Neuropeptide Y Cotransmission with Norepinephrine in the Sympathetic Nerve—Macrophage Interplay

Abstract

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 ...

Postnatal Life Events Affect the Severity of Asthmatic Airway Inflammation in the Adult Rat

“…Only testing ex vivo splenic NK cytotoxicity revealed significantly higher NK cytotoxicity in HA animals. As this finding might well be the result of a differential in vivo stress response mediated via sympathetic neurotransmitters such as noradrenaline and neuropeptide Y (12,16,20,(22)(23)(24)30), to this end, we conclude that the postnatal stressors used in the present study do not primarily affect the immune system of the rats. However, such a conclusion cannot be comprehensive and might differ in the case of other postnatal experiences such as immune "stress" by early postnatal exposure to endotoxin (5,7,16).…”

“…IL-6 is known to be a potent activator of the HPA system and is secreted under stress conditions (29). The IL-6 release from macrophages is furthermore under tight control of the activity of the sympathetic nervous system and related neurotransmitters, which in turn are released by stress (30). However, because IL-6 levels do not differ prechallenge between groups and show under poststress circumstances only a significant decrease in MS and CO groups, these findings are not indicative for an activation of the HPA system by IL-6 but instead may hint to additional differences in the sympathetic response (30) in these animals.…”

Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells

“…Since CD26 cleaves the N-terminus of effector proteins and our data indicated that cleavage of SDF-1 was not a mechanism through which CD26 affects hematopoietic trafficking, we hypothesized that an alternative protein containing an N-terminal CD26 cleavage site is mechanistically involved. A systematic search of protein sequence databases for proteins containing putative CD26 recognition sites intriguingly identified the neurotransmitter NPY (26), a ligand with cognate receptors on monocytes, osteoblasts, stromal cells, and ECs and that has been shown to regulate immune cell and bone homeostasis (27)(28)(29)(30). In addition, recent studies suggest a role for NPY in the regulation of BM niche components and HSPC trafficking (31,32).…”

Neuropeptide Y Negatively Influences Monocyte Recruitment to the Central Nervous System during Retrovirus Infection

“…In the current study, we found that NPY, a small peptide that is produced by neurons of the central and peripheral nervous systems (23,38), was an important inhibitor of monocyte recruitment to the brain during retrovirus infection. Mice deficient in NPY were more susceptible to retrovirus-induced neurological disease.…”