Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels.
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.
Instituto de Parasitología y Biomedicina-CSIC, Granada, Spain.
Per
P
Anderson
Elena
E
Gonzalez-Rey
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D060908:CTLA-4 Antigen; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*
D015703:Antigens, CD; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases