The Ability of Secretory Leukocyte Protease Inhibitor to Inhibit Apoptosis in Monocytes Is Independent of Its Antiprotease Activity.

Niamh Mcgarry,Catherine M Greene,Clifford C Taggart,Sinéad Weldon,Noel G Mcelvaney

doi:10.1155/2015/507315

Abstract

Secretory Leukocyte Protease Inhibitor (SLPI) is a serine protease inhibitor produced by epithelial and myeloid cells with anti-inflammatory properties. Research has shown that SLPI exerts its anti-inflammatory activity by directly binding to NF-κB DNA binding sites and, in so doing, prevents binding and subsequent transcription of proinflammatory gene expression. In the current study, we demonstrate that SLPI can inhibit TNF-α-induced apoptosis in U937 cells and peripheral blood monocytes. Specifically, SLPI inhibits TNF-α-induced caspase-3 activation and DNA degradation associated with apoptosis. We go on to show that this ability of SLPI to inhibit apoptosis is not dependent on its antiprotease activity as antiprotease deficient variants of SLPI can also inhibit TNF-α-induced apoptosis. This reduction in monocyte apoptosis may preserve monocyte function during inflammation resolution and promote infection clearance at mucosal sites.

Highlights

Secretory Leukocyte Protease Inhibitor (SLPI) is a small molecular weight protein with multifunctional properties including antiprotease, antibacterial, antiviral, and antiinflammatory effects [1]
We demonstrate that SLPI can inhibit apoptosis in monocytic cells in a way that does not depend on the protease inhibition effect of SLPI
In comparison to cells treated with TNF-α alone, a significant decrease in caspase-3 and caspase-7 activity was observed in U937 monocytes pretreated with SLPI

Summary

Introduction

Secretory Leukocyte Protease Inhibitor (SLPI) is a small molecular weight protein with multifunctional properties including antiprotease, antibacterial, antiviral, and antiinflammatory effects [1]. The mature SLPI protein is 11.7 kDa in length and consists of 107 amino acids which are arranged in two domains of similar folding, giving SLPI a boomerang shape [2, 3]. Each domain is homologous to the whey acidic protein (WAP) four-disulphide core (WFDC) domain [4]. SLPI is produced and secreted by a number of different cell types including neutrophils and macrophages and by the epithelial cells that line mucosal surfaces. Lung epithelial lining fluid levels of SLPI can be as high as 10 μg/mL, SLPI concentrations have been found to be higher in upper respiratory airways than in lower airways [1, 9, 10]. The production of SLPI in such defense sensitive locations where protection against pathogen is pivotal reinforces the important role SLPI plays in innate immune defense

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