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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
.
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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.
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