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The Journal of Neuroscience, May 15, 2000, 20(10):3622-3630
Vasoactive Intestinal Peptide and Pituitary Adenylyl
Cyclase-Activating Polypeptide Inhibit Tumor Necrosis Factor-
Production in Injured Spinal Cord and in Activated Microglia via a
cAMP-Dependent Pathway
Woong-Ki
Kim1,
Yanqing
Kan1,
Doina
Ganea1,
Ronald P.
Hart1,
Illana
Gozes2, and
G. Miller
Jonakait1
1 Department of Biological Sciences, Rutgers
University, Newark, New Jersey 07102, and 2 Department
of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv
University, Tel Aviv 69978, Israel
Tumor necrosis factor- (TNF-) 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- 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- in injured CNS. In culture, increases in TNF- mRNA
resulting from lipopolysaccharide (LPS) stimulation were reduced
significantly by 10 7 M VIP and
completely eliminated by PACAP at the same concentration. TNF-
protein levels were reduced 90% by VIP or PACAP at
107 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- from activated microglia by a cAMP-dependent pathway.
Key words:
VIP; PACAP; TNF-; microglia; cAMP; PKA; spinal cord
injury; LPS
Copyright © 2000 Society for Neuroscience 0270-6474/00/20103622-09$05.00/0
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