Exogenous Nitric Oxide Regulates the Degranulation of Human Basophils and Rat Peritoneal  Mast Cells

Iikura, Motoyasu; Takaishi, Toshiaki; Hirai, Koichi; Yamada, Hirokazu; Iida, Masaki; Koshino, Takeshi; Morita, Yutaka

doi:10.1159/000023892

Cited by 40 publications

(24 citation statements)

References 25 publications

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“…44 Such complex regulation must arise from involved and necessarily overlapping control machinery. 44 Previous studies in rodent MCs 7,38 and human basophils 45 have shown a role for endogenous and exogenous NO in inhibition of granule mediator secretion. We have shown here for the first time that MC-derived NO, localized to the nuclear membrane, modulates LT produced immediately (Ͻ 30 minutes) after activation.…”

Section: Discussionmentioning

confidence: 98%

Expression, localization, and regulation of NOS in human mast cell lines: effects on leukotriene production

Gilchrist

McCauley

Befus

2004

Blood

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Nitric oxide (NO) is a potent radical produced by nitric oxide synthase (NOS) and has pleiotrophic activities in health and disease. As mast cells (MCs) play a central role in both homeostasis and pathology, we investigated NOS expression and NO production in human MC populations. Endothelial NOS (eNOS) was ubiquitously expressed in both human MC lines and skin-derived MCs, while neuronal NOS (nNOS) was variably expressed in the MC populations studied. The inducible (iNOS) isoform was not detected in human MCs.Both growth factor-independent (HMC-1) and -dependent (LAD 2) MC lines showed predominant nuclear eNOS protein localization, with weaker cytoplasmic expression. nNOS showed exclusive cytoplasmic localization in HMC-1. Activation with Ca 2؉ ionophore (A23187) or IgE-anti-IgE induced eNOS phosphorylation and translocation to the nucleus and nuclear and cytoplasmic NO formation. eNOS colocalizes with the leukotriene (LT)-initiating enzyme 5-lipoxygenase (5-LO) in the MC nucleus. The NO donor, S-nitrosoglutathione (SNOG), inhibited, whereas the NOS inhibitor, N G -nitro-L-arginine methyl ester (L-NAME), potentiated LT release in a dose-dependent manner. Thus, human MC lines produce NO in both cytoplasmic and nuclear compartments, and endogenously produced NO can regulate LT production by MCs. IntroductionMast cells (MCs) are tissue-resident effector cells that arise from bone marrow precursors. 1 They produce and secrete numerous bioactive agents and have been implicated in diverse homeostatic functions such as angiogenesis, wound healing, and tissue remodeling. 2 Due to their plethora of mediators and strategic localization, MCs also play central roles in various disease states, including multiple sclerosis and T-helper type 2 (T H 2)-driven inflammatory conditions such as asthma. 3,4 Nitric oxide (NO) is a potent radical with diverse roles in regulating cellular activation. 5 NO is derived from L-arginine by the nitric oxide synthase (NOS) family of enzymes. The Ca 2ϩ -dependent members include endothelial (eNOS) and neuronal (nNOS), characterized by constitutive expression and low NO production. Inducible NOS (iNOS) is up-regulated by a variety of inflammatory mediators and functions independently of cellular Ca 2ϩ levels and releases large amounts of NO. 6 Numerous investigators have shown that rodent MCs are regulated by endogenous NO from both constitutive and inducible sources. 7,8 However, little is known about the production of NO by human MCs or the potential involvement of NO as modulator of human MC function.The aim of this study was to investigate the expression of NOS and production of NO in human MCs. Furthermore, we studied the regulation of NOS and the resulting functional effects on the release of leukotrienes. Our results indicate that NO may be a novel modulator that determines the functional phenotype of human MCs. Materials and methods ReagentsThe NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME), inactivate enantiomer N G -nitro-D-arginine methyl ester (D-NAME), and NO donor S-n...

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Section: Discussionmentioning

confidence: 98%

Expression, localization, and regulation of NOS in human mast cell lines: effects on leukotriene production

Gilchrist

McCauley

Befus

2004

Blood

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“…Functional receptors other than the high-affinity IgE receptor (FcεRI) have been implicated in the immediate hypersensitivity response of IgE-deficient mice, suggesting that, for example, IgG1 receptors (FcγRI/II/III) expressed by mast cells may be involved in anaphylactic reactions [46]. In addition, nitric oxide has been described as a further regulator of mast cell degranulation [47]. …”

Section: Pathogenesismentioning

confidence: 99%

Allergy and the Gut

Bischoff

Mayer

Manns³

2000

Int Arch Allergy Immunol

103

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There have frequently been doubts as to the relevance of food allergy, in particular as far as the involvement of the intestinal tract is concerned. Several studies, however, have confirmed the existence of allergic reactions in the gut, with an estimated prevalence of about 1–2% in adults. Clinical symptoms are unspecific and include nausea, vomiting, abdominal pain, cramping and diarrhea. Intestinal mast cells, as well as intestinal eosinophils, have been shown to be involved in the pathogenesis of food-allergy-related enteropathy. In addition to classical IgE-dependent degranulation, further agonists have been demonstrated for mast cell activation, for example IL-4. The methods used to confirm the diagnosis of instestinal allergy are still insufficient. Until now, blinded oral challenge procedures with food antigens have been accepted as the ‘gold standard’ in diagnosing food allergy, although these tests have practical problems. Therefore, new test systems have been developed, such as endoscopic provocation tests, that may improve diagnostic procedures. Elimination diet still presents the main basis of therapy. Aspects to be focused on in the future are the role fo IgE-independent allergic mechanisms in intestinal allergy, the impact of cross-reactivity with other allergens and the relationship to other inflammatory bowel diseases such as Crohn’s disease, ulcerative colitis, celiac disease and irritable bowel syndrome.

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“…For example, NO inhibits IgE-dependent histamine and serotonin secretion (21,22,25,42,43), platelet-activating factor production (24), and adhesion to fibronectin (26), but potentiates TNF-mediated cytotoxicity (23). How the up-regulation of CD8␣ expression by NO fits in with this spectrum of other effects of NO on MC is not currently clear.…”

Section: Discussionmentioning

confidence: 99%

Regulation of CD8 Expression in Mast Cells by Exogenous or Endogenous Nitric Oxide

Nohara

Kulka

et al. 2001

The Journal of Immunology

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We recently reported a novel CD8 molecule on rat alveolar macrophages and peritoneal mast cells (PMC). However, little is known about the regulation of CD8 expression and function on these cells. We investigated the regulation of CD8 expression on PMC by NO, because NO can regulate inflammatory responses and also because anti-CD8 Ab stimulates inducible NO synthase and NO production by PMC and alveolar macrophages. Ligation of CD8α on PMC with Ab (OX8) induced CD8α mRNA expression after 3–6 h, and flow cytometry demonstrated that OX8 treatment increased CD8α protein expression compared with PMC treated with isotype control IgG1. To test whether NO mediates the up-regulation of CD8α, we used the NO donor S-nitrosoglutathione (500 μM) and NO synthase inhibitors (NG-monomethyl-l-arginine and NG-nitro-l-arginine methyl ester; 100 μM). S-nitrosoglutathione up-regulated both mRNA and protein expression of CD8α in PMC compared with that in sham-treated cells, while NO synthase inhibitors down-regulated OX8 Ab-induced CD8α expression. To investigate how NO regulates CD8 expression on PMC, we examined the cGMP-dependent pathway using 8-bromo-cGMP (2 mM) and the guanylate cyclase inhibitor, 1H-oxadiazoloquinoxalin-1-one (20 μM). 8-Bromo-cGMP up-regulated CD8 expression, whereas 1H-oxadiazoloquinoxalin-1-one down-regulated its expression. Thus, ligation of CD8 up-regulates CD8 expression on PMC, a response mediated at least in part by NO through a cGMP-dependent pathway. The significance of this up-regulation of CD8α on mast cells (MC) is unclear, but since ligation of CD8 on MC with OX8 Ab can alter gene expression and mediator secretion, up-regulation of CD8 may enhance the MC response to natural ligation of this novel form of CD8.

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Exogenous Nitric Oxide Regulates the Degranulation of Human Basophils and Rat Peritoneal Mast Cells

Cited by 40 publications

References 25 publications

Expression, localization, and regulation of NOS in human mast cell lines: effects on leukotriene production

Expression, localization, and regulation of NOS in human mast cell lines: effects on leukotriene production

Allergy and the Gut

Regulation of CD8 Expression in Mast Cells by Exogenous or Endogenous Nitric Oxide

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