RT Journal Article
SR Electronic
T1 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
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3622
OP 3630
DO 10.1523/JNEUROSCI.20-10-03622.2000
VO 20
IS 10
A1 Woong-Ki Kim
A1 Yanqing Kan
A1 Doina Ganea
A1 Ronald P. Hart
A1 Illana Gozes
A1 G. Miller Jonakait
YR 2000
UL http://www.jneurosci.org/content/20/10/3622.abstract
AB 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 10−7m VIP and completely eliminated by PACAP at the same concentration. TNF-α protein levels were reduced 90% by VIP or PACAP at 10−7m. 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.