Protein phosphatase 2A regulates innate immune and proteolytic responses to cigarette smoke exposure in the lung.
Protein phosphatase 2A (PP2A) is the primary serine-threonine phosphatase of eukaryotic cells, and changes in its activity have been linked to neoplastic and neurodegenerative diseases. However, the role of PP2A in noncancerous lung diseases such as chronic obstructive pulmonary disease (COPD) has not been previously examined. This study determined that PP2A activity was significantly increased in the lungs of advanced emphysema subjects compared with age-matched controls. Furthermore, we found that cigarette smoke exposure increases PP2A activity in mouse lung in vivo and in primary human small airway epithelial (SAE) cells in vitro. In mice, intratracheal transfection of PP2A protein prior to cigarette smoke exposure prevented acute smoke-induced lung inflammation. Conversely, inhibiting PP2A activity during smoke exposure exacerbated inflammatory responses in the lung. To further determine how PP2A modulates the responses to cigarette smoke in the lung, enzyme levels were manipulated in SAE cells using protein transfection and short hairpin RNA (shRNA) techniques. Increasing PP2A activity in SAE cells via PP2A protein transfection downregulated cytokine expression and prevented the induction of proteases following cigarette smoke extract (CSE) treatment. Conversely, decreasing enzymatic activity by stably transfecting SAE cells with shRNA for the A subunit of PP2A exacerbated these smoke-mediated responses. This study establishes that PP2A induction by cigarette smoke modulates immune and proteolytic responses to cigarette smoke exposure. Together, these findings suggest that manipulation of PP2A activity may be a plausible means to treat COPD and other inflammatory diseases.
Department of Medicine, Division of Molecular Medicine, Columbia University, New York, New York 10032, USA.
Alison M
AM
Wallace
Andrew
A
Hardigan
Patrick
P
Geraghty
Shaneeza
S
Salim
Adam
A
Gaffney
Jincy
J
Thankachen
Leo
L
Arellanos
Jeanine M
JM
D'Armiento
Robert F
RF
Foronjy
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004646:Emphysema / Q000201:enzymology; D004789:Enzyme Activation; D006801:Humans; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059748:Proteolysis; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana
D016207:Cytokines; D012906:Smoke; D054648:Protein Phosphatase 2