Published ahead of print on June 27, 2008, doi:10.1165/rcmb.2007-0306OC Am. J. Respir. Cell Mol. Biol., Volume 39, Number 6, December 2008, 747-757 A more recent version of this article appeared on December 1, 2008
Submitted on August 20, 2007 Overexpression of Apoptotic Cell Removal Receptor MERTK in Alveolar Macrophages of Cigarette SmokersAngeliki Kazeros1,1 Division of Pulmonary and Critical Care, Weill Medical College of Cornell University, New York, New York, United States, 2 Division of Pulmonary and Critical Care, Weill Medical College of Cornell University, New York, New York, United States; Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, USA, 3 Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, USA * To whom correspondence should be addressed. E-mail: geneticmedicine{at}med.cornell.edu.
Mononuclear phagocytes play an important role in the removal of apoptotic cells by expressing cell surface receptors that recognize and remove apoptotic cells. Based on the knowledge that cigarette smoking is associated with increased lung cell turnover, we hypothesized that alveolar macrophages(AM) of normal cigarette smokers may exhibit enhanced expression of apoptotic cell removal receptor genes. AM obtained by bronchoalveolar lavage of normal nonsmokers(n=11) and phenotypic normal smokers(n=13, 36 ± 6 pack-yr) were screened for mRNA expression of all known apoptotic cell removal receptors using Affymetrix HG-U133 Plus 2.0 microarray chips with TaqMan RT-PCR confirmation. Of the 14 known apoptotic receptors expressed, only MER Tyrosine Kinase(MERTK), a transmembrane tyrosine kinase receptor, was significantly up-regulated in smokers. MERTK expression was then assessed in AM of smokers vs nonsmokers by TaqMan RT-PCR, immunocytochemistry, Western and flow analysis. Smoker AM had up-regulation of MERTK mRNA levels (smoker vs nonsmoker, 3.6-fold by microarray, p<0.003; 9.5-fold by TaqMan RT-PCR, p<0.02). Immunocytochemistry demonstrated a qualitative increase in MERTK protein expression on AM of smokers. Increased protein expression of MERTK on AM of smokers was confirmed by Western and flow analyses (p<0.007 and p<0.0002, respectively). MERTK, a cell surface receptor that recognizes apoptotic cells, is expressed on human AM, and its expression is up-regulated in AM of cigarette smokers. This upregulation of MERTK may reflect an increased demand for removal of apoptotic cells in smokers, an observation with implications for the development of chronic obstructive pulmonary disease(COPD), a disorder associated with dysregulated apoptosis of lung parenchymal cells
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