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PMID: 12032334 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 11 ·2002-05-28 ·Pages 7628-33

Jin SL, Conti M

Abstract

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.

MeSH Terms
3',5'-Cyclic-AMP Phosphodiesterases/biosynthesis,genetics Animals 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 Humans Interleukin-6/blood Leukocytes/drug effects,immunology Lipopolysaccharides/pharmacology Macrophages, Peritoneal/drug effects,immunology Mice Restriction Mapping Reverse Transcriptase Polymerase Chain Reaction Transcription, Genetic Transcriptional Activation Tumor Necrosis Factor-alpha/genetics,metabolism
Chemicals
Interleukin-6 Lipopolysaccharides Tumor Necrosis Factor-alpha 3',5'-Cyclic-AMP Phosphodiesterases Cyclic Nucleotide Phosphodiesterases, Type 3 Cyclic Nucleotide Phosphodiesterases, Type 4 PDE4B protein, human PDE4D protein, human
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Jin S-L Catherine
Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA 94305-5317, USA.
Conti Marco
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.122041599
Published
2002-05-28
Pages
7628-33
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC124305
Subset
IM
Grants
NICHD NIH HHS · R01 HD020788 · United States
NICHD NIH HHS · HD20788 · United States
External Links
PubMed source DOI: 10.1073/pnas.122041599 PMC Full Text View journal details
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