Document Detail

Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses.
MedLine Citation:
PMID:  12032334     Owner:  NLM     Status:  MEDLINE    
Lipopolysaccharide (LPS) stimulation of the innate immune response requires the activation of signaling cascades that culminate in the synthesis and secretion of proinflammatory cytokines. Given the inhibitory effects of phosphodiesterase (PDE) inhibitors on LPS-induced cytokine production, we have investigated LPS responses in mice deficient in PDE4 (type 4 cAMP-specific PDE)-B and PDE4D. LPS stimulation of mouse peripheral leukocytes induced PDE4B mRNA accumulation and increased PDE4 activity. This response was completely absent in mice deficient in PDE4B but not PDE4D. LPS induction of tumor necrosis factor-alpha secretion by circulating leukocytes was decreased by approximately 90% in mice deficient in PDE4B but not in mice lacking PDE4D. The impaired LPS response was evident regardless of the LPS dose used for stimulation and was associated with a more than 90% decrease in tumor necrosis factor-alpha mRNA accumulation. A decreased responsiveness to LPS was also present in other inflammatory cells, including peritoneal and lung macrophages. These findings demonstrate that PDE4B gene activation by LPS constitutes a feedback regulation essential for an efficient immune response.
S-L Catherine Jin; Marco Conti
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  99     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2002 May 
Date Detail:
Created Date:  2002-05-28     Completed Date:  2002-07-01     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7628-33     Citation Subset:  IM    
Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA 94305-5317, USA.
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MeSH Terms
3',5'-Cyclic-AMP Phosphodiesterases / biosynthesis,  genetics*
Bronchoalveolar Lavage Fluid / cytology
Cell Line
Cells, Cultured
Cyclic Nucleotide Phosphodiesterases, Type 3
Cyclic Nucleotide Phosphodiesterases, Type 4
Gene Expression Regulation, Enzymologic*
Genetic Vectors
Genomic Library
Interleukin-6 / blood
Leukocytes / drug effects,  immunology*
Lipopolysaccharides / pharmacology*
Macrophages, Peritoneal / drug effects,  immunology*
Restriction Mapping
Reverse Transcriptase Polymerase Chain Reaction
Transcription, Genetic
Transcriptional Activation
Tumor Necrosis Factor-alpha / genetics*,  metabolism
Grant Support
Reg. No./Substance:
0/Interleukin-6; 0/Lipopolysaccharides; 0/Tumor Necrosis Factor-alpha; EC',5'-Cyclic-AMP Phosphodiesterases; EC Nucleotide Phosphodiesterases, Type 3; EC Nucleotide Phosphodiesterases, Type 4; EC protein, human; EC protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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