Vasoactive intestinal peptide and pituitary adenylyl cyclase-activating polypeptide inhibit tumor necrosis factor-α production in injured spinal cord and in activated microglia via a cAMP-dependent pathway

Woong Ki Kim, Yanqing Kan, Doina Ganea, Ronald Hart, Illana Gozes, G. Miller Jonakait

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

Tumor necrosis factor-α (TNF-α) production accompanies CNS insults of all kinds. Because the neuropeptide vasoactive intestinal peptide (VIP) and the structurally related peptide pituitary adenylyl cyclase-activating polypeptide (PACAP) have potent anti-inflammatory effects in the periphery, we investigated whether these effects extend to the CNS. TNF-α mRNA was induced within 2 hr after rat spinal cord transection, and its upregulation was suppressed by a synthetic VIP receptor agonist. Cultured rat microglia were used to examine the mechanisms underlying this inhibition because microglia are the likely source of TNF-α in injured CNS. In culture, increases in TNF-α mRNA resulting from lipopolysaccharide (LPS) stimulation were reduced significantly by 10-7 M VIP and completely eliminated by PACAP at the same concentration. TNF-α protein levels were reduced 90% by VIP or PACAP at 10-7 M. An antagonist of VPAC1 receptors blocked the action of VIP and PACAP, and a PAC1 antagonist blocked the action of PACAP. A direct demonstration of VIP binding on microglia and the existence of mRNAs for VPAC1 and PAC1 (but not VPAC2) receptors argue for a receptor-mediated effect. The action of VIP is cAMP-mediated because (1) activation of cAMP by forskolin mimics the action; (2) PKA inhibition by H89 reverses the neuropeptide-induced inhibition; and (3) the lipophilic neuropeptide mimic, stearyl-norleucine17 VIP (SNV), which does not use a cAMP-mediated pathway, fails to duplicate the inhibition. We conclude that VIP and PACAP inhibit the production of TNF-α from activated microglia by a cAMP-dependent pathway.

Original languageEnglish (US)
Pages (from-to)3622-3630
Number of pages9
JournalJournal of Neuroscience
Volume20
Issue number10
DOIs
StatePublished - May 15 2000

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • CAMP
  • LPS
  • PACAP
  • PKA
  • Spinal cord injury
  • TNF-α microglia
  • VIP

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