Vasoactive intestinal peptide inhibits toll-like receptor 3-induced nitric oxide production in Schwann cells and subsequent sensory neuronal cell death in vitro.
We have previously reported that polyinosinic-polycytidylic acids [poly(I:C)], a synthetic toll-like receptor 3 (TLR3) agonist, induce Schwann cell activation, which exerts neurotoxic effects on sensory neurons. In this study, we investigated the effects of vasoactive intestinal peptide (VIP), a neuropeptide implicated in nerve regeneration, on TLR3-induced Schwann cell activation. VIP receptors VPAC1 and VPAC2 were constitutively expressed in rat Schwann cells. VIP pretreatment inhibited TLR3-induced inducible nitric oxide synthase (iNOS) gene expression and NO production in Schwann cells. Studies on the intracellular signal transduction pathways indicate that the VIP effect is mediated by protein kinase A activation. VIP also inhibited the poly(I:C)-induced p38 activation that is responsible for the iNOS gene expression in Schwann cells. Finally, VIP inhibited dorsal rooyt ganglion neuronal cell death caused by NO produced in activated Schwann cells. Taken together, our data suggest that VIP exerts a neuroprotective effect by inhibiting neurotoxic Schwann cell activation.
Lee
Hyunkyoung
H
Program in Molecular and Cellular Neuroscience, DRI, and Department of Oral Physiology, School of Dentistry, Seoul National University, Seoul, Korea.
Park
Kyungpyo
K
Kim
Joong Soo
JS
Lee
Sung Joong
SJ
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D020287:In Situ Nick-End Labeling / Q000379:methods; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects*; D011984:Sensory Receptor Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000502:physiology*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C530472:TLR3 protein, rat; D051196:Toll-Like Receptor 3; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D052247:Nitric Oxide Synthase Type II; D011070:Poly I-C