Cadmium suppresses IL-1β production and release in monocytes. (P3010)

Abstract

Abstract Tobacco smoke is the primary cause of chronic obstructive pulmonary disease (COPD) in the U.S. Immune dysfunction in the lung of chronic smokers increases the risk of respiratory infections. IL-1β is a vital cytokine in host defense and its expression is decreased in the lungs of these patients. Cadmium (Cd) is abundant in cigarette smoke and a major contributor to smoking-related lung disease. The purpose of this investigation is to determine whether Cd suppresses IL-1β in monocytes. THP-1 cells were differentiated into macrophages using PMA and then treated overnight with Cd, followed by combined LPS and ATP stimulation. Primary human monocytes were isolated from blood using CD14+ positive selection and subject to similar exposures. Analysis of THP-1 and monocyte cultures revealed that Cd suppresses IL-1β release following stimulation with LPS and ATP. Additionally, there was a decrease in IL-1β mRNA in Cd-treated LPS stimulated macrophages. We observed a decrease in phospho-p65 translocation into the nucleus of Cd-treated macrophages after LPS stimulation. Consistent with this, using a cell-free system, we observed that Cd inhibits IKKβ kinase activity (IC50 of ~100 nM). From these studies we conclude that Cd acts as an inhibitor of the canonical NF-κB pathway and inhibits IL-1β production. Accordingly, Cd may play a critical role in COPD pathogenesis by impairing monocyte immune function.