\/5400\/8007666"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5,1]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2009,5,1]]},"published-print":{"date-parts":[[2009,5,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0804255","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,5]]},"published":{"date-parts":[[2009,5,1]]}}}