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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 10⁷ 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

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20103622-09$05.00/0

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