Secretory leukoprotease inhibitor is required for efficient quercetin-mediated suppression of TNFα secretion

Stefania De Santis,Mauro Mastronardi,Aldo Pinto,Maria Lucia Caruso,Vanessa Galleggiante,Marcello Chieppa,Grazia Serino,Nicole Ranson,Rajaraman Eri,Pietro Campiglia,Elisabetta Cavalcanti,Dale Kunde,Angelo Santino

doi:10.18632/oncotarget.12415

Abstract

Dendritic cells (DCs) are professional antigen presenting cells (APCs) that in response to microbial infections generate long-lasting adaptive immune response. Following microbial uptake, DCs undergo a cascade of cellular differentiation that ultimately leads to “mature” DCs. Mature DCs produce a variety of inflammatory cytokines, including tumor necrosis factor-α (TNFα) a key cytokine for the inflammatory cascade. In numerous studies, polyphenols, including quercetin, demonstrated their ability to suppress TNFα secretion and protect from the onset of chronic inflammatory disorders. We show that murine bone marrow derived DCs express Slpi following quercetin exposure. Slpi is known to suppress LPS mediated NFκB activation, thus, it was hypothesized that its expression could be the key step for polyphenol induced inflammatory suppression. Slpi-KO DCs poorly respond to quercetin administration failing to reduce TNFα secretion in response to quercetin exposure. Supernatant from quercetin exposed DCs could also reduce LPS-mediated TNFα secretion by unrelated DCs, but this property is lost using an anti-Slpi antibody. In vivo, oral administration of quercetin is able to induce Slpi expression. Human biopsies from inflamed tract of the intestine reveal the presence of numerous SLPI+ cells and the expression level could be further increased by quercetin administration. We propose that quercetin induces Slpi expression that in turn reduces the inflammatory response. Our data encourages the development of nutritional strategies to improve the efficiency of current therapies for intestinal chronic inflammatory syndrome and reduce the risks of colorectal cancer development.

Highlights

Plant polyphenols represent one of the largest and most ubiquitous groups of secondary metabolites that are an integral part of the human diet [1, 2]
We identified secretory leukocyte protease inhibitor (Slpi) among the transcripts differently up-regulated in polyphenol exposed bone marrow dendritic cells (BMDCs) following LPS stimulation (2.7-fold, P
The microarray data was confirmed by qPCR where Slpi expression was significantly up-regulated in the ROBs-QP treated BMDCs reaching a 26-fold (P

Summary

INTRODUCTION

Plant polyphenols represent one of the largest and most ubiquitous groups of secondary metabolites that are an integral part of the human diet [1, 2]. At the same time Slpi is a potent antimicrobial factor mainly produced in the mucosal tissues [17, 18] antagonizing LPS induced signaling and inflammatory cytokines secretion [14, 19] It has been described as a potent inflammatory inhibitory protein able to antagonize LPS induced activation of NFκB [14, 20]. Evidence of the importance of Slpi in inflammatory suppression and tissue repair has come from thymic stromal lymphopoietin (Tslp) knockout (KO) mice that have reduced Slpi expression [21] These mice demonstrate a similar development of colitis as wild-type mice when exposed to dextran sulfate sodium (DSS), have a higher mortality rate due to a reduced healing ability. Our data shows that the absence of Slpi reduces the efficiency of DC response to polyphenols providing a rationale for developing polyphenol enriched diets to protect from TNFα mediated mucosal inflammatory responses

RESULTS

DISCUSSION

MATERIALS AND METHODS