Abstract
Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent. In addition to the deactivation of macrophages, dendritic cells, and microglia, VIP shifts the Th1/Th2 balance, promoting the preferential differentiation and survival of Th2 cells, to the detriment of the proinflammatory Th1 effectors. Several mechanisms operate in the Th1/Th2 shift induced by VIP. Here we report on a novel mechanism for the effect of VIP on T cell differentiation, and show that VIP inhibits Th1 differentiation by interfering directly with the IL-12Jak2/STAT4 signaling pathway in T cells. The effect of VIP is cAMP-dependent, and appears to be mediated through the activation of protein tyrosine phosphatases (PTP), with SHP-2 as a potential target. The activation of PTPs represents a novel cAMP-downstream target for the immunomodulatory effects of VIP.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / drug effects*
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Cyclic AMP / metabolism*
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Flow Cytometry
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Interleukin-12 / pharmacology
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Janus Kinase 2 / metabolism*
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Lymphocyte Activation / drug effects
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Male
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Mice
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Models, Biological
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Phosphorylation / drug effects
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Protein Tyrosine Phosphatases / antagonists & inhibitors
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Protein Tyrosine Phosphatases / metabolism*
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STAT4 Transcription Factor / metabolism*
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Signal Transduction
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Th1 Cells / cytology
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Th1 Cells / drug effects
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Th1 Cells / metabolism
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Vasoactive Intestinal Peptide / pharmacology*
Substances
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STAT4 Transcription Factor
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Interleukin-12
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Vasoactive Intestinal Peptide
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Cyclic AMP
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Janus Kinase 2
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Cyclic AMP-Dependent Protein Kinases
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Protein Tyrosine Phosphatases