Document Detail

Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels.
MedLine Citation:
PMID:  20231362     Owner:  NLM     Status:  MEDLINE    
Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory neuropeptide that, by inhibiting Th1-driven responses and inducing the emergence of regulatory T cells (T(reg)), has been proven successful in the induction of tolerance in various experimental models of autoimmune disorders. Here, we investigate the molecular mechanisms involved in VIP-induced tolerance. VIP treatment in the presence of T-cell receptor (TCR) signaling and CD28 costimulation induced cell cycle arrest in human T cells. VIP blocked G(1)/S transition and inhibited the synthesis of cyclins D3 and E and the activation of the cyclin-dependent kinases (CDKs) cdk2 and cdk4. This effect was accompanied by maintenance of threshold levels of the CDK inhibitor p27(kip1) and impairment of phosphatidylinositol 3-kinase (PI3K)-Akt signaling. Inhibition of interleukin 2 (IL-2) transcription and downregulation of signaling through NFAT, AP-1, and Ras-Raf paralleled the VIP-induced cell cycle arrest. Noteworthy from a functional point of view is the fact that VIP-treated T cells show a regulatory phenotype characterized by high expression of CD25, cytotoxic-T-lymphocyte-associated protein 4 (CTLA4), and Forkhead box protein 3 (FoxP3) and potent suppressive activities against effector T cells. CTLA4 appears to be critically involved in the generation and suppressive activities of VIP-induced T(reg). Finally, cyclic AMP (cAMP) and protein kinase A (PKA) activation seems to mediate the VIP-induced cell cycle arrest and T(reg) generation.
Per Anderson; Elena Gonzalez-Rey
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-15
Journal Detail:
Title:  Molecular and cellular biology     Volume:  30     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-04-27     Completed Date:  2010-06-02     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2537-51     Citation Subset:  IM    
Instituto de Parasitología y Biomedicina-CSIC, Granada, Spain.
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MeSH Terms
Antigens, CD / genetics,  metabolism
Antigens, CD28 / metabolism
Antigens, CD3 / metabolism
CTLA-4 Antigen
Cell Cycle / drug effects*,  physiology
Cyclic AMP / metabolism
Cyclic AMP-Dependent Protein Kinases / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / genetics,  metabolism
Cytokines / metabolism
Forkhead Transcription Factors / genetics,  metabolism
Interleukin-2 / metabolism
Lymphocyte Activation
Peptide Fragments / genetics,  pharmacology
Receptors, Antigen, T-Cell / metabolism
Signal Transduction / drug effects*
T-Lymphocyte Subsets / cytology,  drug effects,  metabolism*
T-Lymphocytes / cytology,  drug effects*,  metabolism*
Vasoactive Intestinal Peptide / agonists,  antagonists & inhibitors,  genetics,  pharmacology*
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, CD28; 0/Antigens, CD3; 0/CTLA-4 Antigen; 0/CTLA4 protein, human; 0/Cytokines; 0/FOXO1 protein, human; 0/Forkhead Transcription Factors; 0/Interleukin-2; 0/Peptide Fragments; 0/Receptors, Antigen, T-Cell; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 37221-79-7/Vasoactive Intestinal Peptide; 60-92-4/Cyclic AMP; EC AMP-Dependent Protein Kinases

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