Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2127-2134 ◽  
Author(s):  
Derek S. Sim ◽  
Glenn Merrill-Skoloff ◽  
Barbara C. Furie ◽  
Bruce Furie ◽  
Robert Flaumenhaft
Keyword(s):  
Vascular Injury ◽  
Intracellular Signaling ◽  
Thrombus Formation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
In Vivo Model ◽  
The Status ◽  
Platelet Accumulation ◽  
Camp Levels

Abstract Platelet accumulation at sites of vascular injury is the primary event in arterial thrombosis. Initial platelet accrual into thrombi is mediated by interactions of platelet adhesion receptors with ligands on the injured endothelium or in the sub-endothelial matrix. The role of intracellular signals in initial platelet accumulation at sites of endothelial injury, however, is the subject of debate. We have used a newly discovered inhibitor of phosphodiesterase 3A (PDE3A) and the well-characterized PDE3A inhibitor, cilostazol, to modulate 3′,5′-cyclic adenosine monophosphate (cAMP) levels in an in vivo model that enables the kinetic analysis of platelet accumulation. These studies demonstrate that elevation of basal cAMP levels results in an overall decline in platelet accumulation at the site of vascular injury. In particular, the initial rate of accumulation of platelets is inhibited by elevation of cAMP. Analysis of the kinetics of individual platelets at injury sites using intravital microscopy demonstrates that cAMP directs the rate at which platelets attach to and detach from thrombi. These studies demonstrate that cAMP in circulating platelets controls attachment to and detachment from sites of arteriolar injury. Thus, the status of the intracellular signaling machinery prior to engagement of platelet receptors influences the rate of platelet accumulation during thrombus formation.

scholarly journals RGS/Gi2α interactions modulate platelet accumulation and thrombus formation at sites of vascular injury

Blood ◽  
2010 ◽  
Vol 116 (26) ◽  
pp. 6092-6100 ◽  
Author(s):  
Rachel S. Signarvic ◽  
Aleksandra Cierniewska ◽  
Timothy J. Stalker ◽  
Karen P. Fong ◽  
Manash S. Chatterjee ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Vascular Injury ◽  
Thrombus Formation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Active Role ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Platelet Accumulation

Abstract Although much is known about extrinsic regulators of platelet function such as nitric oxide and prostaglandin I2 (PGI2), considerably less is known about intrinsic mechanisms that prevent overly robust platelet activation after vascular injury. Here we provide the first evidence that regulators of G-protein signaling (RGS) proteins serve this role in platelets, using mice with a G184S substitution in Gi2α that blocks RGS/Gi2 interactions to examine the consequences of lifting constraints on Gi2-dependent signaling without altering receptor:effector coupling. The results show that the Gi2α(G184S) allele enhances platelet aggregation in vitro and increases platelet accumulation after vascular injury when expressed either as a global knock-in or limited to hematopoietic cells. Biochemical studies show that these changes occur in concert with an attenuated rise in cyclic adenosine monophosphate levels in response to prostacyclin and a substantial increase in basal Akt activation. In contrast, basal cyclic adenosine monophosphate (cAMP) levels, agonist-stimulated increases in [Ca++]i, Rap1 activation, and α-granule secretion were unaffected. Collectively, these observations (1) demonstrate an active role for RGS proteins in regulating platelet responsiveness, (2) show that this occurs in a pathway-selective manner, and (3) suggest that RGS proteins help to prevent unwarranted platelet activation as well as limiting the magnitude of the normal hemostatic response.

scholarly journals Mel1c Mediated Monochromatic Light-Stimulated IGF-I Synthesis through the Intracellular Gαq/PKC/ERK Signaling Pathway

2019 ◽  
Vol 20 (7) ◽  
pp. 1682
Author(s):  
Shujie Ning ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong ◽  
Yaoxing Chen
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Monochromatic Light ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Erk Signaling ◽  
Sham Operation ◽  
Intracellular Signaling Pathway ◽  
Igf I

Previous studies have demonstrated that monochromatic light affects plasma melatonin (MEL) levels, which in turn regulates hepatic insulin-like growth factor I (IGF-I) secretion via the Mel1c receptor. However, the intracellular signaling pathway initiated by Mel1c remains unclear. In this study, newly hatched broilers, including intact, sham operation, and pinealectomy groups, were exposed to either white (WL), red (RL), green (GL), or blue (BL) light for 14 days. Experiments in vivo showed that GL significantly promoted plasma MEL formation, which was accompanied by an increase in the MEL receptor, Mel1c, as well as phosphorylated extracellular regulated protein kinases (p-ERK1/2), and IGF-I expression in the liver, compared to the other light-treated groups. In contrast, this GL stimulation was attenuated by pinealectomy. Exogenous MEL elevated the hepatocellular IGF-I level, which is consistent with increases in cyclic adenosine monophosphate (cAMP), Gαq, phosphorylated protein kinase C (p-PKC), and p-ERK1/2 expression. However, the Mel1c selective antagonist prazosin suppressed the MEL-induced expression of IGF-I, Gαq, p-PKC, and p-ERK1/2, while the cAMP concentration was barely affected. In addition, pretreatment with Ym254890 (a Gαq inhibitor), Go9863 (a PKC inhibitor), and PD98059 (an ERK1/2 inhibitor) markedly attenuated MEL-stimulated IGF-I expression and p-ERK1/2 activity. These results indicate that Mel1c mediates monochromatic GL-stimulated IGF-I synthesis through intracellular Gαq/PKC/ERK signaling.

Endobrevin/VAMP-8-Mediated Dense Granule Release Is Required for Efficient Thrombus Formation in Vivo.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1836-1836
Author(s):  
Price S. Blair ◽  
Qiansheng Ren ◽  
Gwenda J. Graham ◽  
James R. Dilks ◽  
Sidney W. Whiteheart ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Thrombus Formation ◽  
Dense Granule ◽  
Wild Type ◽  
Platelet Accumulation ◽  
Induced Aggregation ◽  
Kinetics Of ◽  
Granule Release

Abstract Individuals whose platelets lack dense core or alpha-granules suffer varying degrees of abnormal bleeding, implying that granule cargo contributes to hemostasis. Despite these clinical observations, little is known regarding the effects of impaired platelet granule secretion on thrombus formation in vivo. The release of cargo from platelet granules requires a group of membrane proteins called SNAREs (Soluble NSF Attachment Protein Receptors) that mediate fusion of granule membranes to the plasma membrane and open canalicular system. Endobrevin/VAMP-8 is the primary vesicular-SNARE (v-SNARE) responsible for efficient release of dense core and a-granule contents. To evaluate the importance of VAMP-8-mediated secretion on the kinetics of thrombus formation in vivo, we measured platelet accumulation following laser-induced vascular injury in VAMP-8−/− mice. Three different phases of thrombus formation - initiation, maximal accumulation, and stabilized platelet accumulation - were tested. Analysis of initial thrombus formation from wild-type and VAMP-8−/− mice showed that average platelet accumulation in VAMP- 8−/− mice was 23% of accumulation in wild-type mice (P=0.009) at 30 sec following injury. There was a trend towards smaller maximal thrombus size in VAMP-8−/− mice, but the difference was not statistically significant (P=0.1). Average stabilized platelet accumulation at 180 sec in VAMP-8−/− mice was 40% of wild-type mice (P=0.05). Thus, thrombus formation is delayed and decreased in VAMP-8−/− mice, but not absent. Dense granule release occurs more rapidly than alpha-granule release, which does not occur for 2–3 min following laser-induced vascular injury. Agonist-induced dense granule release from VAMP-8−/− platelets is defective. To directly evaluate the role of dense granule release on the kinetics of thrombus formation, we assessed thrombus formation in the mouse model of Hermansky-Pudlak syndrome, ruby-eye, which lack dense granules. Thrombus formation following laser-induced vascular injury was nearly abolished in ruby-eye mice such that maximal platelet accumulation was 15% that of wild-type mice. In vitro, the thrombin doses required to induce irreversible aggregation in wild-type, VAMP-8−/−, and ruby-eye platelets were 25 mU, 50 mU, and 150 mU, respectively. Incubation with apyrase had little effect on thrombin-induced aggregation of VAMP-8−/− or ruby-eye platelets. In contrast, incubation of wild-type platelets with apyrase reduced their thrombin sensitivity compared to that of ruby-eye platelets. Supplementation with a substimulatory ADP concentration reversed the thrombin-induced aggregation defect in VAMP-8−/− and ruby-eye mice. Thus, defective ADP release is the primary abnormality leading to impaired aggregation in VAMP-8−/− and ruby-eye mice. Tail bleeding times were assessed in VAMP- 8−/− mice to evaluate the role of VAMP-8 in hemostasis. In contrast to ruby-eye mice, which have a markedly prolonged bleeding time, tail bleeding times in VAMP-8−/− mice were not significantly prolonged compared to those in wild-type mice. These results demonstrate the importance of VAMP-8 and dense granule release in the initial phases of thrombus formation and validate the distal platelet secretory machinery as a potential target for anti-platelet therapies.

Protective mechanisms of adenosine 5′-monophosphate in platelet activation and thrombus formation

2014 ◽  
Vol 111 (03) ◽  
pp. 491-507 ◽  
Author(s):  
Eduardo Fuentes ◽  
Lina Badimon ◽  
Julio Caballero ◽  
Teresa Padró ◽  
Gemma Vilahur ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Adenosine Receptor ◽  
Thrombus Formation ◽  
Antiplatelet Agent ◽  
Binding Pocket ◽  
In Vivo Model ◽  
Platelet Surface ◽  
Camp Levels

SummaryPlatelet activation is relevant to a variety of acute thrombotic events. We sought to examine adenosine 5′-monophosphate (AMP) mechanisms of action in preventing platelet activation, thrombus formation and platelet-related inflammatory response. We assessed the effect of AMP on 1) P-selectin expression and GPIIb/IIIa activation by flow cytometry; 2) Platelet aggregation and ATP secretion induced by ADP, collagen, TRAP-6, convulxin and thrombin; 3) Platelet rolling and firm adhesion, and platelet-leukocyte interactions under flow-controlled conditions; and, 4) Platelet cAMP levels, sP-selectin, sCD40L, IL-1β, TGF-β1 and CCL5 release, PDE3A activity and PKA phosphorylation. The effect of AMP on in vivo thrombus formation was also evaluated in a murine model. The AMP docking with respect to A2 adenosine receptor was determined by homology. AMP concentration-dependently (0.1 to 3 mmol/l) inhibited P-selectin expression and GPIIb/IIIa activation, platelet secretion and aggregation induced by ADP, collagen, TRAP-6 and convulxin, and diminished platelet rolling and firm adhesion. Furthermore, AMP induced a marked increase in the rolling speed of leukocytes retained on the platelet surface. At these concentrations AMP significantly decreased inflammatory mediator from platelet, increased intraplatelet cAMP levels and inhibited PDE3A activity. Interestingly, SQ22536, ZM241385 and SCH58261 attenuated the antiplatelet effect of AMP. Docking experiments revealed that AMP had the same orientation that adenosine inside the A2 adenosine receptor binding pocket. These in vitro antithrombotic properties were further supported in an in vivo model of thrombosis. Considering the successful use of combined antiplatelet therapy, AMP may be further developed as a novel antiplatelet agent.

scholarly journals Regulation of Protein Disulfide Isomerase By S-Nitrosylation Controls Its Function during Thrombus Formation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 93-93
Author(s):  
Roelof H Bekendam ◽  
Gopal Srila ◽  
Pavan K Bendapudi ◽  
James R Dilks ◽  
Lin Lin ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Vascular Injury ◽  
Protein Disulfide Isomerase ◽  
Thrombus Formation ◽  
Reductase Activity ◽  
Wild Type ◽  
Disulfide Isomerase ◽  
Platelet Accumulation ◽  
Protein Disulfide

Abstract Protein disulfide isomerase (PDI) is an oxidoreductase that is essential for thrombus formation following vascular injury. Clinical trials testing the efficacy and safety of PDI inhibition in the setting of thrombotic disease are currently underway. Yet while preclinical and clinical trials of PDI in thrombosis have progressed rapidly, the mechanisms by which PDI is regulated in the vasculature and how it mediates thrombosis remain unknown. PDI has an a-b-b'-x-a' domain structure, where the a and a' domains contain a CGHC motif responsible for cleaving and forming disulfide bonds. The active site cysteines within the catalytic CGHC motif that perform oxidoreductive reactions can also undergo S-nitrosylation. We have evaluated the hypothesis that nitric oxide (NO) converts PDI into a nitrosylase and regulates PDI oxidoreductase activity in the vasculature during thrombus formation. Initial studies demonstrated that incubation of recombinant PDI with the NO donor, SNAP, resulted in an 83±1.4% decrease in its reductase activity. A transnitrosylase assay using the NO indicator DAF-FM showed that S-nitrosylated PDI (SNO-PDI) transferred NO into platelets and inhibited platelet aggregation. To define the molecular determinants of PDI nitrosylation activity, we evaluated mutant PDIs containing Cys -> Ala mutations of the CGHC (a domain)/CGHC (a' domain) motifs in the platelet-based transnitrosylase assay. Wild-type PDI (CGHC/CGHC) demonstrated full reductase and nitrosylase activity and the enzymatically dead mutant (AGHA/AGHA) showed neither activity. In contrast, the CGHA/CGHA mutant maintained nitrosylase activity (41±0.23%), but had no reductase activity. This observation suggested that reductase and nitrosylase activities were separable. To further evaluate this supposition, we screened a series of PDI mutants in which intervening sequences of the CGHC domain had been modified. The screen identified CGPC/CGPC as a nitrosylase-biased mutant that showed a 59±2.31% decrease in reductase activity, but a 72±1.83% increase in nitrosylase activity compared to wild-type PDI. Another nitrosylase-biased mutant, CGRC/CGRC, showed a similar activity pattern. Since PDI is prothrombotic and SNO-PDI is antithrombotic, we compared the activity of nitrosylase-biased mutants with wild-type PDI in platelet aggregation studies in the presence of physiological concentrations of GSNO. While wild-type PDI had little effect on platelet aggregation, nitrosylase-biased PDIs such as the CGPC/CGPC and CGRC/CGRC mutant completely inhibited platelet aggregation. These studies show that the prothrombotic oxidoreductase activities of PDI are separable from their antithrombotic nitrosylase activities and that nitrosylase-biased PDI mutants have antiplatelet activity. We next evaluated the effect of PDI nitrosylation on thrombus formation in vivo. Infusion of SNO-PDI into mice inhibited thrombus formation following laser-induced vascular injury of cremaster arterioles. Mice deficient in glutathione-S-nitrosyl reductase (GSNOR) were used to assess the role of endogenous NO in thrombus formation. GSNOR enzymatically reduces GSNO, the main storage form of NO in cells. Platelet accumulation and fibrin formation were hardly detectable in GSNOR-/- mice. Infusion of recombinant WT PDI, but not an enzymatically dead PDI, reversed the defect in platelet accumulation and fibrin generation to levels of WT mice. In order to visualize NO during thrombus formation, the NO-sensitive dye DAF-FM was infused into mice and NO signal in endothelium monitored following laser-induced injury. DAF-FM signal decreased rapidly following laser injury of cremaster arterioles, indicating an activation-induced reduction in endothelial NO in vivo. In conclusion, our studies show that oxidoreductase and nitrosylase activities of PDI are separable and support a model whereby high endothelial NO levels maintain vascular quiescence in part by maintaining PDI as a nitrosylase and blocking its prothrombotic PDI activity. We propose that the reduction of NO levels that occurs with vascular injury or endothelial dysfunction contributes to the conversion of PDI from an anti-thrombotic nitrosylase to a prothrombotic reductase. Disclosures No relevant conflicts of interest to declare.

Development of a Stable Thrombotic Core with Limited Access to Plasma Proteins During Thrombus Formation In Vivo

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2013-2013 ◽  
Author(s):  
Timothy J. Stalker ◽  
Elizabeth A. Traxler ◽  
Scott L. Diamond ◽  
Lawrence F. Brass
Keyword(s):  
Vascular Injury ◽  
Central Region ◽  
Plasma Proteins ◽  
Conflicts Of Interest ◽  
Thrombus Formation ◽  
Surface Expression ◽  
Activation Markers ◽  
Platelet Surface ◽  
Platelet Accumulation

Abstract Abstract 2013 Several studies examining thrombus formation in vivo have described the formation of a thrombotic core composed of stably adherent, apparently activated platelets covered by several layers of minimally activated, loosely adherent platelets. Using confocal fluorescence intravital microscopy in mouse cremaster muscle arterioles, we sought to 1) determine whether the stable thrombus core could be defined by the presence of platelet activation markers (e.g. P-selectin); 2) define the spatial and temporal characteristics of the stable thrombus core as it develops; and 3) determine whether the accessibility of plasma proteins to the inner regions of a stable thrombus is limited. We found that P-selectin platelet surface expression is associated with stable platelet incorporation into a growing thrombus following either laser- or wall puncture-induced vascular injury in vivo. The P-selectin positive core originated at the site of vascular injury and subsequently expanded outward into the central region of the developing thrombus with kinetics that were distinct from total platelet accumulation. Further, using two related approaches, we determined that the accessibility of plasma components to the stable thrombus core is limited. In the first approach, fluorescently labeled anti-P-selectin antibody was infused after a stable thrombus had formed (25 minutes after injury), and was found to bind to a monolayer of platelets on the luminal surface of the stable thrombus core, but was unable to penetrate this layer of platelets and bind to platelets in the central region of the thrombus. In the second approach, we directly measured the porosity of thrombi as they evolved by infusing fluorescently labeled dextran to illuminate the plasma in the gaps between platelets. We found that the porosity of the stable thrombus core was significantly decreased as compared to the porosity of the growing platelet mass before the core developed. Taken together, these results demonstrate that a stable core composed of degranulated platelets develops during thrombus formation in vivo with spatial localization and kinetics that are distinct from total platelet accumulation, and that development of this core limits the accessibility of plasma components to the central region of a stable thrombus. Disclosures: No relevant conflicts of interest to declare.

PAK Membrane Translocation and Phosphorylation Regulate Platelet Aggregation Downstream of Gi and G12/13 Pathways

2020 ◽  
Vol 120 (11) ◽  
pp. 1536-1547
Author(s):  
Jianjun Zhang ◽  
Yan Zhang ◽  
Shuang Zheng ◽  
Yangyang Liu ◽  
Lin Chang ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Akt Phosphorylation ◽  
Pathway Activation ◽  
Simultaneous Activation ◽  
P21 Activated Kinase

AbstractPlatelet activation plays a pivotal role in physiological hemostasis and pathological thrombosis causing heart attack and stroke. Previous studies conclude that simultaneous activation of Gi and G12/13 signaling pathways is sufficient to cause platelet aggregation. However, using Gq knockout mice and Gq-specific inhibitors, we here demonstrated that platelet aggregation downstream of coactivation of Gi and G12/13 depends on agonist concentrations; coactivation of Gi and G12/13 pathways only induces platelet aggregation under higher agonist concentrations. We confirmed Gi and G12/13 pathway activation by showing cAMP (cyclic adenosine monophosphate) decrease and RhoA activation in platelets stimulated at both low and high agonist concentrations. Interestingly, we found that though Akt and PAK (p21-activated kinase) translocate to the platelet membrane upon both low and high agonist stimulation, membrane-translocated Akt and PAK only phosphorylate at high agonist concentrations, correlating well with platelet aggregation downstream of concomitant Gi and G12/13 pathway activation. PAK inhibitor abolishes Akt phosphorylation, inhibits platelet aggregation in vitro and arterial thrombus formation in vivo. We propose that the PAK-PI3K/Akt pathway mediates platelet aggregation downstream of Gi and G12/13, and PAK may represent a potential antiplatelet and antithrombotic target.

scholarly journals Highly sensitive genetically-encoded sensors for population and subcellular imaging of cAMP in vivo

2021 ◽  
Author(s):  
Crystian I Massengill ◽  
Landon Bayless-Edwards ◽  
Cesar C Ceballos ◽  
Elizabeth R Cebul ◽  
Maozhen Qin ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Intracellular Signaling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Fluorescence Lifetime Imaging ◽  
Lifetime Imaging ◽  
Highly Sensitive ◽  
Increased Sensitivity ◽  
Resolution Imaging

AbstractCyclic adenosine monophosphate (cAMP) integrates information from diverse G protein-coupled receptors, such as neuromodulator receptors, to regulate pivotal biological processes in a cellular- and subcellular-specific manner. However, in vivo cellular-resolution imaging of cAMP dynamics in neurons has not been demonstrated. Here, we screen existing genetically-encoded cAMP sensors, and further develop the best performer to derive three improved variants, called cAMPFIREs. These sensors exhibit up to ten-fold increased sensitivity to cAMP and a corrected, cytosolic distribution. cAMPFIREs are compatible with both ratiometric and fluorescence lifetime imaging, and can detect cAMP dynamics elicited by norepinephrine at physiologically-relevant, nanomolar concentrations. Imaging of cAMPFIREs in awake mice reveals tonic levels of cAMP in cortical neurons that are associated with wakefulness, and are differentially regulated in different subcellular compartments. Furthermore, enforced locomotion elicits neuron-specific, bidirectional cAMP dynamics, in part, mediated by norepinephrine. Finally, cAMPFIREs also function in Drosophila, suggesting that they have broad applicability for studying intracellular signaling in vivo.

scholarly journals Upregulation of cAMP prevents antibody-mediated thrombus formation in COVID-19

2022 ◽  
Vol 6 (1) ◽  
pp. 248-258
Author(s):  
Jan Zlamal ◽  
Karina Althaus ◽  
Hisham Jaffal ◽  
Helene Häberle ◽  
Lisann Pelzl ◽  
...  
Keyword(s):  
Time Course ◽  
Thrombus Formation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Intracellular Camp ◽  
Igg Antibodies ◽  
Potential Therapeutic Target ◽  
Increased Risk ◽  
Risk For Thrombosis ◽  
Camp Levels

Abstract Thromboembolic events are frequently reported in patients infected with the SARS-CoV-2 virus. The exact mechanisms of COVID-19-associated hypercoagulopathy, however, remain elusive. Recently, we observed that platelets (PLTs) from patients with severe COVID-19 infection express high levels of procoagulant markers, which were found to be associated with increased risk for thrombosis. In the current study, we investigated the time course as well as the mechanisms leading to procoagulant PLTs in COVID-19. Our study demonstrates the presence of PLT-reactive IgG antibodies that induce marked changes in PLTs in terms of increased inner-mitochondrial transmembrane potential (Δψ) depolarization, phosphatidylserine (PS) externalization, and P-selectin expression. The IgG-induced procoagulant PLTs and increased thrombus formation were mediated by ligation of PLT Fc-γ RIIA (FcγRIIA). In addition, contents of calcium and cyclic-adenosine-monophosphate (cAMP) in PLTs were identified to play a central role in antibody-induced procoagulant PLT formation. Most importantly, antibody-induced procoagulant events, as well as increased thrombus formation in severe COVID-19, were inhibited by Iloprost, a clinically approved therapeutic agent that increases the intracellular cAMP levels in PLTs. Our data indicate that upregulation of cAMP could be a potential therapeutic target to prevent antibody-mediated coagulopathy in COVID-19 disease.

scholarly journals Anti-Allergic and Anti-Inflammatory Effects of Undecane on Mast Cells and Keratinocytes

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1554
Author(s):  
Dabin Choi ◽  
Wesuk Kang ◽  
Taesun Park
Keyword(s):  
Mast Cells ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Allergic Diseases ◽  
Intracellular Camp ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Skin Conditions ◽  
Factor Α ◽  
Camp Levels

The critical roles of keratinocytes and resident mast cells in skin allergy and inflammation have been highlighted in many studies. Cyclic adenosine monophosphate (cAMP), the intracellular second messenger, has also recently emerged as a target molecule in the immune reaction underlying inflammatory skin conditions. Here, we investigated whether undecane, a naturally occurring plant compound, has anti-allergic and anti-inflammatory activities on sensitized rat basophilic leukemia (RBL-2H3) mast cells and HaCaT keratinocytes and we further explored the potential involvement of the cAMP as a molecular target for undecane. We confirmed that undecane increased intracellular cAMP levels in mast cells and keratinocytes. In sensitized mast cells, undecane inhibited degranulation and the secretion of histamine and tumor necrosis factor α (TNF-α). In addition, in sensitized keratinocytes, undecane reversed the increased levels of p38 phosphorylation, nuclear factor kappaB (NF-κB) transcriptional activity and target cytokine/chemokine genes, including thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and interleukin-8 (IL-8). These results suggest that undecane may be useful for the prevention or treatment of skin inflammatory disorders, such as atopic dermatitis, and other allergic diseases.

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