title: The protease inhibitor cystatin C down-regulates the release of IL-β and TNF-α in lipopolysaccharide activated monocytes.
abstract: Human cystatin C, a member of the cysteine proteinase-inhibitory family, is produced by all nucleated cells and has important roles in regulating natural immunity. Nematode homologs to human cystatin C have been shown to have anti-inflammatory effects on monocytes and to reduce colitis in mice. In Crohn's disease, pathogenic activated monocytes help drive inflammatory processes via the release of proinflammatory cytokines and chemokines. In particular, tumor necrosis factor-α-producing inflammatory monocytes have a central role in the intestinal inflammation in patients with Crohn's disease. We investigated the potential of human cystatin C to regulate pathogenic activated monocytes and its potential as an Immunomodulator in Crohn's disease. We found that cystatin C significantly decreased the lipopolysaccharide-stimulated release and expression of interleukin-1β and tumor necrosis factor-α in monocyte and peripheral blood mononuclear cell cultures from healthy donors, whereas interleukin-6 and interleukin-8 levels were unchanged. A similar reduction of interleukin-1β and tumor necrosis factor-α was also seen in peripheral blood mononuclear cell cultures from patients with Crohn's disease, and in particular, tumor necrosis factor-α was reduced in supernatants from lamina propria cell cultures from patients with Crohn's disease. Further investigation revealed that cystatin C was internalized by monocytes via an active endocytic process, decreased phosphorylation of the mitogen-activated protein kinase pathway extracellular signal-regulated kinase-1/2, and altered surface marker expression. The ability of cystatin C to modulate the cytokine expression of monocytes, together with its protease-inhibitory function, indicates that modulation of the local cystatin C expression could be an option in future Crohn's disease therapy.
authors.affiliation: Cellular Pharmacology, Novo Nordisk A/S, Måløv, Denmark; Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.
authors.forename: Susanne Thiesen
authors.initials: ST
authors.lastname: Gren
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Sabina
authors.initials: S
authors.lastname: Janciauskiene
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Salipalli
authors.initials: S
authors.lastname: Sandeep
authors.affiliation: Institute of Pathology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover, Germany; and.
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.affiliation: Histology and Bioimaging, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Peter Helding
authors.initials: PH
authors.lastname: Kvist
authors.affiliation: Cellular Pharmacology, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Jens Gammeltoft
authors.initials: JG
authors.lastname: Gerwien
authors.affiliation: Cellular Pharmacology, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Katarina
authors.initials: K
authors.lastname: Håkansson
authors.affiliation: Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden; olof.grip@med.lu.se.
authors.forename: Olof
authors.initials: O
authors.lastname: Grip
mesh_terms: D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics; D002232:Carbocyanines; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D003424:Crohn Disease / Q000097:blood / Q000276:immunology*; D055316:Cystatin C / Q000494:pharmacology* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: C569686:Alexa Fluor 647; D000954:Antigens, Surface; C525030:CST3 protein, human; D002232:Carbocyanines; D055316:Cystatin C; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D020170:Caspase 1
keywords: Crohn’s disease; cytokines; immunomodulator; inflammation; monocytes