Casticin inhibits interleukin-1β-induced ICAM-1 and MUC5AC expression by blocking NF-κB, PI3K-Akt, and MAPK signaling in human lung epithelial cells.

Chian-Jiun Liou,Wen-Chung Huang

doi:10.18632/oncotarget.20933

Abstract

The compound casticin, isolated from Vitex rotundifolia, exerts anti-inflammatory effects and causes apoptosis of cancer cells. In this study, we explored the anti-inflammatory effects of casticin and modulation of cyclooxygenase (COX)-2, intercellular adhesion molecule 1 (ICAM-1), and mucin 5AC (MUC5AC) expression in interleukin-1β (IL-1β)–activated A549 human pulmonary epithelial cells. A549 cells were treated with various concentrations of casticin (5–20 μM), and an inflammatory response was triggered with interleukin (IL)-1β cytokines. Casticin decreased levels of IL-6, tumor necrosis factor α, and IL-8 and suppressed COX-2 expression and prostaglandin E2 production. It also reduced MUC5AC, proinflammatory cytokine, and chemokine gene expression and inhibited ICAM-1 expression for monocyte adhesion in IL-1β–stimulated A549 cells. In addition, casticin inhibited phosphorylation of Akt, phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) and blocked nuclear transcription factor kappa-B (NF-κB) subunit p65 protein translocation into the nucleus. Co-culture of NF-κB, MAPK, and PI3K inhibitors with casticin also led to more significantly suppressed ICAM-1 expression in inflammatory A549 cells. These results provide evidence that casticin has an anti-inflammatory effect by blocking proinflammatory cytokine, chemokine, and ICAM-1 expression via suppression of the PI3K/Akt, NF-κB, and MAPK signaling pathways in IL-1β–stimulated inflammatory pulmonary epithelial cells.

Highlights

The inflammatory response of airways is a physical danger signal and defense mechanism against microbe infection or injurious airborne particles [1]
We evaluated the anti-inflammatory effect of casticin and explored the mechanism of involvement of the nuclear transcription factor kappa-B (NF-κB), PI3k/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways in IL-1β–stimulated A549 cells
Casticin had a dose-dependent inhibitory effect on levels of IL-6, tumor necrosis factor α (TNF-α), IL-8 (IL-6: 5 μM casticin, 681.86 ± 109.45 pg/ ml, p=0.34; 10 μM casticin, 516.05 ± 83.03 pg/ml, p < 0.05; 20 μM casticin, 263.91 ± 54.85 pg/ml, p < 0.01; vs. IL-1β alone, 717.21 ± 83.08 pg/ml) (TNF-α: 5 μM casticin, 377.92 ± 35.90 pg/ml, p = 0.22; 10 μM casticin, 247.29 ± 35.86 pg/ml, p < 0.01; 20 μM casticin, 136.70 ± 40.97 pg/ml, p < 0.01; vs. IL-1β alone, 439.59 ± 47.50 pg/ml), and casticin could decrease the levels of IL-8, CCL5, and MCP-1 in IL-1β–stimulated A549 cells (Figure 1)

Summary

Introduction

The inflammatory response of airways is a physical danger signal and defense mechanism against microbe infection or injurious airborne particles [1]. Inflammatory pulmonary diseases include asthma, chronic obstructive pulmonary disease (COPD), and bacterial or viral pneumonia [2, 3]. These reactive airway diseases can lead to sputum production, coughing, and wheezing, and the airway of patients may be stimulated to constrict, with excessive mucus secretion leading to dyspnea or suffocation and death [4]. Non-steroidal anti-inflammatory drugs decrease COX-2 activity and reduce inflammation and fever in these patients [11, 12]. Celecoxib is a COX-2 inhibitor that ameliorates newborn hyperoxic lung injury in mice and decreases levels of prostaglandin E2 (PGE2) to suppress lung inflammation in asthma patients [13, 14]. Blocking IL-1β levels could ameliorate the lung inflammatory response in pulmonary disease patients

Methods

Results

Conclusion