Abstract:The CNS modulates immune cells by direct synaptic-like contacts in the brain and at peripheral sites, such as lymphoid organs. To study the nerve-macrophage communication, a superfusion method was used to investigate cotransmission of neuropeptide Y (NPY) with norepinephrine (NE), with interleukin (IL)-6 secretion used as the macrophage read-out parameter. Spleen tissue slices spontaneously released NE, NPY, and IL-6 leading to a superfusate concentration at 3-4 h of 1 nM, 10 pM, and 120 pg/ml, respectively. Under these conditions, NPY dose-dependently inhibited IL-6 secretion with a maximum effect at 10 Ϫ10 M ( p ϭ 0.012) and 10 Ϫ9 M ( p Ͻ 0.001). Simultaneous addition of NPY at 10 Ϫ9 M and the ␣2-adrenergic agonist p-aminoclonidine further inhibited IL-6 secretion ( p Ͻ 0.05). However, simultaneous administration of NPY at 10 Ϫ9 M and the ␤-adrenergic agonist isoproterenol at 10 Ϫ6 M or NE at 10 Ϫ6 M significantly increased IL-6 secretion ( p Ͻ 0.005). To objectify these differential effects of NPY, electrical field stimulation of spleen slices was applied to release endogenous NPY and NE. Electrical field stimulation markedly reduced IL-6 secretion, which was attenuated by the NPY Y1 receptor antagonist BIBP 3226 (10 Ϫ7 M, p ϭ 0.039; 10 Ϫ8 M, p ϭ 0.035). This indicates that NPY increases the inhibitory effect of endogenous NE, which is mediated at low NE concentrations via ␣-adrenoceptors. Blockade of ␣-adrenoceptors attenuated electrically induced inhibition of IL-6 secretion ( p Ͻ 0.001), which was dosedependently abrogated by BIBP 3226. This indicates that under blockade of ␣-adrenoceptors endogenous NPY supports the stimulating effect of endogenous NE via ␤-adrenoceptors. These experiments demonstrate the ambiguity of NPY, which functions as a cotransmitter of NE in the nerve-macrophage interplay. Key Words: Neuropeptide Y-Norepinephrine-Neuroimmune interactionSpleen-Macrophage-Cytokines. J. Neurochem. 75, 2464Neurochem. 75, -2471Neurochem. 75, (2000.Neuropeptide Y (NPY) is a peptide with 36 amino acid residues that was isolated originally from the brain . NPY forms a family of peptides together with peptide YY and pancreatic polypeptide.These peptides have been found in endocrine cells of the gastrointestinal tract (Larsson et al., 1976;Lundberg et al., 1982) and also in neurons of the brainstem (Lundberg et al., 1984). With respect to NPY, a major portion of NPY-immunoreactive nerves in peripheral organs represents classical sympathetic fibers where NPY coexists with norepinephrine (NE) (Ekblad et al., 1984). There is evidence that NPY is stored in large vesicles of the nerve terminal together with NE, whereas small vesicles contain NE but no NPY (Fried et al., 1985). NPY makes direct vasoconstriction, increases effects of different vasoconstrictors, and inhibits some vasorelaxant agents (Hakanson et al., 1986;Itoi et al., 1986;Donoso et al., 1997). NPY is necessary for constriction of the ductus deferens (Stjärne et al., 1986), to increase intracellular Ca 2ϩ (Erdbrugger et al., 1993), to ...

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