Cadmium attenuates the macrophage response to LPS through inhibition of the NF-κB pathway.
Chronic obstructive pulmonary disease (COPD) in the U.S. is primarily caused by cigarette smoking. COPD patients are highly susceptible to respiratory infections in part due to alveolar macrophage dysfunction despite a substantial increase in macrophages in the lung. Cadmium (Cd) is a toxic metal that is concentrated within tobacco and accumulates in the lung of smokers. We hypothesized that Cd uptake into macrophages alters immune function thereby impairing the macrophage response to invading pathogens. Our hypothesis was tested by comparing primary human monocytes and macrophages, primary mouse bronchoalveolar lavage myeloid cells, and related cell lines. Strikingly, Cd exposure followed by LPS stimulation resulted in a dose-dependent, significant decrease in nuclear p65 activity in macrophages that was not observed in monocytes. This corresponded with Cd-mediated inhibition of IKKβ and an impaired ability to transcribe and release cytokines in response to LPS challenge in vivo. These findings provide novel evidence that Cd has the capacity to disrupt macrophage immune function compared with monocytes. Importantly, Cd results in immune dysfunction in macrophages through inhibition of the NF-κB signaling pathway. Based on these findings, we provide new evidence that Cd contributes to immune dysfunction in the lung of COPD subjects and may increase susceptibility to infection.
['Cox|Jessica Napolitano|JN|', 'Rahman|Mohd Akhlakur|MA|', 'Bao|Shengying|S|', 'Liu|Mingjie|M|', 'Wheeler|Sarah E|SE|', 'Knoell|Daren L|DL|']
D000818:Animals D002104:Cadmium D002460:Cell Line D016764:Cell Polarity D016207:Cytokines D005260:Female D006801:Humans D008070:Lipopolysaccharides D016676:Macrophages, Alveolar D008668:Metallothionein D008810:Mice, Inbred C57BL D016328:NF-kappa B D029424:Pulmonary Disease, Chronic Obstructive D015398:Signal Transduction D012907:Smoking D015533:Transcriptional Activation
cadmium macrophages LPS NF-κB