Involvement of Cyclic Nucleotides in the Immunomodulatory Effects of Nitric Oxide on Murine Mast Cells

Bidri, Mohamed; Bécherel, P.A.; Legoff, L.; Pieroni, Luisa; Guillosson, Jean‐Jacques; Debré, Patrice; Arock, Michel

doi:10.1006/bbrc.1995.1689

Cited by 30 publications

(17 citation statements)

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“…Because no soluble guanylate cyclase has been detected in the macrophages employed (19), the reversal of the ANP effect by Ly-83583 can be attributed to an inhibition of cGMP production linked to the particulate guanylate cyclase-linked NPR-A receptor. In accordance with our observations, other data report an inhibition of TNF-␣ production by cyclic nucleotides (43,44,45), both cGMP and cAMP. The effect was observed by the employment of cGMP analogues as well as of phosphodiesterase inhibitors in murine and human mononuclear cells.…”

Section: Discussionsupporting

confidence: 93%

cGMP-Mediated Inhibition of TNF-α Production by the Atrial Natriuretic Peptide in Murine Macrophages

Kiemer¹,

Hartung

Vollmar³

2000

The Journal of Immunology

121

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The atrial natriuretic peptide (ANP) is suggested to regulate inflammatory response by alteration of macrophage functions. The aim of this study was to investigate whether ANP influences production of TNF-α. TNF-α production in murine bone marrow-derived macrophages was induced by LPS, and TNF-α secretion (±ANP) was determined by L929 bioassay. ANP dose dependently (10−8–10−6 M) inhibited TNF-α release by up to 95%. The effect was mediated via the guanylate cyclase-coupled A receptor, as was shown by employing dibutyryl-cGMP, the cGMP-inhibitory compound Ly-83583, and the A receptor antagonist HS-142-1. A specific ligand of the natriuretic peptide “clearance” receptor inhibited TNF-α production only at 10−7 and 10−8 M, but not at 10−6 M. The B receptor ligand C-type natriuretic peptide showed no TNF-α-inhibitory effect. To investigate the underlying mechanism of ANP-mediated TNF-α inhibition, Northern blot was performed. ANP-treated macrophages displayed decreased TNF-α-mRNA levels. Besides the known inhibition of NF-κB activation, in this study we demonstrated that ANP also attenuates the activation of the proinflammatory transcription factor AP-1 (gel shift assay). ANP did not alter subunit composition of AP-1 complexes, as was shown by supershift assays applying anti-c-jun and anti-c-fos Abs. To get information on the ANP effect for human inflammatory processes, we investigated cytokine production in human LPS-activated blood. ANP significantly attenuated production of TNF-α and IL-1β without affecting production of IL-10 and IL-1ra. In summary, ANP was shown to attenuate TNF-α production of LPS-activated macrophages via cGMP. The inhibition is suggested to involve transcriptional processes that are the result of reduced activation of responsible transcription factors.

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Section: Discussionsupporting

confidence: 93%

cGMP-Mediated Inhibition of TNF-α Production by the Atrial Natriuretic Peptide in Murine Macrophages

Kiemer¹,

Hartung

Vollmar³

2000

The Journal of Immunology

121

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“…Two previous studies report NO induced elevation of cGMP levels in the MC (27,28). However, one of these studies used rat peritoneal cells with a high proportion of non-MC and used non-MC-selective activating agents (27).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Calpain Is a Component of Nitric Oxide-Induced Down-Regulation of Human Mast Cell Adhesion

Forsythe

Befus

2003

The Journal of Immunology

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Nitric oxide is an important messenger that regulates mast cell activity by modifications to gene expression and intracellular pathways associated with exocytosis and adhesion. Integrin interactions with extracellular matrix components modulate an array of cell activities, including mediator production and secretion. To investigate the molecular mechanisms underlying NO regulation of mast cell function, we studied its effects on adhesion of a human mast cell line (HMC-1) to fibronectin (FN). The NO donors S-nitrosoglutathione and S-nitroso-N-acetylpenicillamine strongly down-regulated the adhesion of HMC-1 to FN. Inhibitors of soluble guanylate cyclase and protein kinase G did not alter the response of cells to NO. A peroxynitrite scavenger did not affect modulation of adhesion by NO, nor could the effect of NO be mimicked by the peroxynitrite-producing compound 3-morpholinosydnonimine. NO donors inhibited the cysteine protease, calpain, while calpain inhibitors mimicked the effect of NO and led to a decrease in the ability of HMC-1 cells to adhere to FN. Thus, NO is an effective down-regulator of human mast cell adhesion. The mechanism for this action does not involve peroxynitrite or activation of soluble guanylate cyclase. Instead, a portion of NO-induced down-regulation of adhesion may be attributed to inhibition of the cysteine protease, calpain, an enzyme that has been associated with control of integrin activation in other cell types. The inhibition of calpain is most likely mediated via nitrosylation of its active site thiol group. Calpain may represent a novel therapeutic target for the regulation of mast cell activity in inflammatory disorders.

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“…They could also account for the brief cGMP transients found in mast cells (11) and a neuroblastoma cell line (12), the more triphasic response found in aortic smooth muscle (14) and liver slices (36), and the more hyperbolic shape found in tracheal smooth muscle (37) and heart (38). The information encoded in the disparate cellular cGMP profiles generated in response to a common stimulus remains to be understood.…”

Section: Differential Potency Of No For Gc-coupled Receptors In Cellsmentioning

confidence: 99%

“…The shape of the resulting cGMP response in cells, however, varies greatly from one cell to another. For example, in platelets (9, 10), mast cells (11), and a neuroblastoma cell line (12), the response to continued NO application is a transient increase in cGMP, whereas, in a population of glial cells from the cerebellum, cGMP rises hyperbolically with time to attain large plateau concentrations (10). An intermediate response is found in neurons in another part of the brain (13) and in aortic smooth muscle (14).…”

mentioning

confidence: 99%

Kinetics of a Cellular Nitric Oxide/cGMP/Phosphodiesterase-5 Pathway

Amin

Bianco³

et al. 2004

Journal of Biological Chemistry

103

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Rat platelets served as a model to evaluate quantitatively how guanylate cyclase (GC)-coupled nitric oxide (NO) receptors and phosphodiesterases (here phosphodiesterase-5) interact to transduce NO signals in cells. The platelets expressed mRNA only for the ␣ 1 and ␤ 1 GC-coupled receptor subunits. In intact platelets, the potency of NO for elevating cGMP (EC 50 ‫؍‬ 10 nM) was lower than in lysed platelets (EC 50 ‫؍‬ 1.7 nM). The limiting activities of GC and phosphodiesterase in intact platelets were both very high, being equivalent to about 100 M/s. With low phosphodiesterase activity (imposed by 100 M sildenafil), the cGMP response over time was hyperbolic in shape for a range of NO concentrations or GC activities due to GC desensitization. Without a phosphodiesterase inhibitor, NO generated only brief cGMP transients, peaking after 2-5 s but amounting maximally to about 150 M cGMP. The transients were caused partly by GC desensitization, which varied in rate (halftime up to 3 s) and extent (up to 80%) depending on the NO concentration, and partly by an enhancement of the phosphodiesterase catalytic activity with time, which was deduced to be up to 30-fold and to occur with a half-time of up to 5 s. The results were simulated by a quantitative model, which also explains the varied shapes of cGMP responses to NO found in other cells. Downstream phosphorylation in platelets was detectable within 2 s, and, with continuous exposure (1 min), this pathway could be engaged by subnanomolar NO concentrations (EC 50 ‫؍‬ 0.5 nM).Whereas the spatio-temporal dynamics of some of the primary steps of cellular signal transduction, such as synaptic transmission and changes in intracellular Ca 2ϩ , have become well understood in quantitative terms (1, 2), knowledge of downstream signaling cascades remains largely qualitative. Nevertheless, the kinetic properties of the second messenger cascades are likely to be similarly instrumental in determining how cells respond.A case in point is nitric oxide (NO) 1 signaling. NO acts as a diffusible chemical messenger throughout the body, where it subserves diverse functions, including smooth muscle relaxation, inhibition of platelet aggregation, and the induction of synaptic plasticity (3,4). NO elicits these and other physiological effects by binding to its guanylyl cyclase (GC)-coupled receptors, thereby evoking the accumulation of cGMP in target cells. The receptors are ␣␤-heterodimers, of which two main isoforms, ␣ 1 ␤ 1 and ␣ 2 ␤ 1 , exist at differing levels in different tissues (5). Studies on purified receptors (6) and intact cells (7) suggest that activation of GC occurs very rapidly, within a few ms or less of adding NO, and complete deactivation in cells (upon removal of NO) requires only about 500 ms (7). Furthermore, when studied in isolation, the receptors are highly sensitive NO detectors, with only about 1 nM being needed to evoke half-maximal GC activity (8). The shape of the resulting cGMP response in cells, however, varies greatly from one cell to another. For example,...

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Involvement of Cyclic Nucleotides in the Immunomodulatory Effects of Nitric Oxide on Murine Mast Cells

Cited by 30 publications

References 0 publications

cGMP-Mediated Inhibition of TNF-α Production by the Atrial Natriuretic Peptide in Murine Macrophages

cGMP-Mediated Inhibition of TNF-α Production by the Atrial Natriuretic Peptide in Murine Macrophages

Inhibition of Calpain Is a Component of Nitric Oxide-Induced Down-Regulation of Human Mast Cell Adhesion

Kinetics of a Cellular Nitric Oxide/cGMP/Phosphodiesterase-5 Pathway

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