Andrographolide antagonizes cigarette smoke extract-induced inflammatory response and oxidative stress in human alveolar epithelial A549 cells through induction of microRNA-218.

Abstract

Andrographolide is a major bioactive labdane diterpenoid isolated from Andrographis paniculata and has protective effects against cigarette smoke (CS)-induced lung injury. This study was done to determine whether such protective effects were mediated through modulation of microRNA (miR)-218 expression. Therefore, we exposed human alveolar epithelial A549 cells to cigarette smoke extract (CSE) with or without andrographolide pretreatment and measured the level of glutathione, nuclear factor-kappaB (NF-κB) activation, proinflammatory cytokine production, and miR-218 expression. We found that andrographolide pretreatment significantly restored the glutathione level in CSE-exposed A549 cells, coupled with reduced inhibitor κB (IκB)-α phosphorylation and p65 nuclear translocation and interleukin (IL)-8 and IL-6 secretion. The miR-218 expression was significantly upregulated by andrographolide pretreatment. To determine the biological role of miR-218, we overexpressed and downregulated its expression using miR-218 mimic and anti-miR-218 inhibitor, respectively. We observed that miR-218 overexpression led to a marked reduction in IκB-α phosphorylation, p65 nuclear accumulation, and NF-κB-dependent transcriptional activity in CSE-treated A549 cells. In contrast, miR-218 silencing enhanced IκB-α phosphorylation and p65 nuclear accumulation in cells with andrographolide pretreatment and reversed andrographolide-mediated reduction of IL-6 and IL-8 production. In addition, depletion of miR-218 significantly reversed the upregulation of glutathione levels in A549 cells by andrographolide. Taken together, our results demonstrate that andrographolide mitigates CSE-induced inflammatory response in A549 cells, largely through inhibition of NF-κB activation via upregulation of miR-218, and thus has preventive benefits in CS-induced inflammatory lung diseases.

• Authors: Ying-jie Li, Chang-hai Yu, Jing-bo Li, Xi-ya Wu
• Journal: Experimental lung research (Exp Lung Res) Vol. 39 Issue 10 Pg. 463-71 (Dec 2013) ISSN: 1521-0499 [Electronic] England
• PMID: 24298938 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• CXCL8 protein, human
• Diterpenes
• Drugs, Chinese Herbal
• I-kappa B Proteins
• IL6 protein, human
• Interleukin-6
• Interleukin-8
• MIRN218 microRNA, human
• MicroRNAs
• NF-kappa B
• NFKBIA protein, human
• Smoke
• NF-KappaB Inhibitor alpha
• andrographolide
• Glutathione

Topics

• Alveolar Epithelial Cells (drug effects, metabolism, pathology)
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Cell Line
• Diterpenes (pharmacology)
• Drugs, Chinese Herbal (pharmacology)
• Gene Silencing
• Glutathione (metabolism)
• Humans
• I-kappa B Proteins (metabolism)
• Interleukin-6 (biosynthesis)
• Interleukin-8 (biosynthesis)
• MicroRNAs (antagonists & inhibitors, biosynthesis, genetics)
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors)
• Oxidative Stress (drug effects)
• Smoke (adverse effects)
• Tobacco (adverse effects)