Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Inhibition of MAPK and STAT3-SOCS3 by Sakuranetin Attenuated Chronic Allergic Airway Inflammation in Mice.
Santana FPR
,
da Silva RC
,
Grecco SDS
,
Pinheiro AJMCR
,
Caperuto LC
,
Arantes-Costa FM
,
Claudio SR
,
Yoshizaki K
,
Macchione M
,
Ribeiro DA
,
Tibério IFLC
,
Lima-Neto LG
,
Lago JHG
,
Prado CM
.
Abstract
Asthma allergic disease is caused by airway chronic inflammation. Some intracellular signaling pathways, such as MAPK and STAT3-SOCS3, are involved in the control of airway inflammation in asthma. The flavonoid sakuranetin demonstrated an anti-inflammatory effect in different asthma models. Our aim was to clarify how sakuranetin treatment affects MAPK and STAT3-SOCS3 pathways in a murine experimental asthma model. Mice were submitted to an asthma ovalbumin-induction protocol and were treated with vehicle, sakuranetin, or dexamethasone. We assayed the inflammatory profile, mucus production, and serum antibody, STAT3-SOCS3, and MAPK levels in the lungs. Morphological alterations were also evaluated in the liver. LPS-stimulated RAW 264.7 cells were used to evaluate the effects of sakuranetin on nitric oxide (NO) and cytokine production. In vivo, sakuranetin treatment reduced serum IgE levels, lung inflammation (eosinophils, neutrophils, and Th2/Th17 cytokines), and respiratory epithelial mucus production in ovalbumin-sensitized animals. Considering possible mechanisms, sakuranetin inhibits the activation of ERK1/2, JNK, p38, and STAT3 in the lungs. No alterations were found in the liver for treated animals. Sakuranetin did not modify in vitro cell viability in RAW 264.7 and reduced NO release and gene expression of IL-1β and IL-6 induced by LPS in these cells. In conclusion, our data showed that the inhibitory effects of sakuranetin on eosinophilic lung inflammation can be due to the inhibition of Th2 and Th17 cytokines and the inhibition of MAPK and STAT3 pathways, reinforcing the idea that sakuranetin can be considered a relevant candidate for the treatment of inflammatory allergic airway disease.
Figure 1. Sakuranetin structure, 5,4′-dihydroxy-7-methoxy flavanone, isolated from B. retusa.
Figure 4. Sakuranetin inhibits the activation of the MAPK pathway. (a) Image intensity of p38, p-p38, ERK1/2, and p-ERK1/2. (b) Expression of p38 and p-p38. (c) Expression of ERK1/2 and p-ERK1/2. (d) Expression and image intensity of JNK and p-JNK in lung tissue measured by immunoblotting. Sakuranetin reduced the phosphorylation of p38, ERK1/2, and JNK that was enhanced in the asthmatic group. ∗p < 0.001, ∗∗p < 0.01, and #p < 0.05. Data represent mean ± SEM from 5 to 8 mice per group.
Figure 5. Sakuranetin inhibits the activation of the STAT3-SOCS3 pathway. Expression and intensity of (a) STAT3 and p-STAT3 and (b) SOCS3 in lung tissue detected by immunoblotting. Sakuranetin reduced the phosphorylation of STAT3 that was enhanced in the asthmatic group. ∗p < 0.001, ∗∗p < 0.01, and #p < 0.05. Data represent mean ± SEM from 5 to 8 mice per group.
Atherton,
IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation.
2003, Pubmed
Atherton,
IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation.
2003,
Pubmed
Bittencourt-Mernak,
Prophylactic and therapeutic treatment with the flavonone sakuranetin ameliorates LPS-induced acute lung injury.
2017,
Pubmed
,
Echinobase
Brüggemann,
Cigarette Smoke Increases CD8α+ Dendritic Cells in an Ovalbumin-Induced Airway Inflammation.
2017,
Pubmed
Caperuto,
Modulation of bone morphogenetic protein-9 expression and processing by insulin, glucose, and glucocorticoids: possible candidate for hepatic insulin-sensitizing substance.
2008,
Pubmed
Chen,
Astragalus membranaceus modulates Th1/2 immune balance and activates PPARγ in a murine asthma model.
2014,
Pubmed
Chen,
Total flavonoids of Mosla scabra leaves attenuates lipopolysaccharide-induced acute lung injury via down-regulation of inflammatory signaling in mice.
2013,
Pubmed
Chialda,
Inhibitors of mitogen-activated protein kinases differentially regulate costimulated T cell cytokine production and mouse airway eosinophilia.
2005,
Pubmed
Christianson,
Mechanisms of sustained signalling in asthma.
2013,
Pubmed
Dahan,
Food-drug interaction: grapefruit juice augments drug bioavailability--mechanism, extent and relevance.
2004,
Pubmed
Daviskas,
Hyperosmolar agents and clearance of mucus in the diseased airway.
2006,
Pubmed
Dong,
MAP kinases in the immune response.
2002,
Pubmed
Duan,
Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model.
2004,
Pubmed
Gavett,
Interleukin-4 receptor blockade prevents airway responses induced by antigen challenge in mice.
1997,
Pubmed
Gavino,
STAT3 inhibition prevents lung inflammation, remodeling, and accumulation of Th2 and Th17 cells in a murine asthma model.
2016,
Pubmed
Grecco,
In vitro antileishmanial and antitrypanosomal activities of flavanones from Baccharis retusa DC. (Asteraceae).
2012,
Pubmed
,
Echinobase
Harris,
Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity.
2007,
Pubmed
Hasegawa,
Increased serum IL-17A and Th2 cytokine levels in patients with severe uncontrolled asthma.
2017,
Pubmed
Hernández,
Effects of naturally occurring dihydroflavonols from Inula viscosa on inflammation and enzymes involved in the arachidonic acid metabolism.
2007,
Pubmed
Huang,
OX40L induces helper T cell differentiation during cell immunity of asthma through PI3K/AKT and P38 MAPK signaling pathway.
2018,
Pubmed
Jang,
Hypergravity enhances the therapeutic effect of dexamethasone in allergic asthma and rhinitis animal model.
2018,
Pubmed
Khorasanizadeh,
Mitogen-activated protein kinases as therapeutic targets for asthma.
2017,
Pubmed
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
Kim,
Sakuranetin Inhibits Inflammatory Enzyme, Cytokine, and Costimulatory Molecule Expression in Macrophages through Modulation of JNK, p38, and STAT1.
2016,
Pubmed
Kujime,
p38 mitogen-activated protein kinase and c-jun-NH2-terminal kinase regulate RANTES production by influenza virus-infected human bronchial epithelial cells.
2000,
Pubmed
Le Gros,
Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells.
1990,
Pubmed
Li,
Apigenin protects ovalbumin-induced asthma through the regulation of Th17 cells.
2013,
Pubmed
Martínez-Rivera,
Mucus hypersecretion in asthma is associated with rhinosinusitis, polyps and exacerbations.
2018,
Pubmed
Meduri,
Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome.
1995,
Pubmed
Moon,
Dietary flavonoids: effects on xenobiotic and carcinogen metabolism.
2006,
Pubmed
Murphy,
Recent advances in the pathophysiology of asthma.
2010,
Pubmed
Pinheiro,
Punica granatum L. Leaf Extract Attenuates Lung Inflammation in Mice with Acute Lung Injury.
2018,
Pubmed
Possa,
Eosinophilic inflammation in allergic asthma.
2013,
Pubmed
Pu,
TRPC1 intensifies house dust mite-induced airway remodeling by facilitating epithelial-to-mesenchymal transition and STAT3/NF-κB signaling.
2019,
Pubmed
Sakoda,
Sakuranetin reverses vascular peribronchial and lung parenchyma remodeling in a murine model of chronic allergic pulmonary inflammation.
2016,
Pubmed
,
Echinobase
Santana,
Evidences of Herbal Medicine-Derived Natural Products Effects in Inflammatory Lung Diseases.
2016,
Pubmed
,
Echinobase
Seki,
SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses.
2003,
Pubmed
Sjölander,
Induction of a Th1 immune response and simultaneous lack of activation of a Th2 response are required for generation of immunity to leishmaniasis.
1998,
Pubmed
Sun,
MBD2-mediated Th17 differentiation in severe asthma is associated with impaired SOCS3 expression.
2018,
Pubmed
Taguchi,
A flavanone from Baccharis retusa (Asteraceae) prevents elastase-induced emphysema in mice by regulating NF-κB, oxidative stress and metalloproteinases.
2015,
Pubmed
,
Echinobase
Tas,
Targeting of proangiogenic signalling pathways in chronic inflammation.
2016,
Pubmed
Toledo,
Flavonone treatment reverses airway inflammation and remodelling in an asthma murine model.
2013,
Pubmed
WEIBEL,
Principles and methods for the morphometric study of the lung and other organs.
1963,
Pubmed
Ye,
Differences in airway remodeling and airway inflammation among moderate-severe asthma clinical phenotypes.
2017,
Pubmed
Yin,
SOCS3 and its role in associated diseases.
2015,
Pubmed
Yoshizaki,
Subchronic effects of nasally instilled diesel exhaust particulates on the nasal and airway epithelia in mice.
2010,
Pubmed
Yun,
Prunus yedoensis bark inhibits lipopolysaccharide-induced inflammatory cytokine synthesis by IκBα degradation and MAPK activation in macrophages.
2014,
Pubmed
Zafra,
SOCS3 silencing attenuates eosinophil functions in asthma patients.
2015,
Pubmed
de Oliveira,
Therapeutic potential of biodegradable microparticles containing Punica granatum L. (pomegranate) in murine model of asthma.
2013,
Pubmed
