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

// Stefania De Santis 1, 2, * , Dale Kunde 3, * , Grazia Serino 1 , Vanessa Galleggiante 1, 4 , Maria Lucia Caruso 5 , Mauro Mastronardi 6 , Elisabetta Cavalcanti 5 , Nicole Ranson 3 , Aldo Pinto 4 , Pietro Campiglia 4, 7 , Angelo Santino 2 , Rajaraman Eri 3, * , Marcello Chieppa 1, 3, 4, 7, * 1 IRCCS “de Bellis”, Laboratory of Experimental Immunopathology, Castellana Grotte (BA), Italy 2 Institute of Sciences of Food Production, C.N.R. Unit of Lecce, Lecce, Italy 3 Mucosal Biology, School of Human Life Sciences, University of Tasmania, Launceston, TAS, Australia 4 Department of Pharmacy, School of Pharmacy, University of Salerno, Fisciano (SA), Italy 5 IRCCS “de Bellis”, Department of Pathology, Castellana Grotte (BA), Italy 6 IRCCS “de Bellis”, Department of Gastroenterology, Castellana Grotte (BA), Italy 7 European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy * These authors have contributed equally to this work Correspondence to: Marcello Chieppa, email: transmed@irccsdebellis.it Keywords: polyphenols, dendritic cells, inflammation, SLPI, nutrition Received: August 02, 2016 Accepted: September 21, 2016 Published: October 03, 2016 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.