Vasoactive intestinal peptide and pitiutary adenylate cyclase-activating polypeptide inhibit nuclear factor-κB-dependent gene activation at multiple levels in the human monocytic cell line THP-1

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Abstract

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) suppress monocyte/macrophage production of proinflammatory agents. The transcription factor NF-κB regulates the transcription of most agents. VIP/PACAP inhibit NF-κB transactivation in the lipopolysaccharide-stimulated human monocytic cell line THP-1 at multiple levels. First, VIP/PACAP inhibit p65 nuclear translocation and NF-κB DNA binding by stabilizing the inhibitor IκBα. 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-κB transactivation. Third, VIP and PACAP reduce the phosphorylatlon 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-κB 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-κB at various levels and through different transduction pathways could offer a significant advantage over other anti-inflammatory agents.

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APA

Delgado, M., & Ganea, D. (2001). Vasoactive intestinal peptide and pitiutary adenylate cyclase-activating polypeptide inhibit nuclear factor-κB-dependent gene activation at multiple levels in the human monocytic cell line THP-1. Journal of Biological Chemistry, 276(1), 369–380. https://doi.org/10.1074/jbc.M006923200

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