title: 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.
authors.affiliation: Axikin Pharmaceuticals, Inc., San Diego, California, United States of America.
authors.forename: Stefen A
authors.identifier: http://orcid.org/0000-0001-5560-1645
authors.initials: SA
authors.lastname: Boehme
authors.affiliation: DNA Consulting, Inc., San Diego, California, United States of America.
authors.forename: Karin
authors.initials: K
authors.lastname: Franz-Bacon
authors.affiliation: Axikin Pharmaceuticals, Inc., San Diego, California, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Ludka
authors.affiliation: Axikin Pharmaceuticals, Inc., San Diego, California, United States of America.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: DiTirro
authors.affiliation: Axikin Pharmaceuticals, Inc., San Diego, California, United States of America.
authors.forename: Tai Wei
authors.initials: TW
authors.lastname: Ly
authors.affiliation: Axikin Pharmaceuticals, Inc., San Diego, California, United States of America.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Bacon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000201:enzymology* / Q000209:etiology / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012137:Respiratory System / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D020930:MAP Kinase Kinase Kinases; C000621380:MAP3K19 protein, human