Regulation and activity of secretory leukoprotease inhibitor (SLPI) is altered in smokers

Abstract

A hallmark of cigarette smoking is a shift in the protease/antiprotease balance, in favor of protease activity. However, it has recently been shown that smokers have increased expression of a key antiprotease, secretory leukoprotease inhibitor (SLPI), yet the mechanisms involved in SLPI transcriptional regulation and functional activity of SLPI remain unclear. We examined SLPI mRNA and protein secretion in differentiated nasal epithelial cells (NECs) and nasal lavage fluid (NLF) from nonsmokers and smokers and demonstrated that SLPI expression is increased in NECs and NLF from smokers. Transcriptional regulation of SLPI expression was confirmed using SLPI promoter reporter assays followed by chromatin immunoprecipitation. The role of STAT1 in regulating SLPI expression was further elucidated using WT and stat1(-/-) mice. Our data demonstrate that STAT1 regulates SLPI transcription in epithelial cells and slpi protein in the lungs of mice. Additionally, we reveal that NECs from smokers have increased STAT1 mRNA/protein expression. Finally, we demonstrate that SLPI contained in the nasal mucosa of smokers is proteolytically cleaved but retains functional activity against neutrophil elastase. These results demonstrate that smoking enhances expression of SLPI in NECs in vitro and in vivo, and that this response is regulated by STAT1. In addition, despite posttranslational cleavage of SLPI, antiprotease activity against neutrophil elastase is enhanced in smokers. Together, our findings show that SLPI regulation and activity is altered in the nasal mucosa of smokers, which could have broad implications in the context of respiratory inflammation and infection.

Distribution and factors associated with salivary secretory leukocyte protease inhibitor concentrations

“…Smoking is known to have direct effects on oral immune status (Lee et al , ). The higher salivary SLPI concentrations among current smokers observed in this study are consistent with findings from other studies that have reported increased SLPI secretions among smokers (Bouloukaki et al , ; Meyer et al , ). Smoking has been shown to enhance the expression of the signal transducer and activator of transcription (STAT1 protein), which, in turn, leads to increased SLPI expression (Meyer et al , ).…”

Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations

“…During virus infection, we clearly demonstrate in a range of models that FP has a suppressive effect on airway SLPI production. Since STAT1 has previously been shown to regulate SLPI expression 52 , FP likely impairs SLPI production during RV infection by suppressing PRR-induced IFN production thereby reducing subsequent IFNAR-mediated STAT1 activation. This mechanism is supported by our finding that IFNAR1 −/− mice also had reduced RV induction of SLPI.…”

Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments

“…Sharma et al (109) found that CSE inhibits platelet-activating factor (PAF) acetylhydrolase activity, which enhances PAF production and PMN adherence. Similarly, Meyer et al (83) showed that the expression of secretory leukoprotease inhibitor (SLPI) is regulated by Stat1, and both are increased in nasal epithelial cells and BALF of smokers, indicating that altered SLPI regulation and activity induced by CS could play a role in the development of respiratory inflammation and infection.…”