An NF-κB–Independent and Erk1/2-Dependent Mechanism Controls CXCL8/IL-8 Responses of Airway Epithelial Cells to Cadmium

Abstract

Airway epithelial cells in the lung are the first line of defense against pathogens and environmental pollutants. Inhalation of the environmental pollutant cadmium has been linked to the development of lung cancer and chronic obstructive pulmonary disease, which are diseases characterized by chronic inflammation. To address the role of airway epithelial cells in cadmium-induced lung inflammation, we investigated how cadmium regulates secretion of interleukin 8 (IL-8) by airway epithelial cells. We show that exposure of human airway epithelial cells to subtoxic doses of cadmium in vitro promotes a characteristic inflammatory cytokine response consisting of IL-8, but not IL-1β or tumor necrosis factor-alpha. We also found that intranasal delivery of cadmium increases lung levels of the murine IL-8 homologs macrophage inflammatory protein-2 and keracinocyte-derived chemokine and results in an influx of Gr1+ cells into the lung. We determined that inhibition of the nuclear factor-κB (NF-κB) pathway had no effect on cadmium-induced IL-8 secretion by human airway epithelial cells, suggesting that IL-8 production was mediated through an NF-κB-independent pathway. Mitogen-activated protein kinases (MAPKs) are often involved in proinflammatory signaling. Cadmium could activate the main MAPKs (i.e., p38, JNK, and Erk1/2) in human airway epithelial cells. However, only pharmacological inhibition of Erk1/2 pathway or knockdown of the expression of Erk1 and Erk2 using small interfering RNAs suppressed secretion of IL-8 induced by cadmium. Our findings identify cadmium as a potent activator of the proinflammatory cytokine IL-8 in lung epithelial cells and reveal for the first time the role of an NF-κB-independent but Erk1/2-dependent pathway in cadmium-induced lung inflammation.

Transcription Elongation Factor P-TEFb Is Involved in IL-17F Signaling in Airway Smooth Muscle Cells

“…It is thought that NF-κB is generally involved in IL-8 gene expression [37], but in our study the addition of an NF-κB inhibitor did not reduce IL-17F-induced IL-8 expression. Consistent with this, previous reports have demonstrated that cadmium or rhinovirus induced IL-8 expression through an NF-κB-independent pathway in airway epithelial cells [38, 39]. Thus, the exact role of NF-κB signaling may vary depending on the cell types and stimulus used.…”

BRaf and MEK Inhibitors Differentially Regulate Cell Fate and Microenvironment in Human Hepatocellular Carcinoma

“…This regulation argues for CXCL8 as potential candidate for a functional, though indirect, readout of ERK phosphorylation in hepatoma cells that may be even further developed as noninvasive biomarker for response to multikinase inhibitors in the blood of patients with hepatocellular carcinoma. This hypothesis is supported by the identification of an ERK1/2-dependent mechanism of CXCL8 expression in airway epithelial cells (50). Inhibition of the p38 and ERK pathways downregulated CXCL10 and CXCL8 expression in epithelial cells (51,52).…”

Transcriptional mechanisms and protein kinase signaling mediate organic dust induction of IL-8 expression in lung epithelial and THP-1 cells

“…MAPKs differentially regulate IL-8 expression depending on the cell type and the stimulus. In human airway epithelial cells, although cadmium activated ERK, p38, and JNK MAPKs, only inhibition of ERK MAPK suppressed IL-8 secretion (12). In U937 cells, Helicobacter pylori VacA protein induces IL-8 expression primarily via activation of p38 MAPK even though ERK MAPK is also activated (20).…”