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Protein phosphatase 2A regulates innate immune and proteolytic responses to cigarette smoke exposure in the lung.

ABSTRACT: 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.

SUBMITTER: Wallace AM

PROVIDER: S-EPMC3307605 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Protein phosphatase 2A regulates innate immune and proteolytic responses to cigarette smoke exposure in the lung.

Wallace Alison M AM Hardigan Andrew A Geraghty Patrick P Salim Shaneeza S Gaffney Adam A Thankachen Jincy J Arellanos Leo L D'Armiento Jeanine M JM Foronjy Robert F RF

Toxicological sciences : an official journal of the Society of Toxicology 20120105 2

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 ...[more]

PMID: 22223484

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Project description:Increased exposure to household air pollution and ambient air pollution has become one of the world's major environmental health threats. In developing and developed countries, environmental cigarette smoke (CS) exposure is one of the main sources of household air pollution (HAP). Moreover, results from different epidemiological and experimental studies indicate that there is a strong association between HAP, specifically CS exposure, and the development of allergic diseases that often persists into later life. Here, we investigated the impact of prenatal and postnatal CS exposure on offspring susceptibility to the development of allergic airway responses by using a preclinical mouse model. Pregnant BALB/c mice were exposed to either CS or air during pregnancy and lactation and in order to induce allergic asthma the offspring were sensitized and challenged with house dust mite (HDM). Decreased lung function parameters, like dynamic compliance and pleural pressure, were observed in PBS-treated offspring born to CS-exposed mothers compared to offspring from air-exposed mothers. Maternal CS exposure significantly increased the HDM-induced airway eosinophilia and neutrophilia in the offspring. Prenatal and postnatal CS exposure increased the frequency of Th2 cells in the lungs of HDM-treated offspring compared to offspring born to air-exposed mothers. Offspring born to CS-exposed mothers showed increased levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid compared to offspring from air-exposed mothers. Ex-vivo restimulation of lung cells isolated from HDM-treated offspring born to CS-exposed mothers also resulted in increased IL-4 production. Finally, serum immunoglobulins levels of HDM-specific IgE and HDM-specific IgG1 were significantly increased upon a HDM challenge in offspring born to CS-exposed mothers compared to offspring from air-exposed mothers. In summary, our results reveal a biological plausibility for the epidemiological studies indicating that prenatal and postnatal CS exposure increases the susceptibility of offspring to allergic immune responses.

Dataset Information

Protein phosphatase 2A regulates innate immune and proteolytic responses to cigarette smoke exposure in the lung.

Publications

Protein phosphatase 2A regulates innate immune and proteolytic responses to cigarette smoke exposure in the lung.

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