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Protective role of the cholinergic anti-inflammatory pathway in a mouse model of viral myocarditis.

Cheng Z, Li-Sha G, Jing-Lin Z, Wen-Wu Z, Xue-Si C, Xing-Xing C, Yue-Chun L - PLoS ONE (2014)

Bottom Line: Nicotine treatments significantly improved survival rate, attenuated myocardial lesions, and downregulated the expression of TNF-α and IL-6.Because nicotine is a α7nAchR agonist and methyllycaconitine is a α7nAchR antagonist, we conclude that α7nAchR activation increases the phosphorylation of STAT3, reduces the expression of TNF-α and IL-6, and, ultimately, alleviates viral myocarditis.We also conclude that blocking α7nAchR reduces the phosphorylation of STAT3, increases the expression of TNF-α and IL-6, aggravating viral myocarditis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

ABSTRACT

Background: Activation of the cholinergic anti-inflammatory pathway, which relies on the α7nAchR (alpha 7 nicotinic acetylcholine receptor), has been shown to decrease proinflammatory cytokines. This relieves inflammatory responses and improves the prognosis of patients with experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, pancreatitis, arthritis and other inflammatory syndromes. However, whether the cholinergic anti-inflammatory pathway has an effect on acute viral myocarditis has not been investigated. Here, we studied the effects of the cholinergic anti-inflammatory pathway on acute viral myocarditis.

Methodology/principal findings: In a coxsackievirus B3 murine myocarditis model (Balb/c), nicotine and methyllycaconitine were used to stimulate and block the cholinergic anti-inflammatory pathway, respectively. Relevant signal pathways were studied to compare their effects on myocarditis, survival rate, histopathological changes, ultrastructural changes, and cytokine levels. Nicotine treatments significantly improved survival rate, attenuated myocardial lesions, and downregulated the expression of TNF-α and IL-6. Methyllycaconitine decreased survival rate, aggravated myocardial lesions, and upregulated the expression of TNF-α and IL-6. In addition, levels of the signaling protein phosphorylated STAT3 were higher in the nicotine group and lower in the methyllycaconitine group compared with the untreated myocarditis group.

Conclusions/significance: These results show that nicotine protects mice from CVB3-induced viral myocarditis and that methyllycaconitine aggravates viral myocarditis in mice. Because nicotine is a α7nAchR agonist and methyllycaconitine is a α7nAchR antagonist, we conclude that α7nAchR activation increases the phosphorylation of STAT3, reduces the expression of TNF-α and IL-6, and, ultimately, alleviates viral myocarditis. We also conclude that blocking α7nAchR reduces the phosphorylation of STAT3, increases the expression of TNF-α and IL-6, aggravating viral myocarditis.

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Related in: MedlinePlus

Correlation between p-STAT3, NF-κB and cytokines (TNF-α and IL-6) on day 7. The bivariate correlation analysis fit a straight line to the significant negative relationship between the expression of p-STAT3 and the levels of TNF-α and IL-6 on day 7 (upper panel). However, the levels of TNF-α and IL-6 were not correlated with the expression of NF-κB p65 (lower panel).
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pone-0112719-g007: Correlation between p-STAT3, NF-κB and cytokines (TNF-α and IL-6) on day 7. The bivariate correlation analysis fit a straight line to the significant negative relationship between the expression of p-STAT3 and the levels of TNF-α and IL-6 on day 7 (upper panel). However, the levels of TNF-α and IL-6 were not correlated with the expression of NF-κB p65 (lower panel).

Mentions: We used the Pearson’s correlation analysis method to assess the relationship between the expression of p-STAT3 and NF-κB and the levels of the inflammatory cytokines TNF-α and IL-6. The bivariate correlation analysis fit a straight line to the significant negative relationship between the expression of p-STAT3 and the levels of TNF-α (r = −0.8523; Figure 7) and IL-6 (r = −0.8270; Figure 7) on day 7. However, the levels of TNF-α and IL-6 were not correlated with the expression of NF-κB p65 (Figure 7).


Protective role of the cholinergic anti-inflammatory pathway in a mouse model of viral myocarditis.

Cheng Z, Li-Sha G, Jing-Lin Z, Wen-Wu Z, Xue-Si C, Xing-Xing C, Yue-Chun L - PLoS ONE (2014)

Correlation between p-STAT3, NF-κB and cytokines (TNF-α and IL-6) on day 7. The bivariate correlation analysis fit a straight line to the significant negative relationship between the expression of p-STAT3 and the levels of TNF-α and IL-6 on day 7 (upper panel). However, the levels of TNF-α and IL-6 were not correlated with the expression of NF-κB p65 (lower panel).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232511&req=5

pone-0112719-g007: Correlation between p-STAT3, NF-κB and cytokines (TNF-α and IL-6) on day 7. The bivariate correlation analysis fit a straight line to the significant negative relationship between the expression of p-STAT3 and the levels of TNF-α and IL-6 on day 7 (upper panel). However, the levels of TNF-α and IL-6 were not correlated with the expression of NF-κB p65 (lower panel).
Mentions: We used the Pearson’s correlation analysis method to assess the relationship between the expression of p-STAT3 and NF-κB and the levels of the inflammatory cytokines TNF-α and IL-6. The bivariate correlation analysis fit a straight line to the significant negative relationship between the expression of p-STAT3 and the levels of TNF-α (r = −0.8523; Figure 7) and IL-6 (r = −0.8270; Figure 7) on day 7. However, the levels of TNF-α and IL-6 were not correlated with the expression of NF-κB p65 (Figure 7).

Bottom Line: Nicotine treatments significantly improved survival rate, attenuated myocardial lesions, and downregulated the expression of TNF-α and IL-6.Because nicotine is a α7nAchR agonist and methyllycaconitine is a α7nAchR antagonist, we conclude that α7nAchR activation increases the phosphorylation of STAT3, reduces the expression of TNF-α and IL-6, and, ultimately, alleviates viral myocarditis.We also conclude that blocking α7nAchR reduces the phosphorylation of STAT3, increases the expression of TNF-α and IL-6, aggravating viral myocarditis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

ABSTRACT

Background: Activation of the cholinergic anti-inflammatory pathway, which relies on the α7nAchR (alpha 7 nicotinic acetylcholine receptor), has been shown to decrease proinflammatory cytokines. This relieves inflammatory responses and improves the prognosis of patients with experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, pancreatitis, arthritis and other inflammatory syndromes. However, whether the cholinergic anti-inflammatory pathway has an effect on acute viral myocarditis has not been investigated. Here, we studied the effects of the cholinergic anti-inflammatory pathway on acute viral myocarditis.

Methodology/principal findings: In a coxsackievirus B3 murine myocarditis model (Balb/c), nicotine and methyllycaconitine were used to stimulate and block the cholinergic anti-inflammatory pathway, respectively. Relevant signal pathways were studied to compare their effects on myocarditis, survival rate, histopathological changes, ultrastructural changes, and cytokine levels. Nicotine treatments significantly improved survival rate, attenuated myocardial lesions, and downregulated the expression of TNF-α and IL-6. Methyllycaconitine decreased survival rate, aggravated myocardial lesions, and upregulated the expression of TNF-α and IL-6. In addition, levels of the signaling protein phosphorylated STAT3 were higher in the nicotine group and lower in the methyllycaconitine group compared with the untreated myocarditis group.

Conclusions/significance: These results show that nicotine protects mice from CVB3-induced viral myocarditis and that methyllycaconitine aggravates viral myocarditis in mice. Because nicotine is a α7nAchR agonist and methyllycaconitine is a α7nAchR antagonist, we conclude that α7nAchR activation increases the phosphorylation of STAT3, reduces the expression of TNF-α and IL-6, and, ultimately, alleviates viral myocarditis. We also conclude that blocking α7nAchR reduces the phosphorylation of STAT3, increases the expression of TNF-α and IL-6, aggravating viral myocarditis.

Show MeSH
Related in: MedlinePlus