Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit nuclear factor-kappa B-dependent gene activation at multiple levels in the human monocytic cell line THP-1.
The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) suppress monocyte/macrophage production of proinflammatory agents. The transcription factor NF-kappa B regulates the transcription of most agents. VIP/PACAP inhibit NF-kappa B transactivation in the lipopolysaccharide-stimulated human monocytic cell line THP-1 at multiple levels. First, VIP/PACAP inhibit p65 nuclear translocation and NF-kappa B DNA binding by stabilizing the inhibitor I kappa B alpha. Second, VIP/PACAP induce phosphorylation of the CRE-binding protein (CREB) and its binding to the CREB-binding protein (CBP). This results in a decrease in p65.CBP complexes, which further reduces NF-kappa B transactivation. Third, VIP and PACAP reduce the phosphorylation of the TATA box-binding protein (TBP), resulting in a reduction in TBP binding to both p65 and the TATA box. All these effects are mediated through the specific receptor VPAC1. The cAMP/cAMP-dependent protein kinase pathway mediates the effects on CBP and TBP, whereas a cAMP-independent pathway is the major transducer for the effects on p65 nuclear translocation. Since NF-kappaB represents a focal point for various stimuli and induces the expression of many proinflammatory genes, its targeting by VIP and PACAP positions them as important anti-inflammatory agents. The VIP/PACAP inhibition of NF-kappa B at various levels and through different transduction pathways could offer a significant advantage over other anti-inflammatory agents.
Delgado
M
M
Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA.
Ganea
D
D
D050882:CREB-Binding Protein; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D018005:Receptors, Vasoactive Intestinal Peptide / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D015398:Signal Transduction / Q000187:drug effects*; D035181:TATA-Box Binding Protein; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
C495401:ADCYAP1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009479:Neuropeptides; D009687:Nuclear Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D035181:TATA-Box Binding Protein; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D014660:Vasoactive Intestinal Peptide; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D017868:Cyclic AMP-Dependent Protein Kinases