Neuropeptide Y cotransmission with norepinephrine in the sympathetic nerve-macrophage interplay.
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(-10) M: (p = 0.012) and 10(-9) M: (p < 0.001). Simultaneous addition of NPY at 10(-9) M: and the alpha-2-adrenergic agonist p-aminoclonidine further inhibited IL-6 secretion (p < 0.05). However, simultaneous administration of NPY at 10(-9) M: and the beta-adrenergic agonist isoproterenol at 10(-6) M: or NE at 10(-6) M: significantly increased IL-6 secretion (p < 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(-7) M, p = 0.039; 10(-8) M, p = 0.035). This indicates that NPY increases the inhibitory effect of endogenous NE, which is mediated at low NE concentrations via alpha-adrenoceptors. Blockade of alpha-adrenoceptors attenuated electrically induced inhibition of IL-6 secretion (p < 0.001), which was dose-dependently abrogated by BIBP 3226. This indicates that under blockade of alpha-adrenoceptors endogenous NPY supports the stimulating effect of endogenous NE via beta-adrenoceptors. These experiments demonstrate the ambiguity of NPY, which functions as a cotransmitter of NE in the nerve-macrophage interplay.
Straub
R H
RH
Department of Internal Medicine I, University Hospital, Regensburg, Germany. Rainer.Straub@klinik.uni-regernsburg.de
Schaller
T
T
Miller
L E
LE
von Hörsten
S
S
Jessop
D S
DS
Falk
W
W
Schölmerich
J
J
D000322:Adrenergic Agonists / Q000494:pharmacology; D000320:Adrenergic Fibers / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009292:Narcotic Antagonists / Q000494:pharmacology; D009478:Neuropeptide Y / Q000378:metabolism* / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D013154:Spleen / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000166:cytology / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
D000322:Adrenergic Agonists; D000317:Adrenergic alpha-Antagonists; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D009292:Narcotic Antagonists; D009478:Neuropeptide Y; D017450:Receptors, Opioid, mu; D009638:Norepinephrine