P669 Human β-defensin 2 suppresses TNF-α secretion in human and mouse dendritic cells mediated by chemokine receptor-2. (16th January 2018)

• Record Type: Journal Article
• Authors: Armbruster, N S; Sidelmann Brinch, K; Andersen, B; Stange, E F; Malek, N; Nordkild, P; Wehkamp, J
• Is Part Of: Journal of Crohn's and colitis. Volume 12:Number 1(2018:Jan.)Supplement 1
• Page Start: S449
• Page End: S449
• Publication Date: 2018-01-16
• Subjects: Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjx180.796
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background: Defensins are small endogenous peptide antibiotics and are part of the innate immune system. They possess broad-spectrum antimicrobial activity against viruses, bacteria, and fungi. Human β-defensins are expressed by epithelial cells in the entire body. Especially human β-defensin-2 (hBD2) has strong antimicrobial and immune modulatory functions and is induced by inflammatory stimuli or exogenous microbial substances. HBD2 promotes intestinal wound healing and angiogenesis in vitro and can act as a chemoattractant for dendritic cells (DCs), monocytes, and T cells through interaction with the chemokine receptor-2 (CCR2) and -6 (CCR6). Methods: PBMCs were isolated and stimulated with various bacterial cell wall components such as LPS and were additionally stimulated with or without hBD2. In the next step, we generated human monocyte-derived dendritic cells (mo-DCs) out of PBMCs and pretreated them with a CCR2 inhibitor prior to the stimulation. Furthermore, bone marrow-derived dendritic cells (BM-DCs) were generated out of C57BL/6 or CCR2−/− mice and were treated equally like the human mo-DCs. Results: HBD2 dose-dependently downregulates the pro-inflammatory cytokines TNF-α ( p < 0.0001) and IL-1β ( p < 0.0001) in LPS stimulated PBMCs while in contrast inducing the secretion of the anti-inflammatory IL-10 ( p < 0.001). In a next step, dendritic cells were identified as the probably responsible cell fraction in PBMCs modulated by hBD2. Human mo-DCs ( p < 0.0001) as well as murine BM-DCs ( p < 0.0001) showed decreasing effects of TNF-α after hBD2 and LPS stimulation. Inhibition of dendritic cell TNF-α production was depending on the presence of CCR2. This effect was completely abolished in CCR2−/− BM-DCs. Conclusions: The data in this study provide evidence that hBD2 acts like an anti-TNF agent. It is a highly efficient immunomodulatory substance which will be further developed to treat inflammatory diseases in man. Herein we describe hBD2 highly efficient as a therapeutic anti-TNF agent.