Differential Effects of Neuropeptides on Cytokine Production by Mouse Helper T Cell Subsets

Kawamura, Noriyuki; Tamura, Hiroo; Obana, S; Wenner, Marcus; Ishikawa, Takahiro; Nakata, Akinori; Yamamoto, Hiroshi

doi:10.1159/000026321

Cited by 109 publications

(63 citation statements)

References 25 publications

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“…10 NPY also has an active role on the adaptive immune response by skewing the T-cell profile towards Th2 effector by directly promoting the release of IL-4 and inhibiting interferon-g secretion in vitro. 13 Moreover, NPY modulates the DC functionality, initiator of the Th2 orientation, ass lack of Y1 signalling impairs DC's capacity to induce an adaptive immune response. 10 Finally, like in the airway allergic reaction, the delayed type hypersensitivity model requires both a challenge and sensitization with the antigen, contributing to an exacerbated inflammatory response.…”

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confidence: 99%

Y1 signalling has a critical role in allergic airway inflammation

et al. 2011

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Asthma affects 300 million people worldwide, yet the mechanism behind this pathology has only been partially elucidated. The documented connection between psychological stress and airway inflammation strongly suggests the involvement of the nervous system and its secreted mediators, including neuropeptides, on allergic respiratory disease. In this study, we show that neuropeptide Y (NPY), a prominent neurotransmitter, which release is strongly upregulated during stress, exacerbates allergic airway inflammation (AAI) in mice, via its Y1 receptor. Our data indicate that the development of AAI was associated with elevated NPY expression in the lung and that lack of NPY-mediated signalling in NPYKO mice or its Y1 receptor in Y1KO mice significantly improved AAI. In vivo, eosinophilia in the bronchoalveolar fluid as well as circulating immunoglobulin E in response to AAI, were significantly reduced in NPY-and Y1-deficient compared with wild-type mice. These changes correlated with a blunting of the Th2 immune profile that is characteristic for AAI, as shown by the decreased release of interleukin-5 during ex vivo re-stimulation of T cells isolated from the thoracic draining lymph nodes of NPY-or Y1-deficient mice subjected to AAI. Taken together this study demonstrates that signalling through Y1-receptors emerges as a critical pathway for the development of airway inflammation and as such potentially opens novel avenues for therapeutic intervention in asthma. Asthma is a chronic inflammation of the airways characterized by recurrent episodes of airway obstruction and associated with an inappropriate immune response to harmless environmental antigens. It is initiated and perpetuated by CD4 positive Th2 lymphocytes that secrete interleukin (IL)-4, 5 and 13, which are involved in the remodelling of airway epithelium, the hypereosinophilia and the secretion of Immunoglobulin E (IgE) by B lymphocytes. 1 The exact mechanisms involved in this immune response initiation still remains unclear. Recent evidence has highlighted the 'neuroimmune' crosstalk as a contributor to the development of the airway inflammation. 2 Indeed, a dysfunction of airway innervation can lead to asthma symptoms like breathlessness and cough. Neurotrophin and tackinin like bradykinin A and substance P, secreted by sensory nerves innervating the lung, directly contribute to the immune cell activation, bronchoconstriction and vasodilatation eventually leading to asthma development. 3 On the other hand, neural mediators can also have a protective role as levels of a-melanocyte-stimulating hormone, which is known to have an anti-inflammatory role and protect mice from allergic airway inflammation (AAI), is decreased in the lung of asthmatic patients. 4 However, the most convincing circumstantial evidence that the nervous system has a key role on asthma development is the fact that psychological stress worsens asthmatic syndrome. 2 Stress causes a highly complex response and thus what causes its worsened effects on asthma remains elusive. Stress is also k...

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confidence: 99%

Y1 signalling has a critical role in allergic airway inflammation

et al. 2011

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“…␣CGRP also contributes to local neurogenic inflammation and nociception (6). Moreover, the functions of immune cells such as macrophages (7,8), Langerhans cells (8), and T cells (9,10) are modulated by ␣CGRP. However, the precise functional differences between ␣CGRP and ␤CGRP remain unclear.…”

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confidence: 99%

Hypertension and dysregulated proinflammatory cytokine production in receptor activity-modifying protein 1-deficient mice

Tsujikawa

Yayama

Hayashi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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122

132

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Calcitonin gene-related peptide (CGRP) is thought to be a prominent neuropeptide in cardiovascular regulation and neuroimmune modulation. There are two isoforms of CGRP (␣CGRP and ␤CGRP), and the main CGRP receptors are probably composed of a calcitonin receptor-like receptor (CLR) and a receptor activity-modifying protein (RAMP)1. However, the physiological functions of CGRP that are mediated through the CLR/RAMP1 receptors remain to be clarified. For an improved understanding of the functions, we generated mice deficient in RAMP1, a specific subunit of CGRP receptors, by a conditional gene-targeting technique. The RAMP1-deficient mice (RAMP1 ؊/؊ ) exhibited high blood pressure, with no changes in heart rate. ␣CGRP was found to have a potent vascular relaxant activity compared with ␤CGRP in the artery of the WT (RAMP1 ؉/؉ ) mice. The activities of both CGRP isoforms were remarkably suppressed in the arteries of the RAMP1 ؊/؊ mice. The LPS-induced inflammatory responses of the RAMP1 ؊/؊ mice revealed a transient and significant increase in the serum CGRP levels and high serum levels of proinflammatory cytokines compared with the RAMP1 ؉/؉ mice. ␣CGRP and ␤CGRP equally suppressed the production of TNF-␣ and IL-12 in bone marrow-derived dendritic cells stimulated with lipopolysaccharide. Their inhibitory effects were not observed in the bone marrow-derived dendritic cells of the RAMP1 ؊/؊ mice. These results indicate that CGRP signaling through CLR/RAMP1 receptors plays a crucial role in the regulation of both blood pressure by vascular relaxation and proinflammatory cytokine production from dendritic cells.gene-disrupted mice ͉ calcitonin gene-related peptide ͉ adrenomedullin ͉ neuropeptide ͉ dendritic cells C alcitonin gene-related peptide (CGRP) is a 37-aa neuropeptide that is produced in the neural body of dorsal root ganglion cells and released from sensory nerve endings. There are two isoforms of CGRP: ␣ and ␤ in rats and mice and I and II in humans. These differ in their peptide sequences by 1 aa (rats) and 3 aa (mice and humans) of the 37 aa (1). ␣CGRP is produced mainly in the nervous system by the tissue-specific alternative splicing of the primary RNA transcript of the calcitonin/CGRP gene. On the other hand, ␤CGRP is produced not only in the neuronal tissues but also in the enteric nerves of the intestine (2) and in immune cells such as T cells (3). Pharmacologically, ␣CGRP is known to have the most potent vasodilatory activity (4). Most blood vessels are surrounded by a dense perivascular CGRPergic neural network, suggesting the physiological importance of CGRP in vasodilatory regulation (5). ␣CGRP also contributes to local neurogenic inflammation and nociception (6). Moreover, the functions of immune cells such as macrophages (7,8), Langerhans cells (8), and T cells (9, 10) are modulated by ␣CGRP. However, the precise functional differences between ␣CGRP and ␤CGRP remain unclear.Historically, CGRP receptors have been classified into two classes: CGRP 1 and CGRP 2 receptors. The CGRP 1 receptors are m...

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“…Nagy dózisú intravénásan beadott NPY a fehérvérsejtek és CD4 T-sejtek mobilizációját fokozza, alacsony dózisú NPY az NK-sejtek és B-lymphocyták szá-mának csökkenését okozta [11]. Az NPY növeli az IL-4, viszont csökkenti az interferon-γ termelését patkánylép lymphocytáiban [15].…”

Section: Npy Hatása Gyulladásos Folyamatokbanunclassified

Neuropeptid Y és P anyag immunreaktív idegrostok és immunkompetens sejtek változása hepatitisben

Fehér

2015

Orvosi Hetilap

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A neuropeptid Y és a P anyag olyan neuropeptidek, amelyek fontos szerepet játszanak az immunsejtek működésében és a gyulladásos folyamatok fenntartásában és eliminálásában. Hepatitisben mindkét neuropeptidet tartalmazó idegrost mennyisége megnövekszik, a neuropeptid Y immunreaktív rostok növekedése szignifi káns. Számos lymphocytá-ban és hízósejtben szintén neuropeptid Y és a P anyag mutatható ki. Gyakran fi gyelhető meg közeli kapcsolat (kevesebb mint 1 μm) a neuropeptid Y immunreaktív idegrostok és a neuropeptid Y pozitív immunsejtek között. Az immunsejtek egy részében tumornekrózis-faktor-α és nukleáris faktor kappa-B-jelölődés is megfi gyelhető. Néhány P anyagot tartalmazó immunsejtben kolokalizációban fi gyelhető meg a tumornekrózis-faktor-α. Feltételezhető, hogy hepatitisben az idegrostokból és immunsejtekből felszabaduló neuropeptid Y és P anyag részt vesz a gyulladásos folyamatokban és azok eliminálásában. Orv. Hetil., 2015, 156(47), 1892-1897. Kulcsszavak: hepatitis, neuropeptid Y, P anyag, neuroimmun-moduláció Changes in neuropeptide Y and substance P immunoreactive nerve fi bres and immune competent cells in hepatitisNeuropeptide Y and substance P were thought to play a role in the function of immune cells and in amplifi cation or elimination of the infl ammatory processes. In hepatitis the number of both neuropeptide Y and substance P immunoreactive nerve fi bres are increased, where the increase of neoropeptide Y is signifi cant. A large number of lymphocytes and mast cells are also stained for neuropeptide Y and substance P. Very close associations (less than 1 μm) were observed between neuropeptide Y immunoreactive nerve fi bres and immune cells stained also with neuropeptide Y. Some immune cells were also found to be immunoreactive for tumor necrosis factor-α and NF-κB. Some of the SP IR immunocells were also stained for TNF-α and nuclear factor kappaB. Based on these data it is hypothesized that neuropeptid Y and substance P released from nerve fi bres and immune cells play a role in infl ammation and elimination of infl ammation in hepatitis.

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Differential Effects of Neuropeptides on Cytokine Production by Mouse Helper T Cell Subsets

Cited by 109 publications

References 25 publications

Y1 signalling has a critical role in allergic airway inflammation

Y1 signalling has a critical role in allergic airway inflammation

Hypertension and dysregulated proinflammatory cytokine production in receptor activity-modifying protein 1-deficient mice

Neuropeptid Y és P anyag immunreaktív idegrostok és immunkompetens sejtek változása hepatitisben

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