MAP3K19 Is Overexpressed in COPD and Is a Central Mediator of Cigarette Smoke-Induced Pulmonary Inflammation and Lower Airway Destruction

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung inflammation resulting in a progressive decline in lung function whose principle cause is cigarette smoke. MAP3K19 is a novel kinase expressed predominantly by alveolar and interstitial macrophages and bronchial epithelial cells in the lung. We found that MAP3K19 mRNA was overexpressed in a limited sampling of lung tissue from COPD patients, and a closer examination found it to be overexpressed in bronchoalveolar macrophages from COPD patients, as well as the bronchial epithelium and inflammatory cells in the lamina propria. We further found MAP3K19 to be induced in various cell lines upon environmental stress, such as cigarette smoke, oxidative and osmotic stress. Exogenous expression of MAP3K19 in cells caused an upregulation of transcriptionally active NF-κB, and secretion of the chemokines CXCL-8, CCL-20 and CCL-7. Inhibition of MAP3K19 activity by siRNA or small molecular weight inhibitors caused a decrease in cigarette smoke-induced inflammation in various murine models, which included a decrease in pulmonary neutrophilia and KC levels. In a chronic cigarette smoke model, inhibition of MAP3K19 significantly attenuated emphysematous changes in airway parenchyma. Finally, in a viral exacerbation model, mice exposed to cigarette smoke and influenza A virus showed a decrease in pulmonary neutrophilia, pro-inflammatory cytokines and viral load upon inhibition of MAP3K19. Collectively, these results suggest that inhibition of MAP3K19 may represent a novel strategy to target COPD that promises to have a potential therapeutic benefit for patients.

The protein kinase MAP3K19 phosphorylates MAP2Ks and thereby activates ERK and JNK kinases and increases viability of KRAS-mutant lung cancer cells

“…Consistent with a pro-survival function for MAP3K19, short-hairpin RNA-mediated knockdown of MAP3K19 suppressed HeLa cell proliferation and survival, further indicating that MAP3K19 plays a role in cancer cell survival (8). In addition, MAP3K19 overexpression was detected in patients with chronic obstructive pulmonary disease, a known risk factor for lung cancer (9,10). MAP3K19 has been reported to regulate transforming growth factor-␤induced SMAD signaling and gene expression, as well as regulate NF-B to promote the release of various cytokines, although the mechanisms underpinning these activities are unknown (9,10).…”

Genes lost during the transition from land to water in cetaceans highlight genomic changes involved in aquatic adaptations

“…Furthermore, overexpression of MAP3K19 was also detected in human patients suffering from chronic obstructive pulmonary disease (COPD) (75), a disease associated with cigarette smoking-induced oxidative stress. MAP3K19 is upregulated in cells in response to oxidative and other types of environmental stress, and promotes the expression of proinflammatory chemokines (75). Further supporting a role of MAP3K19 in the pathogenesis of COPD, inhibition of MAP3K19 in mouse COPD models strongly reduced pulmonary inflammation and airway destruction (75).…”

“…MAP3K19 is upregulated in cells in response to oxidative and other types of environmental stress, and promotes the expression of proinflammatory chemokines (75). Further supporting a role of MAP3K19 in the pathogenesis of COPD, inhibition of MAP3K19 in mouse COPD models strongly reduced pulmonary inflammation and airway destruction (75). A hallmark of COPD is a reduction of alveolar elasticity caused by elastin degradation, which contributes to an incomplete emptying of the lung.…”

Preventive Effect of Garlic Oil and Its Organosulfur Component Diallyl-Disulfide on Cigarette Smoke-Induced Airway Inflammation in Mice

“…The recruited inflammatory cells are activated by CS exposure and produce large quantities of proinflammatory mediators, such as reactive oxygen species (ROS), cytokines, and chemokines, which results in the exacerbation of airway inflammation [ 4 , 5 ]. Eventually, chronic CS exposure leads to the loss of normal lung function [ 6 , 7 ]. Currently, many researchers are investigating therapeutics for the treatment of COPD through in vivo and in vitro experiments [ 8 , 9 ].…”