Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium

https://doi.org/10.1016/j.bbrc.2011.11.096Get rights and content

Abstract

Cadmium is a toxic metal present in the environment and its inhalation can lead to pulmonary disease such as lung cancer and chronic obstructive pulmonary disease. These lung diseases are characterized by chronic inflammation. Here we show that exposure of human airway epithelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal pro-inflammatory cytokines known to play an important role in pulmonary inflammation. We also determined that two distinct pathways controlled secretion of these proinflammatory cytokines by human airway epithelial cells as cadmium-induced IL-6 secretion occurs via an NF-κB dependent pathway, whereas IL-8 secretion involves the Erk1/2 signaling pathway. Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation.

Highlights

► Cadmium induces secretion of IL-6 and IL-8 by two distinct pathways. ► Cadmium increases NAPDH oxidase activity leading to Erk activation and IL-8 secretion. ► Curcumin prevents cadmium-induced secretion of both IL-6 and IL-8 by airway cells. ► Curcumin could be use to suppress lung inflammation due to cadmium inhalation.

Introduction

Cadmium is an environmental pollutant that is currently ranked 7th on the Priority list of Hazardous Substances by the Agency for Toxic Substances and Disease Registry (ATSDR). While only 5–10% of ingested cadmium is absorbed systemically, pulmonary absorption of inhaled cadmium can reach 80% [1], [2]. The level of cadmium in the lung of smokers has been shown to be around 30 μM and could be higher in some areas [3]. Cadmium inhalation has been linked to lung cancer and chronic obstructive pulmonary disease (COPD) [4], [5]. These diseases are characterized by chronic inflammation; cadmium has recently been shown to induce inflammation in the lung of mice [6].

In the lung, airway epithelial cells are the first line of defense and in addition to being a physical barrier, the epithelium can respond to pollutants by secreting inflammatory mediators and by recruiting immune cells [7], [8]. Cadmium was recently shown to induce secretion of interleukin-6 (IL-6) and IL-8 in primary cell cultures from rat lungs [9]. These cytokines have been found to be elevated in mouse models and humans with chronic lung disease [10], [11], [12]. IL-6 secretion in the lung is associated with lung injury [13]. On the other hand, IL-8 is a chemoattractant cytokine responsible for the recruitment of neutrophils and macrophages into the sites of inflammation. Prolonged secretion of IL-8 can have deleterious effects on the lung due to release of toxic products (such as reactive oxygen intermediates) by accumulated neutrophils and macrophages [14], [15], [16].

Curcumin (diferuloylmethane) is a naturally occurring polyphenolic pigment from the Indian spice turmeric that is isolated from the rhizomes of the plant Curcuma longa Linn. Curcumin has anti-tumor, antioxidant, and anti-inflammatory properties. It has long been used in ancient medicine in particular in India and China. It is now part of several clinical trials, mainly for cancer therapy, for its ability to induce apoptosis in cancer cells [17], [18]. The anti-cancer and anti-inflammatory properties of curcumin are in part due to inhibition of the nuclear factor kappa B (NF-κB) pathway [19], [20]. In spite of this, little is known about the anti-inflammatory mechanism of curcumin in the lung.

Several studies showed that high doses of cadmium induce toxicity and cell death, whereas low doses induce inflammation. Here we examined the effect of subtoxic concentrations of cadmium on secretion of cytokines by human airway epithelial cells and the effect of curcumin. We found that curcumin could prevent secretion of both IL-6 and IL-8. We also show that curcumin inhibits the secretion of IL-8 induced by cadmium by preventing activation of the MEK/Erk1/2 pathway.

Section snippets

Tissue culture and reagents

The human bronchial epithelial (HBE) cell line Calu-3 was cultured as previously described [21]. Cadmium sulfate (Sigma, St. Louis, MO) was dissolved in sterile water at a concentration of 100 mM and was diluted in cell culture media to reach the indicated concentration. MAPK inhibitor UO126 was from Calbiochem (La Jolla, CA), and the NF-κB inhibitor Bay 11-7082 was from Santa Cruz Biotechnology (Santa Cruz, CA).

ELISA for analysis of cytokines released into cell supernatants

Confluent HBE cells, Calu-3, were treated as previously described [22]. Unless

Cadmium induces polarized secretion of IL-6 and IL-8 by human bronchial epithelial (HBE) cells

Since cadmium inhalation has been associated with lung diseases where inflammation plays a key role, we investigated whether cadmium directly induces secretion of pro-inflammatory cytokines by human airway epithelial cells. For this purpose, we used Calu-3 cells, which represent a good in vitro model to study HBE cells including inflammatory responses [24], [25]. HBE cells grown on permeable supports are fully polarized and allow collection of both apical and basal media for analysis. Various

Discussion

Cadmium is a toxic metal that can be inhaled via particulate matter and cigarette smoke. Most of the studies on cadmium have focused on its toxicity and there have been even fewer studies on its inflammatory properties. Therefore we investigated the effect of subcytotoxic doses of cadmium on production of inflammatory cytokines by human airway epithelial cells. Here we show that the antioxidant curcumin, a natural inhibitor of NF-κB, can prevent the release of both IL-6 and IL-8 by airway

Acknowledgments

We thank Dr. Kathleen Hayes-Ozello for editorial assistance. This work was supported by the National Institutes of Health Grants RO3 HL095442 (ECB), RO1 HL093463 (NP), and T32 HL07946 (FH), and the American Lung Association GRT00019086 (ECB).

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